ORCID Profile
0000-0003-4914-2299
Current Organisation
Griffith University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Biologically Active Molecules | Infectious Agents | Other Medical and Health Sciences | Medicinal and Biomolecular Chemistry | Pharmaceutical Sciences | Biochemistry and Cell Biology not elsewhere classified | Medical and Health Sciences not elsewhere classified | Protein Trafficking | Pharmacology and Pharmaceutical Sciences | Neurosciences Not Elsewhere Classified | Biochemistry and Cell Biology | Neurology And Neuromuscular Diseases | Medicinal and Biomolecular Chemistry not elsewhere classified | Cellular Nervous System | Therapies And Therapeutic Technology | Cell Neurochemistry
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Chemical Sciences | Infectious Diseases | Horticultural Crops not elsewhere classified | Nervous system and disorders | Organs, diseases and abnormal conditions not elsewhere classified | Expanding Knowledge in the Medical and Health Sciences | Expanding Knowledge in Technology |
Related Links
Publications
Antiplasmodial β-Triketone–Flavanone Hybrids from the Flowers of the Australian Tree Corymbia torelliana
Publisher: American Chemical Society (ACS)
Date: 03-07-2018
DOI: 10.1021/ACS.JNATPROD.8B00154
Abstract: The methanol extract of the flowers of the Australian eucalypt tree Corymbia torelliana yielded six new β-triketone-flavanone hybrids, torellianones A-F (1-6), the tetrahydroxycyclohexane torellianol A (7), and known β-triketones (4 S)-ficifolidione (8) and (4 R)-ficifolidione (9), and β-triketone-flavanones kunzeanone A (10) and kunzeanone B (11). Torellianones A and B, C and D, and E and F were each isolated as inseparable diastereomeric mixtures. Exchange correlations observed in a ROESY spectrum indicated that 5 and 6 also interconverted between stable conformers. The structures of 1-7 were elucidated from the analysis of 1D/2D NMR and MS data. Relative configurations of torellianones C-F and torrellianol A were determined from analysis of ROESY data. Compounds 1-10 were tested for antiplasmodial activity against a drug-sensitive (3D7) strain of Plasmodium falciparum, with 3-6 and 8-10 showing limited antiplasmodial activity, with IC
Identification of MMV Malaria Box Inhibitors of Plasmodium falciparum Early-Stage Gametocytes Using a Luciferase-Based High-Throughput Assay
Publisher: American Society for Microbiology
Date: 12-2013
DOI: 10.1128/AAC.00870-13
Abstract: The design of new antimalarial combinations to treat Plasmodium falciparum infections requires drugs that, in addition to resolving disease symptoms caused by asexual blood stage parasites, can also interrupt transmission to the mosquito vector. Gametocytes, which are essential for transmission, develop as sexual blood stage parasites in the human host over 8 to 12 days and are the most accessible developmental stage for transmission-blocking drugs. Considerable effort is currently being devoted to identifying compounds active against mature gametocytes. However, investigations on the drug sensitivity of developing gametocytes, as well as screening methods for identifying inhibitors of early gametocytogenesis, remain scarce. We have developed a luciferase-based high-throughput screening (HTS) assay using tightly synchronous stage I to III gametocytes from a recombinant P. falciparum line expressing green fluorescent protein (GFP)-luciferase. The assay has been used to evaluate the early-stage gametocytocidal activity of the MMV Malaria Box, a collection of 400 compounds with known antimalarial (asexual blood stage) activity. Screening this collection against early-stage (I to III) gametocytes yielded 64 gametocytocidal compounds with 50% inhibitory concentrations (IC 50 s) below 2.5 μM. This assay is reproducible and suitable for the screening of large compound libraries, with an average percent coefficient of variance (%CV) of ≤5%, an average signal-to-noise ratio (S:N) of , and a Z′ of ∼0.8. Our findings highlight the need for screening efforts directed specifically against early gametocytogenesis and indicate the importance of experimental verification of early-stage gametocytocidal activity in the development of new antimalarial candidates for combination therapy.
Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites
Publisher: Elsevier BV
Date: 12-2015
3,3'-Disubstituted 5,5'-Bi(1,2,4-triazine) Derivatives with Potent in Vitro and in Vivo Antimalarial Activity.
Publisher: American Chemical Society (ACS)
Date: 04-02-2019
DOI: 10.1021/ACS.JMEDCHEM.8B01799
Abstract: A series of 3,3'-disubstituted 5,5'-bi(1,2,4-triazine) derivatives was synthesized and screened against the erythrocytic stage of Plasmodium falciparum 3D7 line. The most potent dimer, 6k, with an IC
Acrotrione: An Oxidized Xanthene from the Roots of Acronychia pubescens
Publisher: American Chemical Society (ACS)
Date: 13-03-2019
DOI: 10.1021/ACS.JNATPROD.8B00956
Abstract: A new oxidized xanthene, acrotrione (1), and two known acetophenones (2 and 3) were isolated from a methanol extract of the roots of Acronychia pubescens. The structure of 1 was elucidated on the basis of its (+)-HRESIMS, 2D NMR, and ECD data. Acritrione (1) contains an unusual oxidized furo[2,3- c]xanthene moiety that has not been previously reported. Moderate antiplasmodial activity for these natural products against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum was determined with IC
Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases
Publisher: American Chemical Society (ACS)
Date: 11-12-2019
DOI: 10.1021/ACS.JMEDCHEM.8B01310
Abstract: There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax. The M1 and M17 metalloexopeptidases play key roles in Plasmodium hemoglobin digestion and are validated drug targets. We used a multitarget strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum ( Pf-M1 and Pf-M17) and P. vivax ( Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1' pockets of the four target enzymes. Structural characterization by cocrystallization showed that selected compounds utilize new and unexpected binding modes most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates.
Metabolomics and lipidomics reveal perturbation of sphingolipid metabolism by a novel anti-trypanosomal 3-(oxazolo[4,5-b]pyridine-2-yl)anilide
Publisher: Springer Science and Business Media LLC
Date: 07-2016
Psammaplysenes C and D, Cytotoxic Alkaloids from Psammoclemma sp.
Publisher: American Chemical Society (ACS)
Date: 11-2007
DOI: 10.1021/NP0703646
Abstract: The sponge Psammoclemma sp. was investigated as part of our studies to discover P2X 7 receptor antagonists for the treatment of inflammatory disease. The biological activity of this extract was found to be due to the cytotoxicity of two new bromotyrosine alkaloids, psammaplysenes C (1) and D (2), and not P2X 7-specific activity. Their structures were determined by 1D and 2D NMR spectroscopy.
(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium
Publisher: Proceedings of the National Academy of Sciences
Date: 12-2014
Abstract: Useful antimalarial drugs must be rapidly acting, highly efficacious, and have low potential for developing resistance. (+)-SJ733 targets a Plasmodium cation-transporting ATPase, ATP4. (+)-SJ733 cleared parasites in vivo as quickly as artesunate by specifically inducing eryptosis/senescence in infected, treated erythrocytes. Although in vitro selection of pfatp4 mutants with (+)-SJ733 proceeded with moderate frequency, during in vivo selection of pbatp4 mutants, resistance emerged slowly and produced marginally resistant mutants with poor fitness. In addition, (+)-SJ733 met all other criteria for a clinical candidate, including high oral bioavailability, a high safety margin, and transmission blocking activity. These results demonstrate that targeting ATP4 has great potential to deliver useful drugs for malaria eradication.
Assay development in leishmaniasis drug discovery: a comprehensive review
Publisher: Informa UK Limited
Date: 24-11-2021
DOI: 10.1080/17460441.2022.2002843
Abstract: Cutaneous, muco-cutaneous and visceral leishmaniasis occur due to an infection with the protozoan parasite The authors have highlighted the recent progress, limitations and successes achieved in assay development for leishmaniasis drug discovery. It is true that sophisticated and robust phenotypic
Erratum: SC83288 is a clinical development candidate for the treatment of severe malaria
Publisher: Springer Science and Business Media LLC
Date: 06-04-2017
DOI: 10.1038/NCOMMS15273
Abstract: Nature Communications 8 Article number:14193 (2017) Published 31 January 2017 Updated 6 Apr 2017 This Article contains errors in Figs. 1 and 8 that were introduced during the production process. The compound on the lower right side of Fig. 1 is labelled incorrectly and should be labelled ‘SC83288’. The correct version of Fig.
The cubane paradigm in bioactive molecule discovery: further scope, limitations and the cyclooctatetraene complement
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9OB01238A
Abstract: Trials and tribulations of the cubane paradigm in biomolecule discovery highlight synthetic limitations, culminating in a continuing guide for practitioners, which includes cyclooctatetraene.
Tedaniophorbasins A and B—Novel Fluorescent Pteridine Alkaloids Incorporating a Thiomorpholine from the Sponge Tedaniophorbas ceratosis
Publisher: MDPI AG
Date: 07-02-2021
DOI: 10.3390/MD19020095
Abstract: Two new fluorescent pteridine alkaloids, tedaniophorbasins A (1) and B (2), together with the known alkaloid N-methyltryptamine, were isolated, through application of mass directed purification, from the sponge Tedaniophorbas ceratosis collected from northern New South Wales, Australia. The structures of tedaniophorbasins A and B were deduced from the analysis of 1D/2D NMR and MS data and through application of 13C NMR DFT calculations. Tedaniophorbasin A possesses a novel 2-imino-1,3-dimethyl-2,3,7,8-tetrahydro-1H-[1,4]thiazino[3,2-g]pteridin-4(6H)-one skeleton, while tedaniophorbasin B is its 2-oxo derivative. The compounds show significant Stokes shifts (~14,000 cm−1) between excitation and emission wavelengths in their fluorescence spectra. The new compounds were tested for bioactivity against chloroquine-sensitive and chloroquine-resistant strains of the malaria parasite Plasmodium falciparum, breast and pancreatic cancer cell lines, and the protozoan parasite Trypanosoma brucei brucei but were inactive against all targets at 40 µM.
Trypanocidal Activity of Marine Natural Products
Publisher: MDPI AG
Date: 22-10-2013
DOI: 10.3390/MD11104058
Antiparasitic activity of alkaloids from plant species of Papua New Guinea and Australia
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.IJANTIMICAG.2010.05.008
Abstract: New drugs are needed to help overcome the increasing problem of drug resistance in parasites that cause diseases such as malaria and trypanosomiasis. In this study, alkaloid compounds isolated from extracts of the plants Flindersia amboinensis, Stephania zippeliana and Voacanga papuana from Papua New Guinea and Flindersia acuminata from Australia were examined for their antiparasitic activity against Plasmodium falciparum strains and Trypanosoma brucei brucei as well as their cytotoxicity against the mammalian cell lines HEK 293 and HeLa. The most active compound, dimethylisoborreverine (DMIB), showed submicromolar activity, with 50% inhibitory concentration (IC(50)) values between 20 nM and 810 nM both against drug-sensitive and drug-resistant P. falciparum strains, along with moderate selectivity against T. b. brucei and mammalian cells. Stage specificity studies revealed that P. falciparum trophozoite-stage parasites were more susceptible to DMIB than ring- or schizont-stage parasites. DMIB-treated trophozoites showed changes in food vacuole morphology, with an apparent reduction in haemozoin formation that does not appear to be inhibited via the direct binding of haem. These findings suggest a potential for indole alkaloids from Flindersia spp. as new antiparasitic agents.
Substituted Aminoacetamides as Novel Leads for Malaria Treatment
Publisher: Wiley
Date: 03-07-2019
Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 1
Publisher: American Chemical Society (ACS)
Date: 13-03-2014
DOI: 10.1021/JM500098S
Abstract: A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98% activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 × 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78%) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.
Diversity-oriented synthesis yields novel multistage antimalarial inhibitors
Publisher: Springer Science and Business Media LLC
Date: 07-09-2016
DOI: 10.1038/NATURE19804
A unified call to action from Australian nursing and midwifery leaders: ensuring that Black lives matter
Publisher: Informa UK Limited
Date: 03-07-2020
Solid-phase synthesis of Biotin-S-Farnesyl-l-Cysteine, a surrogate substrate for isoprenylcysteine Carboxylmethyltransferase (ICMT)
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.BMCL.2013.08.022
Abstract: Inhibition of isoprenylcysteine Carboxylmethyltransferase (ICMT) is of particular interest as a potential target for the development of cancer chemotherapeutic agents. Screening for inhibitors of ICMT utilises a scintillation proximity assay (SPA) in which Biotin-S-Farnesyl-L-Cysteine (BFC) acts as a surrogate substrate. A solid-phase synthesis protocol for the preparation of BFC using 2-chlorotrityl chloride resin as a solid support has been developed to provide sufficient supply of BFC for high throughput screening (HTS) and subsequent chemistry c aigns to target inhibitors of ICMT. The BFC prepared by this method can be produced quickly on large scale and is stable when stored at -20 °C as a solid, in solution, or on the resin.
Biological characterization of chemically diverse compounds targeting the Plasmodium falciparum coenzyme A synthesis pathway
Publisher: Springer Science and Business Media LLC
Date: 17-11-2016
Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials
Publisher: American Chemical Society (ACS)
Date: 17-06-2016
Erratum to: Bone-stromal cells up-regulate tumourigenic markers in a tumour-stromal 3D model of prostate cancer
Publisher: Springer Science and Business Media LLC
Date: 08-08-2014
Plasmodium falciparum In Vitro Culture – The Highs and Lows
Publisher: Elsevier BV
Date: 10-2018
Inhibition of Plasmepsin V Activity Blocks Plasmodium falciparum Gametocytogenesis and Transmission to Mosquitoes
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.CELREP.2019.11.073
Abstract: Plasmodium falciparum gametocytes infect mosquitoes and are responsible for malaria transmission. New interventions that block transmission could accelerate malaria elimination. Gametocytes develop within erythrocytes and activate protein export pathways that remodel the host cell. Plasmepsin V (PMV) is an aspartyl protease that is required for protein export in asexual parasites, but its function and essentiality in gametocytes has not been definitively proven, nor has PMV been assessed as a transmission-blocking drug target. Here, we show that PMV is expressed and can be inhibited specifically in P. falciparum stage I-II gametocytes. PMV inhibitors block processing and export of gametocyte effector proteins and inhibit development of stage II-V gametocytes. Gametocytogenesis in the presence of sublethal inhibitor concentrations results in stage V gametocytes that fail to infect mosquitoes. Therefore, PMV primes gametocyte effectors for export, which is essential for the development and fitness of gametocytes for transmission to mosquitoes.
Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity
Publisher: Springer Science and Business Media LLC
Date: 14-08-2017
Design and Synthesis of a Screening Library Using the Natural Product Scaffold 3-Chloro-4-hydroxyphenylacetic Acid
Publisher: American Chemical Society (ACS)
Date: 24-03-2015
DOI: 10.1021/NP500856U
Abstract: The fungal metabolite 3-chloro-4-hydroxyphenylacetic acid (1) was utilized in the generation of a unique drug-like screening library using parallel solution-phase synthesis. A 20-membered amide library (3-22) was generated by first converting 1 to methyl (3-chloro-4-hydroxyphenyl)acetate (2), then reacting this scaffold with a erse series of primary amines via a solvent-free aminolysis procedure. The structures of the synthetic analogues (3-22) were elucidated by spectroscopic data analysis. The structures of compounds 8, 12, and 22 were confirmed by single X-ray crystallographic analysis. All compounds were evaluated for cytotoxicity against a human prostate cancer cell line (LNCaP) and for antiparasitic activity toward Trypanosoma brucei brucei and Plasmodium falciparum and showed no significant activity at 10 μM. The library was also tested for effects on the lipid content of LNCaP and PC-3 prostate cancer cells, and it was demonstrated that the fluorobenzyl analogues (12-14) significantly reduced cellular phospholipid and neutral lipid levels.
Correction for Jiménez-Díaz et al., (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium
Publisher: Proceedings of the National Academy of Sciences
Date: 10-2015
Antiplasmodial Alkaloids from the Australian Bryozoan Amathia lamourouxi
Publisher: American Chemical Society (ACS)
Date: 27-10-2020
Total synthesis and antiplasmodial activity of pohlianin C and analogues
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.BMCL.2014.04.071
Abstract: The first synthesis of the glycine-rich cyclic octapeptide pohlianin C is reported, confirming the structure of this natural product. Screening against Plasmodium falciparum reveals moderate antiplasmodial activity, consistent with data obtained from the natural s le. In addition, the synthesis of three analogues reveals that the antiplasmodial activity of pohlianin C can be preserved or increased with simplified structures.
Whole-cell in vitro screening for gametocytocidal compounds
Publisher: Future Science Ltd
Date: 12-2012
DOI: 10.4155/FMC.12.188
Abstract: The discovery of new chemical starting points with the ability to inhibit Plasmodium falciparum sexual stages, and therefore block the disease transmission, is urgently required. These will form the basis for the development of new therapeutic combinations for the treatment and elimination of malaria and the ultimate goal of global eradication. Recent screening of large chemical libraries against the parasite asexual stages has resulted in the public availability of focused subsets of known antimalarial actives, which represent an excellent starting point for the identification of new gametocytocidal compounds. New stage-specific methodologies aimed at increasing the throughput for assessing compound activity against in vitro cultured gametocytes have recently been published. This article discusses the challenges of assay-oriented large-scale gametocyte culturing and reviews the state-of-the art in gametocytocidal assay development and outcomes.
Luciferase-based, high-throughput assay for screening and profiling transmission-blocking compounds against Plasmodium falciparum gametocytes
Publisher: American Society for Microbiology
Date: 04-2016
DOI: 10.1128/AAC.01949-15
Abstract: The discovery of new antimalarial drugs able to target both the asexual and gametocyte stages of Plasmodium falciparum is critical to the success of the malaria eradication c aign. We have developed and validated a robust, rapid, and cost-effective high-throughput reporter gene assay to identify compounds active against late-stage (stage IV and V) gametocytes. The assay, which is suitable for testing compound activity at incubation times up to 72 h, demonstrates excellent quality and reproducibility, with average Z ′ values of 0.85 ± 0.01. We used the assay to screen more than 10,000 compounds from three chemically erse libraries. The screening outcomes highlighted the opportunity to use collections of compounds with known activity against the asexual stages of the parasites as a starting point for gametocytocidal activity detection in order to maximize the chances of identifying gametocytocidal compounds. This assay extends the capabilities of our previously reported luciferase assay, which tested compounds against early-stage gametocytes, and opens possibilities to profile the activities of gametocytocidal compounds over the entire course of gametocytogenesis.
β-Triketone–Monoterpene Hybrids from the Flowers of the Australian Tree Corymbia intermedia
Publisher: American Chemical Society (ACS)
Date: 06-11-2018
DOI: 10.1021/ACS.JNATPROD.8B00494
Abstract: Four new β-triketone monoterpene hybrids, intermediones A-D (1-4), have been identified from the flowers of the Australian eucalypt tree Corymbia intermedia. Intermediones A-D are β-triketones that incorporate a pinene moiety attached via a benzyl group to a syncarpic acid. The structures of 1-4, including relative configurations, were elucidated from the analysis of 1D/2D NMR and MS data. The absolute configurations of intermediones A and B were determined by comparison of experimental and predicted ECD spectra. Intermedione D possesses a tetracyclic ring system that is related to that found in the meroterpenes, guadials B and C. Low to moderate antiplasmodial activity toward the chloroquine-sensitive (3D7) strain of Plasmodium falciparum, with IC
Experience of acute noninvasive ventilation-insights from 'Behind the Mask': a qualitative study.
Publisher: BMJ
Date: 26-08-2018
DOI: 10.1136/BMJSPCARE-2015-000908
Abstract: Non-invasive ventilation (NIV) is widely used in the management of acute and acute-on-chronic respiratory failure. Understanding the experiences of patients treated with NIV is critical to person-centred care. We describe the subjective experiences of in iduals treated with NIV for acute hypercapnic respiratory failure. Qualitative face-to-face interviews analysed using thematic analysis. Australian tertiary teaching hospital. In iduals with acute hypercapnic respiratory failure treated with NIV outside the intensive care unit. In iduals who did not speak English or were unable or unwilling to consent were excluded. 13 participants were interviewed. Thematic saturation was achieved. Participants described NIV providing substantial relief from symptoms and causing discomfort. They described enduring NIV to facilitate another chance at life. Although participants sometimes appeared passive, others expressed a strong conviction that they knew which behaviours and treatments relieved their distress. Most participants described gaps in their recollection of acute hospitalisation and placed a great amount of trust in healthcare providers. All participants indicated that they would accept NIV in the future, if clinically indicated, and often expressed a sense of compulsion to accept NIV. Participants' description of their experience of NIV was intertwined with their experience of chronic disease. Participants described balancing the benefits and burdens of NIV, with the goal of achieving another chance at life. Gaps in recall of their treatment with NIV were frequent, potentially suggesting underlying delirium. The findings of this study inform patient-centred care, have implications for the care of patients requiring NIV and for advance care planning discussions.
The functional antagonist met-rantes: A modified agonist that induces differential CCR5 trafficking
Publisher: Walter de Gruyter GmbH
Date: 2009
DOI: 10.2478/S11658-009-0017-1
Abstract: CC chemokine receptor 5 (CCR5) is a pro-inflammatory chemokine receptor that is expressed on cells of the immune system, and specializes in cell migration in response to inflammation and tissue damage. Due to its key role in cell communication and migration, this receptor is involved in various inflammatory and autoimmune diseases, in addition to HIV infection. Met-RANTES is a modified CCR5 ligand that has previously been shown to antagonize CCR5 activation and function in response to its natural ligands in vitro. In vivo, Met-RANTES is able to reduce inflammation in models of induced inflammatory and autoimmune diseases. However, due to the fact that Met-RANTES is also capable of partial agonist activity regarding receptor signaling and internalization, it is clear that Met-RANTES does not function as a conventional receptor antagonist. To further elucidate the effect of Met-RANTES on CCR5, receptor trafficking was investigated in a CHO-CCR5-GFP cell line using the Opera confocal plate reader. The internalization response of CCR5 was quantified, and showed that Met-RANTES internalized CCR5 in a slower, less potent manner than the agonists CCL3 and CCL5. Fluorescent organelle labeling and live cell imaging showed CCL3 and CCL5 caused CCR5 to traffic through sorting endosomes, recycling endosomes and the Golgi apparatus. In contrast, Met-RANTES caused CCR5 to traffic through sorting endosomes and the Golgi apparatus in a manner that was independent of recycling endosomes. As receptor trafficking impacts on cell surface expression and the ability of the receptor to respond to more ligand, this information may indicate an alternative regulation of CCR5 by Met-RANTES that allows the modified ligand to reduce inflammation through stimulation of a pro-inflammatory receptor.
Chemical genetics of Plasmodium falciparum
Publisher: Springer Science and Business Media LLC
Date: 05-2010
DOI: 10.1038/NATURE09099
Polydiscamides B−D from a Marine Sponge Ircinia sp. as Potent Human Sensory Neuron-Specific G Protein Coupled Receptor Agonists
Publisher: American Chemical Society (ACS)
Date: 29-12-2007
DOI: 10.1021/NP070094R
Abstract: Polydiscamides B, C, and D (1-3) were isolated from a sponge Ircinia sp. The structures of 1 to 3 were elucidated by the comparison of their NMR and HRESIMS spectroscopic data with that of a structurally related compound, polydiscamide A. All compounds showed potent agonist activity against human sensory neuron-specific G protein couple receptor (SNSR), a receptor involved in the modulation of pain, and they are the first ex les of nonendogenous human SNSR agonists.
Novel Strategies to Speed-Up Query Response
Publisher: Science Alert
Date: 2010
Tomentosones A and B, Hexacyclic Phloroglucinol Derivatives from the Thai Shrub Rhodomyrtus tomentosa
Publisher: American Chemical Society (ACS)
Date: 28-11-2011
DOI: 10.1021/JO201602Y
Abstract: Two phloroglucinols named tomentosones A and B (1 and 2) that each possess a novel hexacyclic ring system were isolated from the CH(2)Cl(2) extract of Rhodomyrtus tomentosa leaves. Their structures were elucidated from analyses of 2D NMR spectroscopic data. Tomentosone A inhibited the growth of chloroquine-resistant and -sensitive strains of the malaria parasite Plasmodium falciparum, with IC(50) values of 1.49 μM and 1.0 μM, respectively, while tomentosone B was significantly less active.
Screening and Audit as Service-Level Strategies to Support Implementation of Australian Guidelines for Cancer Pain Management in Adults: A Feasibility Study.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.PMN.2018.05.004
Abstract: Pain in people with cancer is common but often under-recognized and under-treated. Guidelines can improve the quality of pain care, but need targeted strategies to support implementation. To test the feasibility of two service-level strategies for supporting guideline implementation: a screening system and medical record audit. Multimethods. One oncology outpatient service, and one palliative care outpatient and inpatient service. Patients with advanced cancer. Patients were screened in the waiting room with a modified version of the Edmonton Symptom Assessment System-revised either electronically or in paper-based format. Feasibility indicated the percentage of patients successfully screened from the total number attending the services. An audit assessed adherence to key indicators of pain assessment and management. Feasibility thresholds were set at 75% incidence for screening and a median of 30 minutes per patient for audit. Of 452 patient visits, 95% (n = 429) were successfully screened, 34% (n = 155) electronically and 61% (n = 274) paper-based. Electronic pain screening was technically challenging and time-intensive for nurses. Thirty-one patients consented to have their records audited. The median audit time was 37.5 minutes (range 10-120 minutes). Variability arose from the number and type of record (outpatient or inpatient). Adherence to indicators varied from 63% (pain assessment at first presentation) to 94% (regular pain assessment and medication prescribed at regular intervals). This study confirmed the need to implement evidence-based guidelines for cancer pain and generated useful insights into the feasibility of pain screening and audit.
Improving delirium recognition and assessment for people receiving inpatient palliative care: a mixed methods meta-synthesis.
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.IJNURSTU.2017.07.007
Abstract: Delirium is a serious acute neurocognitive condition frequently occurring for hospitalized patients, including those receiving care in specialist palliative care units. There are many delirium evidence-practice gaps in palliative care, including that the condition is under-recognized and challenging to assess. To report the meta-synthesis of a research project investigating delirium epidemiology, systems and nursing practice in palliative care units. The Delirium in Palliative Care (DePAC) project was a two-phase sequential transformative mixed methods design with knowledge translation as the theoretical framework. The project answered five different research questions about delirium epidemiology, systems of care and nursing practice in palliative care units. Data integration and metasynthesis occurred at project conclusion. There was a moderate to high rate of delirium occurrence in palliative care unit populations and palliative care nurses had unmet delirium knowledge needs and worked within systems and team processes that were inadequate for delirium recognition and assessment. The meta-inference of the DePAC project was that a widely-held but paradoxical view that palliative care and dying patients are different from the wider hospital population has separated them from the overall generation of delirium evidence, and contributed to the extent of practice deficiencies in palliative care units. Improving palliative care nurses' capabilities to recognize and assess delirium will require action at the patient and family, nurse, team and system levels. A broader, hospital-wide perspective would accelerate implementation of evidence-based delirium care for people receiving palliative care, both in specialist units, and the wider hospital setting.
The synthesis, antimalarial activity and CoMFA analysis of novel aminoalkylated quercetin analogs
Publisher: Elsevier BV
Date: 2015
Synthesis of New Triazolopyrazine Antimalarial Compounds
Publisher: MDPI AG
Date: 21-04-2021
DOI: 10.3390/MOLECULES26092421
Abstract: A radical approach to late-stage functionalization using photoredox and Diversinate™ chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4) resulted in the synthesis of 12 new analogues, which were characterized by NMR, UV, and MS data analysis. The structures of four triazolopyrazines were confirmed by X-ray crystal structure analysis. Several minor and unexpected side products were generated during these studies, including two resulting from a possible disproportionation reaction. All compounds were tested for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum (3D7 and Dd2 strains) and for cytotoxicity against a human embryonic kidney (HEK293) cell line. Moderate antimalarial activity was observed for some of the compounds, with IC50 values ranging from 0.3 to µM none of the compounds displayed any toxicity against HEK293 at 80 µM.
Blood Schizontocidal and Gametocytocidal Activity of 3-Hydroxy-N′-arylidenepropanehydrazonamides: A New Class of Antiplasmodial Compounds
Publisher: American Chemical Society (ACS)
Date: 25-09-2014
DOI: 10.1021/JM500811P
Abstract: 3-Hydroxy-N'-arylidenepropanehydrazonamides represent a new class of antiplasmodial compounds. The two most active phenanthrene-based derivatives showed potent in vitro antiplasmodial activity against the 3D7 (sensitive) and Dd2 (multidrug-resistant) strains of Plasmodium falciparum with nanomolar IC50 values in the range of 8-28 nM. Further studies revealed that the most promising derivative, bearing a 4-fluorobenzylidene moiety, demonstrated in vivo antiplasmodial activity after oral administration in a P. berghei malaria model, although no complete parasite elimination was achieved with a four-dose regimen. The in vivo efficacy correlated well with the plasma concentration levels, and no acute toxicity symptoms (e.g., death or changes in general behavior or physiological activities) were observed, which is in agreement with a >1000-fold lower activity against L6 cells, a primary cell line derived from mammalian (rat) skeletal myoblasts. This indicates that lead compound 29 displays selective activity against P. falciparum. Moreover, both phenanthrene-based derivatives were active against stage IV/V gametocytes of P. falciparum in vitro.
Hit-to-lead optimization of novel benzimidazole phenylacetamides as broad spectrum trypanosomacides
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0MD00058B
Abstract: A series of benzimidazole phenylacetamides were developed from a phenotypic hit as novel trypanosomacides for Chagas disease and human African trypanosomiasis.
Orthoscuticellines A–E, β-Carboline Alkaloids from the Bryozoan Orthoscuticella ventricosa Collected in Australia
Publisher: American Chemical Society (ACS)
Date: 21-01-2020
DOI: 10.1021/ACS.JNATPROD.9B00933
Abstract: Antiplasmodial high-throughput screening of extracts derived from marine invertebrates collected from northern NSW, Australia, resulted in the methanol extract of the bryozoan
Three Chalconoids and a Pterocarpene from the Roots of Tephrosia aequilata
Publisher: MDPI AG
Date: 20-02-2017
Identification and Characterization of FTY720 for the Treatment of Human African Trypanosomiasis
Publisher: American Society for Microbiology
Date: 03-2016
DOI: 10.1128/AAC.02116-15
Abstract: The screening of a focused library identified FTY720 (Fingolimod Gilenya) as a potent selective antitrypanosomal compound active against Trypanosoma brucei gambiense and T. brucei rhodesiense , the causative agents of human African trypanosomiasis (HAT). This is the first report of trypanocidal activity for FTY720, an oral drug registered for the treatment of relapsing multiple sclerosis, and the characterization of sphingolipids as a potential new class of compounds for HAT.
A luciferase based viability assay for ATP detection in 384-well format for high throughput whole cell screening of Trypanosoma brucei brucei bloodstream form strain 427
Publisher: Springer Science and Business Media LLC
Date: 2009
3-(Oxazolo[4,5-b]pyridin-2-yl)anilides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei, the causative agent for human African trypanosomiasis
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.EJMECH.2013.05.007
Abstract: A whole organism high-throughput screen of approximately 87,000 compounds against Trypanosoma brucei brucei led to the recent discovery of several novel compound classes with low micromolar activity against this organism and without appreciable cytotoxicity to mammalian cells. Herein we report a structure-activity relationship (SAR) investigation around one of these hit classes, the 3-(oxazolo[4,5-b]pyridin-2-yl)anilides. Sharp SAR is revealed, with our most active compound (5) exhibiting an IC₅₀ of 91 nM against the human pathogenic strain T.b. rhodesiense and being more than 700 times less toxic towards the L6 mammalian cell line. Physicochemical properties are attractive for many compounds in this series. For the most potent representatives, we show that solubility and metabolic stability are key parameters to target during future optimisation.
N-Aryl-2-aminobenzimidazoles: Novel, Efficacious, Antimalarial Lead Compounds
Publisher: American Chemical Society (ACS)
Date: 21-07-2014
DOI: 10.1021/JM500715U
Abstract: From the phenotypic screening of the AstraZeneca corporate compound collection, N-aryl-2-aminobenzimidazoles have emerged as novel hits against the asexual blood stage of Plasmodium falciparum (Pf). Medicinal chemistry optimization of the potency against Pf and ADME properties resulted in the identification of 12 as a lead molecule. Compound 12 was efficacious in the P. berghei (Pb) model of malaria. This compound displayed an excellent pharmacokinetic profile with a long half-life (19 h) in rat blood. This profile led to an extended survival of animals for over 30 days following a dose of 50 mg/kg in the Pb malaria model. Compound 12 retains its potency against a panel of Pf isolates with known mechanisms of resistance. The fast killing observed in the in vitro parasite reduction ratio (PRR) assay coupled with the extended survival highlights the promise of this novel chemical class for the treatment of malaria.
Screening and hit evaluation of a chemical library against blood-stage Plasmodium falciparum
Publisher: Springer Science and Business Media LLC
Date: 27-05-2014
A novel multiple-stage antimalarial agent that inhibits protein synthesis
Publisher: Springer Science and Business Media LLC
Date: 17-06-2015
DOI: 10.1038/NATURE14451
Investigation of thiazolyl–benzothiophenamides as potential agents for African sleeping sickness
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0MD00277A
Abstract: African sleeping sickness is a potentially fatal neglected disease affecting sub-Saharan Africa.
Screening a natural product-based library against kinetoplastid parasites
Publisher: MDPI AG
Date: 12-10-2017
(−)-Dibromophakellin: An α2B adrenoceptor agonist isolated from the Australian marine sponge, Acanthella costata
Publisher: Elsevier BV
Date: 03-2009
DOI: 10.1016/J.BMC.2009.01.065
Abstract: Bioassay-guided fractionation of the organic extract from the marine sponge Acanthella costata resulted in the isolation of the known natural product, (-)-dibromophakellin (1). Using a fluorescence imaging plate reader (FLIPR) based assay, compound 1 was identified as displaying agonist activity against the alpha(2B) adrenoceptor, with an EC(50) of 4.2muM. Debromination and Suzuki-Miyaura coupling reactions were undertaken in order to provide structure activity data about the pyrrole ring of this marine metabolite. These synthetic studies generated the known natural product analogues, (-)-phakellin (2), and (-)-monobromophakellin (3), along with the new synthetic derivatives (-)-4-bromo-5-phenylphakellin (5) and (-)-4,5-diphenylphakellin (6). Substitution of the C-5 Br of 1 with H (2 and 3) or phenyl (5 and 6) resulted in loss of activity indicating that Br at C-5 is required for agonist activity.
Antibacterial properties of breast milk: Requirements for surface phagocytosis and chemiluminescence
Publisher: Springer Science and Business Media LLC
Date: 12-1991
DOI: 10.1007/BF01984925
An evaluation of Minor Groove Binders as anti- Trypanosoma brucei brucei therapeutics
Publisher: Elsevier BV
Date: 06-2016
Property activity refinement of 2-anilino 4-amino substituted quinazolines as antimalarials with fast acting asexual parasite activity
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.BIOORG.2021.105359
Abstract: Malaria is a devastating disease caused by Plasmodium parasites. Emerging resistance against current antimalarial therapeutics has engendered the need to develop antimalarials with novel structural classes. We recently described the identification and initial optimization of the 2-anilino quinazoline antimalarial class. Here, we refine the physicochemical properties of this antimalarial class with the aim to improve aqueous solubility and metabolism and to reduce adverse promiscuity. We show the physicochemical properties of this class are intricately balanced with asexual parasite activity and human cell cytotoxicity. Structural modifications we have implemented improved LipE, aqueous solubility and in vitro metabolism while preserving fast acting P. falciparum asexual stage activity. The lead compounds demonstrated equipotent activity against P. knowlesi parasites and were not predisposed to resistance mechanisms of clinically used antimalarials. The optimized compounds exhibited modest activity against early-stage gametocytes, but no activity against pre-erythrocytic liver parasites. Confoundingly, the refined physicochemical properties installed in the compounds did not engender improved oral efficacy in a P. berghei mouse model of malaria compared to earlier studies on the 2-anilino quinazoline class. This study provides the framework for further development of this antimalarial class.
3-Alkylthio-1,2,4-triazine dimers with potent antimalarial activity
Publisher: Elsevier BV
Date: 10-2010
DOI: 10.1016/J.BMCL.2010.08.065
Abstract: We report on the discovery of 3-alkylthio-1,2,4-triazine dimers that are potently toxic to Plasmodium falciparum, with single digit nanomolar activity, and up to several thousand-fold lower toxicity to mammalian cells. They are equipotent against chloroquine-resistant strains of P. falciparum.
A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria
Publisher: American Association for the Advancement of Science (AAAS)
Date: 15-07-2015
DOI: 10.1126/SCITRANSLMED.AAA6645
Abstract: The antimalarial drug DSM265 displays activity against blood and liver stages of Plasmodium falciparum and has a long predicted half-life in humans.
Copper, Nickel, and Zinc Cyclam–Amino Acid and Cyclam–Peptide Complexes May Be Synthesized with “Click” Chemistry and Are Noncytotoxic
Publisher: American Chemical Society (ACS)
Date: 23-11-2011
DOI: 10.1021/IC2020012
Abstract: We describe the synthesis of cyclam metal complexes derivatized with amino acids or a tripeptide using a copper(I)-catalyzed Huisgen "click" reaction. The linker triazole formed during the synthesis plays an active coordinating role in the complexes. The reaction conditions do not racemize the amino acid stereocenters. However, a methylene group adjacent to the triazole is susceptible to H/D exchange under ambient conditions, an observation which has potentially important implications for structures involving stereocenters adjacent to triazoles in click-derived structures. The successful incorporation of several amino acids is described, including reactive tryptophan and cysteine side chains. All complexes are formed rapidly upon introduction of the relevant metal salt, including synthetically convenient cases where trifluoroacetate salts of cyclam derivatives are used directly in the metalation. None of the metal complexes displayed any cytotoxicity to mammalian cells, suggesting that the attachment of such complexes to amino acids and peptides does not induce toxicity, further supporting their potential suitability for labeling/imaging studies. One Cu(II)-cyclam-triazole-cysteine disulfide complex displayed moderate activity against MCF-10A breast nontumorigenic epithelial cells.
Corrigendum to “Solid-phase synthesis of Biotin-S-Farnesyl-l-Cysteine, a surrogate substrate for isoprenylcysteine Carboxylmethyltransferase (ICMT)” [Bioorg. Med. Chem. Lett. 23 (2013) [5671–5673]
Publisher: Elsevier BV
Date: 08-2018
Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond
Publisher: Public Library of Science (PLoS)
Date: 28-07-2016
Protocol for a phase III pragmatic stepped wedge cluster randomised controlled trial comparing the effectiveness and cost-effectiveness of screening and guidelines with, versus without, implementation strategies for improving pain in adults with cancer attending outpatient oncology and palliative care services: the Stop Cancer PAIN trial.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2018
Albopunctatone, an Antiplasmodial Anthrone-Anthraquinone from the Australian Ascidian Didemnum albopunctatum
Publisher: American Chemical Society (ACS)
Date: 08-06-2012
DOI: 10.1021/NP300074Z
Abstract: Chemical investigation of a MeOH extract of the Great Barrier Reef ascidian Didemnum albopunctatum has led to the isolation and identification of a new anthrone-anthraquinone, albopunctatone (1), together with the known 1,8-dihydroxy-9,10-anthraquinone (2). The structure of 1 was established from interpretation of 1D and 2D NMR spectroscopic and mass spectrometric data. The compounds were screened for antiplasmodial activity against chloroquine-resistant and -sensitive strains of the malaria parasite, Plasmodium falciparum. Albopunctatone (1) was moderately active against both strains (IC(50) 5.3 and 4.4 ± 0.5 μM, respectively), while 2 was inactive at doses up to 40 μM. Both compounds were also inactive up to 40 μM when tested against a variety of cancerous and normal human cell lines and the kinetoplastid Trypanosoma brucei brucei, indicating selectivity for the malaria parasite, P. falciparum.
Kororamide A, a new tribrominated indole alkaloid from the Australian bryozoan Amathia tortuosa
Publisher: Elsevier BV
Date: 06-2012
Investigation of pyrimidine nucleoside analogues as chemical probes to assess compound effects on the proliferation of Trypanosoma cruzi intracellular parasites
Publisher: Public Library of Science (PLoS)
Date: 12-03-2020
The Perspectives of Health Care Professionals on Providing End of Life Care and Palliative Care for Patients With Chronic Heart Failure: An Integrative Review
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.HLC.2018.10.009
Abstract: Chronic heart failure is a complex and multifaceted syndrome characterised by an unpredictable trajectory, high symptom burden and reduced quality of life. Although palliative care is recommended, patient, provider and system factors limit access. To examine the knowledge, attitudes and perspectives of health care professionals towards end of life care and palliative care for patients with chronic heart failure. This is an integrative review. CINAHL, Academic Search Complete and SCOPUS were searched. Specific inclusion criteria and search terms were used. The integrative review method entailed analysing data from primary articles using the constant comparison method and then synthesising data. Twenty-six (26) articles were selected that explored health care professionals' perspectives towards end of life care and palliative care. The categories that emerged were grouped into patient, provider and system issues. Most health care professionals involved in providing care to heart failure patients have misperceptions of palliative care, often confusing it with end of life and hospice care. This hinders patients' access to palliative care as determining the end of life period in heart failure is difficult. Exploring health care professionals' perspectives towards the delivery of end of life care and palliative care is important for understanding how their practice influences the delivery of palliative care for heart failure patients. Emphasis on increasing awareness of the principles of palliative care in the health care community, as well as addressing organisational issues will improve the care delivered to these patients.
Antimalarial Activity of Pyrroloiminoquinones from the Australian Marine Sponge Zyzzya sp
Publisher: American Chemical Society (ACS)
Date: 20-06-2012
DOI: 10.1021/JM3002795
Abstract: A new bispyrroloiminoquinone alkaloid, tsitsikammamine C (1), displayed potent in vitro antimalarial activity with IC(50) values of 13 and 18 nM against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum, respectively. Tsitsikammamine C (1) displayed selectivity indices of >200 against HEK293 cells and inhibited both ring and trophozoite stages of the malaria parasite life cycle. Previously reported compounds makaluvamines J (2), G (3), L (4), K (5) and damirones A (6) and B (7) were also isolated from the same marine sponge (Zyzzya sp.). Compounds 2-4 displayed potent growth inhibitory activity (IC(50) < 100 nM) against both P. falciparum lines and only moderate cytotoxicity against HEK293 cells (IC(50) = 1-4 μM). Makaluvamine G (3) was not toxic to mice and suppressed parasite growth in P. berghei infected mice following subcutaneous administration at 8 mg kg(-1) day(-1).
A Systematic Review of Successful Elements of Interventions for Heart Failure Patients With Mild Cognitive Impairment
Publisher: Elsevier BV
Date: 2018
Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans
Publisher: American Society for Microbiology
Date: 02-2015
DOI: 10.1128/AAC.04419-14
Abstract: Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising in vitro parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for in vitro and in vivo efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent in vitro activity, with 50% inhibitory concentrations (IC 50 s) of nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory Plasmodium falciparum isolates. Activities against ex vivo clinical isolates of both P. falciparum and Plasmodium vivax were similar, with potencies of 300 to 400 nM. Sexual-stage gametocyte inhibition occurs at micromolar levels however, mature gametocyte progression to gamete formation is inhibited at submicromolar concentrations. Parasite reduction ratio analysis confirms a high asexual-stage rate of killing. Both compounds examined displayed oral efficacy in in vivo mouse models of Plasmodium berghei and P. falciparum infection. The discovery of a rapid and broadly acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria-causing species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.
Discovery of Potent N-Ethylurea Pyrazole Derivatives as Dual Inhibitors of Trypanosoma brucei and Trypanosoma cruzi
Publisher: American Chemical Society (ACS)
Date: 09-09-2020
Cancer drug discovery: recent innovative approaches to tumor modeling
Publisher: Informa UK Limited
Date: 11-08-2016
DOI: 10.1080/17460441.2016.1214562
Abstract: Cell culture models have been at the heart of anti-cancer drug discovery programs for over half a century. Advancements in cell culture techniques have seen the rapid evolution of more complex in vitro cell culture models investigated for use in drug discovery. Three-dimensional (3D) cell culture research has become a strong focal point, as this technique permits the recapitulation of the tumor microenvironment. Biologically relevant 3D cellular models have demonstrated significant promise in advancing cancer drug discovery, and will continue to play an increasing role in the future. In this review, recent advances in 3D cell culture techniques and their application in tumor modeling and anti-cancer drug discovery programs are discussed. The topics include selection of cancer cells, 3D cell culture assays (associated endpoint measurements and analysis), 3D microfluidic systems and 3D bio-printing. Although advanced cancer cell culture models and techniques are becoming commonplace in many research groups, the use of these approaches has yet to be fully embraced in anti-cancer drug applications. Furthermore, limitations associated with analyzing information-rich biological data remain unaddressed.
Pterocarpans and isoflavones from the root bark of Millettia micans and of Millettia dura
Publisher: Elsevier BV
Date: 09-2017
Facile Synthesis and Preliminary Structure–Activity Analysis of New Sulfonamides Against Trypanosoma brucei
Publisher: American Chemical Society (ACS)
Date: 18-03-2014
DOI: 10.1021/ML400487T
Flinderoles A−C: Antimalarial Bis-indole Alkaloids from Flindersia Species
Publisher: American Chemical Society (ACS)
Date: 17-12-2008
DOI: 10.1021/OL802506N
Abstract: With the aim of finding new natural product antimalarials, the novel indole alkaloids flinderole A-C were found to have selective antimalarial activities with IC(50) values between 0.15-1.42 microM. Flinderole A was isolated from the Australian plant Flindersia acuminata and flinderoles B and C from the Papua New Guinean plant F. amboinensis. Flinderoles A-C contain an unprecedented rearranged skeleton compared to their related isomers of the borreverine class of compounds.
Organometallic Conjugates of the Drug Sulfadoxine for Combatting Antimicrobial Resistance
Publisher: Wiley
Date: 13-06-2018
Abstract: Fourteen novel arene Ru II , and cyclopentadienyl (Cp x ) Rh III and Ir III complexes containing an N , N ′‐chelated pyridylimino‐ or quinolylimino ligand functionalized with the antimalarial drug sulfadoxine have been synthesized and characterized, including three by X‐ray crystallography. The rhodium and iridium complexes exhibited potent antiplasmodial activity with IC 50 values of 0.10–2.0 μ m in either all, or one of the three Plasmodium falciparum assays (3D7 chloroquine sensitive, Dd2 chloroquine resistant and NF54 sexual late stage gametocytes) but were only moderately active towards Trichomonas vaginalis . They were active in both the asexual blood stage and the sexual late stage gametocyte assays, whereas the clinical parent drug, sulfadoxine, was inactive. Five complexes were moderately active against Mycobacterium tuberculosis (IC 50 .3 μ m ), while sulfadoxine showed no antitubercular activity. An increase in the size of both the Cp x ligand and the aromatic imino substituent increased hydrophobicity, which resulted in an increase in antiplasmodial activity.
Synthesis and characterisation of new antimalarial fluorinated triazolopyrazine compounds
Publisher: Beilstein Institut
Date: 31-01-2023
DOI: 10.3762/BJOC.19.11
Abstract: Nine new fluorinated analogues were synthesised by late-stage functionalisation using Diversinate™ chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4). The structures of all analogues were fully characterised by NMR, UV and MS data analysis three triazolopyrazines were confirmed by X-ray crystal structure analysis. The inhibitory activity of all compounds against the growth of the malaria parasite Plasmodium falciparum (3D7 and Dd2 strains) and the cytotoxicity against a human embryonic kidney (HEK293) cell line were tested. Some of the compounds demonstrated moderate antimalarial activity with IC 50 values ranging from 0.2 to µM none of the compounds displayed any cytotoxicity against HEK293 cells at 80 µM. Antimalarial activity was significantly reduced when C-8 of the triazolopyrazine scaffold was substituted with CF 3 and CF 2 H moieties, whereas incorporation of a CF 2 Me group at the same position completely abolished antiplasmodial effects.
Clavatadine A, A Natural Product with Selective Recognition and Irreversible Inhibition of Factor XIa
Publisher: American Chemical Society (ACS)
Date: 30-05-2008
DOI: 10.1021/JM800314B
Abstract: Bioassay-guided fractionation of a CH2Cl2/MeOH extract of the sponge Suberea clavata using the serine protease factor XIa to detect antithrombotic activity led to the isolation of the new marine natural products, clavatadines A and B. Clavatadines A and B inhibited factor XIa with IC50's of 1.3 and 27 microM, respectively. A crystal structure of protein-inhibitor (clavatadine A) complex was obtained and revealed interesting selective binding and irreversible inhibition of factor XIa. The cocrystal structure provides guidance for the design and synthesis of future factor XIa inhibitors as antithrombotic agents.
Thiaplakortones A–D: Antimalarial Thiazine Alkaloids from the Australian Marine Sponge Plakortis lita
Publisher: American Chemical Society (ACS)
Date: 25-09-2013
DOI: 10.1021/JO400988Y
Abstract: A high-throughput screening c aign using a prefractionated natural product library and an in vitro antimalarial assay identified active fractions derived from the Australian marine sponge Plakortis lita . Bioassay-guided fractionation of the CH2Cl2/CH3OH extract from P. lita resulted in the purification of four novel thiazine-derived alkaloids, thiaplakortones A-D (1-4). The chemical structures of 1-4 were determined following analysis of 1D/2D NMR and MS data. Comparison of the chiro-optical data for 3 and 4 with literature values of related N-methyltryptophan natural products was used to determine the absolute configuration for both thiaplakortones C and D as 11S. Compounds 1-4 displayed significant growth inhibition against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum (IC50 values 3.9 μM). Thiaplakortone A (1) was the most active natural product, with IC50 values of 51 and 6.6 nM against 3D7 and Dd2 lines, respectively.
6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors
Publisher: American Chemical Society (ACS)
Date: 30-08-2015
DOI: 10.1021/ACS.JMEDCHEM.5B00438
Abstract: From a whole-organism high throughput screen of approximately 87000 compounds against Trypanosoma brucei brucei, we recently identified eight new unique compounds for the treatment of human African trypanosomiasis. In an effort to understand the structure-activity relationships around these compounds, we report for the first time our results on a new class of trypanocides, the pyrazine carboxamides. Attracted by the low molecular weight (270 g·mol(-1)) of our starting hit (9) and its potency (0.49 μM), the SAR around the core was explored, leading to compounds having an EC50 as low as 25 nM against T. b. brucei and being more than 1500 times less toxic against mammalian L6 and HEK293 cell lines. The most potent compounds in the series were exquisitely selective for T. brucei over a panel of other protozoan parasites, showing an excellent correlation with the human infective parasite Trypanosoma brucei rhodesiense, the most potent compound (65) having an EC50 of 24 nM. The compounds are highly drug-like and are able to penetrate the CNS, their only limitation currently being their rate of microsomal metabolism. To that effect, efforts to identify potential metabolites of selected compounds are also reported.
Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity
Publisher: American Chemical Society (ACS)
Date: 26-01-2017
DOI: 10.1021/ACS.JMEDCHEM.6B01673
Abstract: Novel antimalarial therapeutics that target multiple stages of the parasite lifecycle are urgently required to tackle the emerging problem of resistance with current drugs. Here, we describe the optimization of the 2-anilino quinazoline class as antimalarial agents. The class, identified from publicly available antimalarial screening data, was optimized to generate lead compounds that possess potent antimalarial activity against P. falciparum parasites comparable to the known antimalarials, chloroquine and mefloquine. During the optimization process, we defined the functionality necessary for activity and improved in vitro metabolism and solubility. The resultant lead compounds possess potent activity against a multidrug resistant strain of P. falciparum and arrest parasites at the ring phase of the asexual stage and also gametocytogensis. Finally, we show that the lead compounds are orally efficacious in a 4 day murine model of malaria disease burden.
Development of ethynyl-2′-deoxyuridine chemical probes for cell proliferation
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.BMC.2016.07.021
Abstract: A common method of evaluating cellular proliferation is to label DNA with chemical probes. 5-Ethynyl-2'-deoxyuridine (EdU) is a widely utilized chemical probe for labeling DNA, and upon incorporation, EdU treatment of cells is followed by a reaction with a small molecule fluorescent azide to allow detection. The limitations when using EdU include cytotoxicity and a reliance on nucleoside active transport mechanisms for entry into cells. Here we have developed six novel EdU pro-labels that consist of EdU modified with variable lipophilic acyl ester moieties. This pro-label:chemical probe relationship parallels the prodrug:drug relationship that is employed widely in medicinal chemistry. EdU and EdU pro-labels were evaluated for their labeling efficacy and cytotoxicity. Several EdU pro-label analogues incorporate into DNA at a similar level to EdU, suggesting that nucleoside transporters can be bypassed by the pro-labels. These EdU pro-labels also had reduced toxicity compared to EdU.
Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages
Publisher: Springer Science and Business Media LLC
Date: 15-05-2017
Antitrypanosomal Cyclic Polyketide Peroxides from the Australian Marine Sponge Plakortis sp.
Publisher: American Chemical Society (ACS)
Date: 17-03-2010
DOI: 10.1021/NP900535Z
Abstract: Bioassay-guided fractionation of the crude extract from the Australian marine sponge Plakortis sp. led to the isolation of two new cyclic polyketide peroxides, 11,12-didehydro-13-oxo-plakortide Q (1) and 10-carboxy-11,12,13,14-tetranor-plakortide Q (2). Antitrypanosomal studies showed that compound 1 had an IC(50) value of 49 nM against Trypanosoma brucei brucei, and compound 2, where a carboxylic acid is present in the side chain, had a 20-fold reduction of activity. 11,12-Didehydro-13-oxo-plakortide Q (1) is the most active peroxide isolated so far against T. b. brucei, and it indicates the potential therapeutic value of this class of compounds.
Niphatoxin C, a Cytotoxic Tripyridine Alkaloid from Callyspongia sp.
Publisher: American Chemical Society (ACS)
Date: 21-11-2007
DOI: 10.1021/NP070366Q
Abstract: As part of our studies to discover P2X 7 receptor antagonists, the sponge Callyspongia sp. was investigated. A new tripyridine alkaloid niphatoxin C ( 1) was isolated and had P2X 7 receptor antagonism however, cytotoxicity of THP-1 cells was the predominant biological effect at higher concentrations. Its structure was determined by 1- and 2-D NMR spectroscopy.
Approaches to protozoan drug discovery: Phenotypic screening
Publisher: American Chemical Society (ACS)
Date: 20-08-2013
DOI: 10.1021/JM4004279
Abstract: Determining the activity of a compound and the potential impact on a diseased state is frequently undertaken using phenotypic or target-based approaches. Phenotypic screens have the advantage of the whole organism being exposed to the compound and thus all the targets and biological pathways associated with it. Cell penetration and access to targets in their "natural" environment are taken into account. Unless utilizing a genetically modified organism with an additional target associated indicator, elucidation of specific target(s) of active compounds is necessary. Target discovery is desirable to allow development of chemical entities based upon knowledge of the target structure. Phenotypic drug discovery has successfully identified new molecular entities for neglected protozoan disease research. In this perspective, the phenotypic approaches used to identify chemical entities for drug discovery and for use as tools against the parasites Plasmodium falciparum, Trypanosoma brucei brucei, and Trypanosoma cruzi will be outlined.
Antiplasmodial Bis-Indole Alkaloids from the Bark of Flindersia pimenteliana
Publisher: Georg Thieme Verlag KG
Date: 29-10-2020
DOI: 10.1055/A-1028-7786
Abstract: Three new (1–3) and 2 known (4–5) bis-indole alkaloids were identified from the bark of Flindersia pimenteliana (Rutaceae). The structures of 1–3 were elucidated on the basis of their (+)-HRESESIMS and 2D NMR spectroscopic data. Antiplasmodial activity for 1–3 against chloroquine sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum is also reported, with IC50 values ranging from 0.96 to 2.41 µg/mL. These results expand our knowledge of the structure-activity relationships of potently antiplasmodial isoborreverine-type alkaloids, the bioactivity of which have recently attracted significant attention in the literature.
Vanillic Acid Derivatives from the Green Algae Cladophora socialis As Potent Protein Tyrosine Phosphatase 1B Inhibitors
Publisher: American Chemical Society (ACS)
Date: 20-10-2007
DOI: 10.1021/NP070225O
Abstract: A novel vanillic acid derivative (1) and its sulfate adduct (2) were isolated from a green algae, Cladophora socialis. The structures of 1 and 2 were elucidated from NMR and HRESIMS experiments. Both compounds showed potent inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), an enzyme involved in the regulation of insulin cell signaling. Compounds 1 and 2 had IC50 values of 3.7 and 1.7 microM, respectively.
Alkaloids from the Chinese vine gnetum montanum
Publisher: American Chemical Society (ACS)
Date: 31-10-2011
DOI: 10.1021/NP200700F
Abstract: During a high-throughput screening c aign of a prefractionated natural product library, fractions from the Chinese vine Gnetum montanum showed in vitro activity against Pseudomonas aeruginosa wild-type strain, PAO1. UV-directed isolation of the organic extract from the vine leaves resulted in the purification of the new natural products N-methyllaudanosolinium trifluoroacetate (1), 3'-hydroxy-N,N-dimethylcoclaurinium trifluoroacetate (2), 1,9,10-trihydroxy-2-methoxy-6-methylaporphinium trifluoroacetate (3), and 6a,7-didehydro-1,9,10-trihydroxy-2-methoxy-6-methylaporphinium trifluoroacetate (4). Compound 4 is described here for the first time, and this is the first report of compounds 1-3 as natural products. Compounds 1-3 were found to racemize over time. Starting from commercially available (+)-boldine, through a series of semisynthetic reactions, a mechanism for the racemization of the isolated compounds is proposed. The known natural products (-)-latifolian A (5) and magnocurarine (6) were also isolated during these studies. The antibacterial activity was explained by the presence of 5, which displayed an IC50 value of 9.8 μM (MIC = 35 μM).
Primary health care content in Australian undergraduate nursing curricula
Publisher: Elsevier BV
Date: 06-2020
Discovery of HDAC inhibitors with potent activity against multiple malaria parasite life cycle stages
Publisher: Elsevier BV
Date: 07-2014
The Extended Dwell Peripheral Intravenous Catheter Is an Alternative Method of NICU Intravenous Access (vol 18, pg 295, 2018)
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2018
HSQC-TOCSY Fingerprinting-Directed Discovery of Antiplasmodial Polyketides from the Marine Ascidian-Derived Streptomyces sp. (USC-16018)
Publisher: MDPI AG
Date: 30-05-2018
DOI: 10.3390/MD16060189
A simple and predictive phenotypic High Content Imaging assay for Plasmodium falciparum mature gametocytes to identify malaria transmission blocking compounds
Publisher: Springer Science and Business Media LLC
Date: 10-11-2015
DOI: 10.1038/SREP16414
Abstract: Plasmodium falciparum gametocytes, specifically the mature stages, are the only malaria parasite stage in humans transmissible to the mosquito vector. Anti-malarial drugs capable of killing these forms are considered essential for the eradication of malaria and tools allowing the screening of large compound libraries with high predictive power are needed to identify new candidates. As gametocytes are not a replicative stage it is difficult to apply the same drug screening methods used for asexual stages. Here we propose an assay, based on high content imaging, combining “classic” gametocyte viability readout based on gametocyte counts with a functional viability readout, based on gametocyte activation and the discrimination of the typical gamete spherical morphology. This simple and rapid assay has been miniaturized to a 384-well format using acridine orange staining of wild type P. falciparum 3D7A sexual forms and was validated by screening reference antimalarial drugs and the MMV Malaria Box. The assay demonstrated excellent robustness and ability to identify quality hits with high likelihood of confirmation of transmission reducing activity in subsequent mosquito membrane feeding assays.
Antimalarial 3-arylamino-6-benzylamino-1,2,4,5-tetrazines
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.BMCL.2010.06.036
Abstract: We report on novel 3-arylamino-6-benzylamino-1,2,4,5-tetrazines with potent activity against Plasmodium falciparum.
A facilitated approach to family case conferencing for people with advanced dementia living in nursing homes: Perceptions of Palliative Care Planning Coordinators and other health professionals in the IDEAL Study
Publisher: Cambridge University Press (CUP)
Date: 27-06-2017
DOI: 10.1017/S1041610217000977
Abstract: Palliative care for nursing home residents with advanced dementia is often sub-optimal due to poor communication and limited care planning. In a cluster randomized controlled trial, registered nurses (RNs) from 10 nursing homes were trained and funded to work as Palliative Care Planning Coordinators (PCPCs) to organize family case conferences and mentor staff. This qualitative sub-study aimed to explore PCPC and health professional perceptions of the benefits of facilitated case conferencing and identify factors influencing implementation. Semi-structured interviews were conducted with the RNs in the PCPC role, other members of nursing home staff, and physicians who participated in case conferences. Analysis was conducted by two researchers using a thematic framework approach. Interviews were conducted with 11 PCPCs, 18 other nurses, eight allied health workers, and three physicians. Perceived benefits of facilitated case conferencing included better communication between staff and families, greater multi-disciplinary involvement in case conferences and care planning, and improved staff attitudes and capabilities for dementia palliative care. Key factors influencing implementation included: staffing levels and time support from management, staff and physicians and positive family feedback. The facilitated approach explored in this study addressed known barriers to case conferencing. However, current business models in the sector make it difficult for case conferencing to receive the required levels of nursing qualification, training, and time. A collaborative nursing home culture and ongoing relationships with health professionals are also prerequisites for success. Further studies should document resident and family perceptions to harness consumer advocacy.
Naturally Acquired Kelch13 Mutations in Plasmodium falciparum Strains Modulate In Vitro Ring-Stage Artemisinin-Based Drug Tolerance and Parasite Survival in Response to
Publisher: American Society for Microbiology
Date: 26-10-2022
DOI: 10.1128/SPECTRUM.01282-21
Abstract: Artemisinin-based combination therapy (ACT) for treating malaria is under intense scrutiny following treatment failures in the Greater Mekong subregion of Asia. This is further compounded by the potential for extensive loss of life if treatment failures extend to the African continent.
Miniaturized Three-Dimensional Cancer Model for Drug Evaluation
Publisher: Mary Ann Liebert Inc
Date: 09-2013
DOI: 10.1089/ADT.2012.483
Abstract: A more relevant in vitro cell culture model that closely mimics tumor biology and provides better predictive information on anticancer therapies has been the focus of much attention in recent years. We have developed a three-dimensional (3D) human tumor cell culture model that attempts to recreate the in vivo microenvironment and tumor biology in a miniaturized 384-well plate format. This model aims to exploit the potential of 3D cell culture as a screening tool for novel therapeutics for discovery programs. Here we have evaluated a Matrigel™ based induction of 3D tumor formation using standard labware and plate reading equipment. We have demonstrated that with an optimized protocol, reproducible proliferation, and cell viability data can be obtained across a range of cell lines and reagent batches. A panel of reference drugs was used to validate the suitability of the assays for a high throughput drug discovery program. Indicators of assay reproducibility, such as Z'-factor and coefficient of variation, as well as dose response curves confirmed the robustness of the assays. Several methods of drug activity determination were examined, including metabolic and imaging based assays. These data demonstrate this model as a robust tool for drug discovery bridging the gap between monolayer cell culture and animal models, providing insights into drug efficacy at an earlier time point, ultimately reducing costs and high attrition rates.
Novel Conjugated Quinoline–Indoles Compromise Plasmodium falciparum Mitochondrial Function and Show Promising Antimalarial Activity
Publisher: American Chemical Society (ACS)
Date: 26-07-2013
DOI: 10.1021/JM400656S
Abstract: A novel class of antimalarial compounds, based on an indol-3-yl linked to the 2-position of a 4-aminoquinoline moiety, shows promising activity against the malaria parasite, Plasmodium falciparum . Compounds with a quaternary nitrogen on the quinoline show improved activity against the chloroquine-resistant K1 strain. Nonquaternerized 4-aminoquinolines retain significant potency but are relatively less active against the K1 strain. Alkylation of the 4-amino group preferentially improves the activity against the chloroquine-sensitive 3D7 strain. The quinoline-indoles show only weak activity as inhibitors of β-hematin formation, and their activities are only weakly antagonized by a hemoglobinase inhibitor. The compounds appear to dissipate mitochondrial potential as an early event in their antimalarial action and therefore may exert their activity by compromising Plasmodium mitochondrial function. Interestingly, we observed a structural relationship between our compounds and the anticancer and anthelminthic compound, pyrvinium pamoate, which has also been proposed to exert its action via compromising mitochondrial function.
Malaria high-content imaging, where to next?
Publisher: Elsevier BV
Date: 09-2023
Frailty assessment instruments in heart failure: A systematic review
Publisher: Oxford University Press (OUP)
Date: 04-05-2018
Abstract: Frailty is an independent predictor of mortality across many conditions. Reported rates of frailty in heart failure range from 15% to 74%. There are several instruments available to assess frailty however, to date there has been no consensus on the most appropriate instrument for use in in iduals with heart failure. To identify how frailty is assessed in in iduals with heart failure and to elucidate which domains of frailty are most frequently assessed. Key electronic databases were searched (MEDLINE, COCHRANE Central and CINAHL) to identify studies that assessed frailty in in iduals with heart failure using a formal frailty instrument. Twenty studies published in 24 articles were included, for which a total of seven unique frailty instruments were identified. The most commonly used instrument was the Frailty Phenotype ( n= 11), with the majority of studies using a modified version of the Frailty Phenotype ( n= 8). The second most commonly used instrument identified was the Comprehensive Geriatric Assessment ( n= 4). There is an increasing interest in the assessment of frailty, but, to date, there is no frailty instrument validated specifically in the heart failure population.
Impact of Laboratory-Adapted Intracellular Trypanosoma cruzi Strains on the Activity Profiles of Compounds with Anti-T. cruzi Activity
Publisher: MDPI AG
Date: 14-02-2023
DOI: 10.3390/MICROORGANISMS11020476
Abstract: Chagas disease is caused by infection with the protozoan parasite, Trypanosoma cruzi. The disease causes ~12,000 deaths annually and is one of the world’s 20 neglected tropical diseases, as defined by the World Health Organisation. The drug discovery pipeline for Chagas disease currently has few new clinical candidates, with high attrition rates an ongoing issue. To determine if the Trypanosoma cruzi strain utilised to assess in vitro compound activity impacts activity, a comparison of laboratory-adapted T. cruzi strains from differing geographical locations was undertaken for a selection of compounds with anti-T. cruzi activity. To minimise the possible effect of differences in experimental methodology, the same host cell and multiplicity of infection were utilised. To determine whether the compound exposure time influenced results, activity was determined following exposure for 48 and 72 h of incubation. To ascertain whether replication rates affected outcomes, comparative rates of replication of the T. cruzi strains were investigated, using the nucleoside analogue, 5-ethynyl-2′-deoxyuridine. Minimal differences in the in vitro activity of compounds between strains were observed following 48 h incubation, whereas significant differences were observed following 72 h incubation, in particular for the cytochrome P450 inhibitors tested and the cell cycle inhibitor, c tothecin. Thus, the use of panels of laboratory adapted strains in vitro may be dependent on the speed of action that is prioritised. For the identification of fast-acting compounds, an initial shorter duration assay using a single strain may be used. A longer incubation to identify compound activity may alternatively require profiling of compounds against multiple T. cruzi strains.
A New Quinoline Epoxide from the Australian PlantDrummondita calida
Publisher: Georg Thieme Verlag KG
Date: 06-04-2011
Abstract: A drug discovery program aimed at identifying new antimalarial leads from a prefractionated natural product library has resulted in the purification of a new quinoline alkaloid, (2' R)-2',3'-epoxy- N-methylatanine (1), along with eight known natural products, skimmianin, γ-fagarine, maculosidine, evolitrine, dictamnine, pteleine, N-methylatanine, and werneria chromene. Compound 1 displayed 74 % inhibition at 80 µM against a chloroquine -resistant Plasmodium falciparum strain (Dd2).
Iotrochamides A and B, antitrypanosomal compounds from the Australian marine sponge Iotrochota sp
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.BMCL.2012.05.029
Abstract: Bioassay-guided isolation of the CH(2)Cl(2)/MeOH extract from the Australian sponge Iotrochota sp. resulted in the purification of two new N-cinnamoyl-amino acids, iotrochamides A (1) and B (2). The chemical structures of 1 and 2 were determined by 1D/2D NMR and MS data analyses. Compounds 1 and 2 were shown to inhibit Trypanosoma brucei brucei with IC(50) values of 3.4 and 4.7 μM, respectively.
Development of an Alamar Blue™ viability assay in 384-well format for high throughput whole cell screening of Trypanosoma brucei brucei bloodstream form strain 427
Publisher: American Society of Tropical Medicine and Hygiene
Date: 10-2009
DOI: 10.4269/AJTMH.2009.09-0015
Abstract: There is an urgent need for new compounds for the drug development pipeline for treatment of patients with African sleeping sickness. One approach for identifying such compounds is by high throughput screening (HTS) of compound collections. For time and cost considerations, there is a need for the development of an assay that uses at least 384-well formats. To our knowledge, there are currently no viability assays for whole cell screening of trypanosomes in the 384-well plate format. We have developed and optimized an Alamar Blue viability assay in a 384-well format for Trypanosoma brucei brucei bloodstream form strain 427 (BS427). The assay had a Z' > 0.5 and tolerated a final dimethyl-sulfoxide concentration of 0.42%. Drug sensitivity was compared with those reported from previously developed 96-well methods and was found to be comparable. The sensitivity and cost benefit of the Alamar Blue assay make it an excellent candidate for HTS application.
Repositioning: the fast track to new anti-malarial medicines?
Publisher: Springer Science and Business Media LLC
Date: 14-04-2014
Innovative in vitro models for breast cancer drug discovery
Publisher: Elsevier BV
Date: 2016
Evaluating the convergent and discriminant validity of three versions of the frailty phenotype in heart failure: results from the FRAME-HF study
Publisher: Oxford University Press (OUP)
Date: 21-07-2020
Abstract: Frailty is an important predictive measure of mortality and rehospitalisation in people with heart failure. To date, there are no frailty instruments validated for use in people with heart failure. The aim of this study was to evaluate the convergent and discriminant validity of three versions of the frailty phenotype in those with heart failure. A single site, prospective cohort study was undertaken among in iduals with a confirmed diagnosis of heart failure. Frailty was assessed concurrently using three versions of the frailty phenotype: the original frailty phenotype and two modified versions the Survey of Health, Ageing and Retirement in Europe frailty instrument (SHARE-FI) and the St Vincent’s frailty instrument. Convergent and discriminant validity were assessed by reporting the correlations between each version and related heart failure subconstructs, and by evaluating the ability of each version to discriminate between normal and abnormal scores of other physical and psychosocial scales specific to heart failure-related subconstructs. The New York Heart Association classes were moderately correlated with the St Vincent’s frailty instrument ( r=0.47, P⩽0.001), SHARE-FI ( r=0.42, P⩽0.001) and the frailty phenotype ( r=0.42, P⩽0.001). The SHARE-FI and the St Vincent’s frailty instrument were both able to discriminate consistently between normal and abnormal scores in three out of five of the physical and psychosocial subconstructs that were assessed. The SHARE-FI was also able to discriminate between inpatients and outpatients who were classified as frail. Both the SHARE-FI and the St Vincent’s frailty instrument displayed good convergent and discriminant validity.
Endiandrin A, a Potent Glucocorticoid Receptor Binder Isolated from the Australian Plant Endiandra anthropophagorum
Publisher: American Chemical Society (ACS)
Date: 21-06-2007
DOI: 10.1021/NP070073X
Abstract: Bioassay-guided fractionation of the DCM extract from the roots of Endiandra anthropophagorum resulted in the isolation of a new cyclobutane lignan, endiandrin A (1), together with the known natural products nectandrin B (2) and (-)-dihydroguaiaretic acid (3). The structure of 1 was determined by extensive 1D and 2D NMR and MS data analyses. Acetylation and methylation of 1 yielded di-O-acetylendiandrin A (4) and di-O-methylendiandrin A (5), respectively. All compounds were tested in a glucocorticoid receptor binding assay and displayed IC50 values ranging from 0.9 to 35 microM.
Routine In Vitro Culture of Plasmodium falciparum: Experimental Consequences?
Publisher: Elsevier BV
Date: 07-2018
Abstract: The advent of Plasmodium falciparum (Pf) in vitro culturing opened the door for malaria research, yielding dramatic advancements in our understanding of the parasite. However, fundamental foundations taken for granted in our research endeavors can unknowingly be an Achilles heel, resulting in potential misdirection. In relation to malaria research, this could be our nonquestioning acceptance of routine in vitro culture of Pf. There is nothing routine or straightforward regarding the dynamic and intimate relationship between the parasite and the in vitro environment. Here, we discuss recent studies demonstrating the impact that slight variations in in vitro Pf culture parameters can have on scientific conclusions. We reason that culture conditions should be re-established as a primary consideration in in vitro malaria experimentation.
Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles
Publisher: American Chemical Society (ACS)
Date: 14-09-2016
Development of a cancer pain self-management resource to address patient, provider, and health system barriers to care.
Publisher: Cambridge University Press (CUP)
Date: 23-04-2019
DOI: 10.1017/S1478951518000792
Abstract: The majority of self-management interventions are designed with a narrow focus on patient skills and fail to consider their potential as “catalysts” for improving care delivery. A project was undertaken to develop a patient self-management resource to support evidence-based, person-centered care for cancer pain and overcome barriers at the levels of the patient, provider, and health system. The project used a mixed-method design with concurrent triangulation, including the following: a national online survey of current practice two systematic reviews of cancer pain needs and education a desktop review of online patient pain diaries and other related resources consultation with stakeholders and interviews with patients regarding acceptability and usefulness of a draft resource. Findings suggested that an optimal self-management resource should encourage pain reporting, build patients’ sense of control, and support communication with providers and coordination between services. Each of these characteristics was identified as important in overcoming established barriers to cancer pain care. A pain self-management resource was developed to include: (1) a template for setting specific, measureable, achievable, relevant and time-bound goals of care, as well as identifying potential obstacles and ways to overcome these and (2) a pain management plan detailing exacerbating and alleviating factors, current strategies for management, and contacts for support. Self-management resources have the potential for addressing barriers not only at the patient level, but also at provider and health system levels. A cluster randomized controlled trial is under way to test effectiveness of the resource designed in this project in combination with pain screening, audit and feedback, and provider education. More research of this kind is needed to understand how interventions at different levels can be optimally combined to overcome barriers and improve care.
Total Synthesis of the Antimalarial Ascidian Natural Product Albopunctatone
Publisher: American Chemical Society (ACS)
Date: 09-07-2019
DOI: 10.1021/ACS.ORGLETT.9B01838
Abstract: The first approaches to the 10'-anthronyl-2-anthraquinone skeleton have been devised, allowing two syntheses of the marine natural product albopunctatone. Both routes involve regioselective addition of a nucleophilic masked anthraquinone to a protected chrysazin derivative the best affords albopunctatone in five steps and 35% overall yield. Albopunctatone exhibits potent inhibitory activity against
The Novel bis-1,2,4-Triazine MIPS-0004373 Demonstrates Rapid and Potent Activity against All Blood Stages of the Malaria Parasite
Publisher: American Society for Microbiology
Date: 18-10-2021
DOI: 10.1128/AAC.00311-21
Abstract: Novel bis-1,2,4-triazine compounds with potent in vitro activity against Plasmodium falciparum parasites were recently identified. The bis-1,2,4-triazines represent a unique antimalarial pharmacophore and are proposed to act by a novel but as-yet-unknown mechanism of action.
Synthesis, antimalarial properties, and SAR studies of alkoxyurea-based HDAC inhibitors.
Publisher: Wiley
Date: 04-02-2014
Abstract: Histone deacetylase (HDAC) inhibitors are an emerging class of potential antimalarial drugs. We investigated the antiplasmodial properties of 16 alkoxyurea-based HDAC inhibitors containing various cap and zinc binding groups (ZBGs). Ten compounds displayed sub-micromolar activity against the 3D7 line of Plasmodium falciparum. Structure-activity relationship studies revealed that a hydroxamic acid ZBG is crucial for antiplasmodial activity, and that the introduction of bulky alkyl substituents to cap groups increases potency against asexual blood-stage parasites. We also demonstrate that selected compounds cause hyperacetylation of P. falciparum histone H4, indicating inhibition of one or more PfHDACs. To assess the selectivity of alkoxyurea-based HDAC inhibitors for parasite over normal mammalian cells, the cytotoxicity of representative compounds was evaluated against neonatal foreskin fibroblast (NFF) cells. The most active compound, 6-((3-(4-(tert-butyl)phenyl)ureido)oxy)-N-hydroxyhexanamide (1 e, Pf3D7 IC50 : 0.16 μM) was 31-fold more toxic against the asexual blood stages than towards normal mammalian cells. Moreover, a subset of four structurally erse HDAC inhibitors revealed moderate activity against late-stage (IV-V) gametocytes.
SC83288 is a clinical development candidate for the treatment of severe malaria
Publisher: Springer Science and Business Media LLC
Date: 31-01-2017
DOI: 10.1038/NCOMMS14193
Abstract: Severe malaria is a life-threatening complication of an infection with the protozoan parasite Plasmodium falciparum , which requires immediate treatment. Safety and efficacy concerns with currently used drugs accentuate the need for new chemotherapeutic options against severe malaria. Here we describe a medicinal chemistry program starting from amicarbalide that led to two compounds with optimized pharmacological and antiparasitic properties. SC81458 and the clinical development candidate, SC83288, are fast-acting compounds that can cure a P. falciparum infection in a humanized NOD/SCID mouse model system. Detailed preclinical pharmacokinetic and toxicological studies reveal no observable drawbacks. Ultra-deep sequencing of resistant parasites identifies the sarco/endoplasmic reticulum Ca 2+ transporting PfATP6 as a putative determinant of resistance to SC81458 and SC83288. Features, such as fast parasite killing, good safety margin, a potentially novel mode of action and a distinct chemotype support the clinical development of SC83288, as an intravenous application for the treatment of severe malaria.
Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides
Publisher: American Chemical Society (ACS)
Date: 19-09-2016
DOI: 10.1021/ACS.JMEDCHEM.6B00442
Abstract: The parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-(2-phenylthiazol-4-yl)ethyl)amides, carbamates, and ureas, which rapidly, selectively, and potently kill both species of trypanosome. The mode of action of these compounds is unknown but does not involve CYP51 inhibition. They do, however, exhibit clear structure-activity relationships, consistent across both trypanosome species. Favorable physicochemical parameters place the best compounds in CNS drug-like chemical space but, as a class, they exhibit poor metabolic stability. One of the best compounds (64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile cure achieved in one mouse. This family of compounds thus shows significant promise for trypanosomiasis drug discovery.
Mechanical clearance of red blood cells by the human spleen: Potential therapeutic applications of a biomimetic RBC filtration method
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.TRACLI.2015.05.004
Abstract: During their lifespan, circulating RBC are frequently checked for their deformability. This mechanical quality control operates essentially in the human spleen. RBC unable to squeeze though narrow splenic slits are retained and cleared from the blood circulation. Under physiological conditions this prevents microvessels from being clogged by senescent, rigid RBC. Retention of poorly deformable RBC is an important determinant of pathogenesis in malaria and may also impact the clinical benefit of transfusion. Modulating the splenic retention of RBC has already been proposed to support therapeutic approaches in these research fields. To this aim, the development of microplates for high throughput filtration of RBC through microsphere layers (microplate-based microsphiltration) has been undertaken. This review focuses on potential therapeutic applications provided by this technology in malaria chemotherapy and transfusion.
Erratum to Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites [Int. J. Parasitol. Drugs Drug Res. 5 (2015) 117-126].
Publisher: Elsevier BV
Date: 12-2016
The need to compare: assessing the level of agreement of three high-throughput assays against Plasmodium falciparum mature gametocytes
Publisher: Springer Science and Business Media LLC
Date: 05-04-2017
DOI: 10.1038/SREP45992
Abstract: Whole-cell High-Throughput Screening (HTS) is a key tool for the discovery of much needed malaria transmission blocking drugs. Discrepancies in the reported outcomes from various HTS Plasmodium falciparum gametocytocidal assays hinder the direct comparison of data and ultimately the interpretation of the transmission blocking potential of hits. To dissect the underlying determinants of such discrepancies and assess the impact that assay-specific factors have on transmission-blocking predictivity, a 39-compound subset from the Medicines for Malaria Venture Malaria Box was tested in parallel against three distinct mature stage gametocytocidal assays, under strictly controlled parasitological, chemical, temporal and analytical conditions resembling the standard membrane feeding assay (SMFA). Apart from a few assay-specific outliers, which highlighted the value of utilizing multiple complementary approaches, good agreement was observed (average ΔpIC 50 of 0.12 ± 0.01). Longer compound incubation times improved the ability of the least sensitive assay to detect actives by 2-fold. Finally, combining the number of actives identified by any single assay with those obtained at longer incubation times yielded greatly improved outcomes and agreement with SMFA. Screening compounds using extended incubation times and using multiple in vitro assay technologies are valid approaches for the efficient identification of biologically relevant malaria transmission blocking hits.
Citronamine A, an Antiplasmodial Isoquinoline Alkaloid from the Australian Marine Sponge Citronia astra
Publisher: American Chemical Society (ACS)
Date: 24-11-2020
Recent highlights in anti-protozoan drug development and resistance research
Publisher: Elsevier BV
Date: 12-2012
Pimentelamines A–C, Indole Alkaloids Isolated from the Leaves of the Australian Tree Flindersia pimenteliana
Publisher: American Chemical Society (ACS)
Date: 13-12-2017
DOI: 10.1021/ACS.JNATPROD.7B00587
Abstract: Three members of a new class of ascorbic acid-adduct indole alkaloids (1-3), a new prenylated indole alkaloid (4), and five known compounds (5-9) were isolated from the leaves of Flindersia pimenteliana. The structures of 1-4 were elucidated on the basis of their (+)-HRESIMS and 2D NMR spectroscopic data. Antiplasmodial activity was also reported for the natural products against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum with IC
α-Synuclein Aggregation Inhibitory Prunolides and a Dibrominated β-Carboline Sulfamate from the Ascidian Synoicum prunum
Publisher: American Chemical Society (ACS)
Date: 20-01-2022
DOI: 10.1021/ACS.JNATPROD.1C01172
Abstract: Seven new polyaromatic bis-spiroketal-containing butenolides, the prunolides D-I (
Wilsoniamines A and B: novel alkaloids from the temperate Australian bryozoan, Amathia wilsoni
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0OB00538J
Abstract: Two novel alkaloids, wilsoniamines A and B, both possessing a hexahydropyrrolo[1,2-c]imidazol-1-one ring system that has not previously been found in nature, together with a new alkaloid, amathamide H and a known alkaloid, amathamide C were isolated from the temperate Australian bryozoan, Amathia wilsoni. MS and NMR analysis established the structure of the new compounds and indicated that the structure of amathamide C and several related compounds be revised. Amathamides C and H showed moderate anti-malarial and anti-trypanosomal activity.
Ask the Experts: Drug discovery for the treatment of leishmaniasis, African sleeping sickness and Chagas disease
Publisher: Future Science Ltd
Date: 10-2013
DOI: 10.4155/FMC.13.161
Abstract: The trypanosomatid protozoa Leishmania, Trypanosoma brucei and Trypanosoma cruzi are the caustive agents of the human diseases respectively, leishmaniasis, African sleeping sickness and Chagas disease. Among the 17 ‘neglected tropical diseases’ highlighted by WHO, progress towards the treatment of these diseases has improved in recent decades, as a result of increased awareness, the emergence of public–private research partnerships and advances in drug-discovery technologies and techniques. Despite this, the current therapies for these diseases have serious shortcomings and, as such, the need to develop novel drugs, improve diagnosis and control the spread of disease is of paramount importance. Future Medicinal Chemistry invited leading experts in the field to share their thoughts and opinions on the changing face of drug discovery in the pursuit of treatments for trypanosomatid-based diseases.
3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential
Publisher: American Chemical Society (ACS)
Date: 21-03-2012
DOI: 10.1021/JM3001373
Abstract: A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure-activity studies identified a number of promising compounds with selective antiplasmodial activity. One of these frontrunner compounds, 15, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC(50) K1 = 194.0 nM). Compound 15 completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose-response studies generated ED(50) and ED(90) values of 0.83 and 1.74 mg/kg for 15 in the standard four-dose Peters test. Pharmacokinetic studies in the rat indicated that this compound has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life (t(1/2) ∼ 7-8 h).
Detection of complement protein mRNA in human astrocytes by the polymerase chain reaction
Publisher: Elsevier BV
Date: 12-1992
DOI: 10.1016/0165-0270(92)90076-P
Abstract: Primer sets specific for complement proteins, C3, factor B and factor I, were designed and used to lify cDNA from cultured human astrocyte mRNA by the polymerase chain reaction. Appropriately sized PCR products of 506 bp, 885 bp and 146 bp, respectively, were generated and specificity was confirmed with Southern blotting using an enhanced chemiluminescence detection system. The sensitivity of detection was high, with lified product from cDNA of approximately 6250 cells readily visualized. C3 and factor B have previously been reported to be produced by murine astrocytes however, this is the first report indicating synthesis of C3, factor B and factor I by human astrocytes. These results indicate that PCR is a simple and sensitive technique to detect mRNA transcripts for proteins of the alternative pathway of complement in human astrocytes.
Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules
Publisher: American Society for Microbiology
Date: 07-2014
DOI: 10.1128/AAC.02721-13
Abstract: Therapies to prevent transmission of malaria parasites to the mosquito vector are a vital part of the global malaria elimination agenda. Primaquine is currently the only drug with such activity however, its use is limited by side effects. The development of transmission-blocking strategies requires an understanding of sexual stage malaria parasite (gametocyte) biology and the identification of new drug leads. Lysine acetylation is an important posttranslational modification involved in regulating eukaryotic gene expression and other essential processes. Interfering with this process with histone deacetylase (HDAC) inhibitors is a validated strategy for cancer and other diseases, including asexual stage malaria parasites. Here we confirm the expression of at least one HDAC protein in Plasmodium falciparum gametocytes and show that histone and nonhistone protein acetylation occurs in this life cycle stage. The activity of the canonical HDAC inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA Vorinostat) and a panel of novel HDAC inhibitors on early/late-stage gametocytes and on gamete formation was examined. Several compounds displayed early/late-stage gametocytocidal activity, with TSA being the most potent (50% inhibitory concentration, 70 to 90 nM). In contrast, no inhibitory activity was observed in P. falciparum gametocyte exflagellation experiments. Gametocytocidal HDAC inhibitors caused hyperacetylation of gametocyte histones, consistent with a mode of action targeting HDAC activity. Our data identify HDAC inhibitors as being among a limited number of compounds that target both asexual and sexual stage malaria parasites, making them a potential new starting point for gametocytocidal drug leads and valuable tools for dissecting gametocyte biology.
New Galloylated Flavanonols from the Australian Plant Glochidion sumatranum
Publisher: Georg Thieme Verlag KG
Date: 07-2010
Abstract: Bioassay-guided fractionation of the CH(2)Cl(2)/MeOH extract from the Australian plant Glochidion sumatranum resulted in the isolation of four new galloylated flavanonols, (2R,3R)-dihydromyricetin-4'-O-(3''-O-methyl)-gallate (1), (2R,3R)-dihydromyricetin-3'-O-(3''-O-methyl)-gallate (2), (2R,3R)-dihydromyricetin-4'-O-gallate (3), and (2R,3R)-dihydromyricetin-3'-O-gallate (4), along with the known compound, (2R,3R)-dihydromyricetin (5). The structures of 1-5 were determined by NMR and MS analysis and their absolute configuration was elucidated by comparison of the CD data with literature values. Compounds 1/2 and 3/4 are two pairs of structural isomers that were shown to interconvert by transesterification during NMR and LC-MS studies. This process involved the intramolecular migration of the galloyl moieties between C-3' and C-4' of the flavanonol skeleton. Compounds 1 and 3 were identified as the more stable isomers. Compounds 1, 3, and 5 showed weak activity against the gram-negative bacterium Pseudomonas aeruginosa and the gram-positive bacterium Staphylococcus aureus.
Identification of inhibitors of Plasmodium falciparum gametocyte development
Publisher: Springer Science and Business Media LLC
Date: 11-11-2013
Synthesis and Evaluation of the Tetracyclic Ring-System of Isocryptolepine and Regioisomers for Antimalarial, Antiproliferative and Antimicrobial Activities
Publisher: MDPI AG
Date: 30-05-2021
DOI: 10.3390/MOLECULES26113268
Abstract: A series of novel quinoline-based tetracyclic ring-systems were synthesized and evaluated in vitro for their antiplasmodial, antiproliferative and antimicrobial activities. The novel hydroiodide salts 10 and 21 showed the most promising antiplasmodial inhibition, with compound 10 displaying higher selectivity than the employed standards. The antiproliferative assay revealed novel pyridophenanthridine 4b to be significantly more active against human prostate cancer (IC50 = 24 nM) than Puromycin (IC50 = 270 nM) and Doxorubicin (IC50 = 830 nM), which are used for clinical treatment. Pyridocarbazoles 9 was also moderately effective against all the employed cancer cell lines and moreover showed excellent biofilm inhibition (9a: MBIC = 100 µM 9b: MBIC = 100 µM).
Hemin Prevents Increased Glycolysis in Macrophages upon Activation: Protection by Microbiota-Derived Metabolites of Polyphenols
Publisher: MDPI AG
Date: 11-11-2020
Abstract: Meat consumption plays a critical role in the development of several types of cancer. Hemin, a metabolite of myoglobin produced after meat intake, has been demonstrated to be involved in the cancer initiation phase. Macrophages are key components of the innate immunity, which, upon activation, can prevent cancer development by eliminating neoplastic cells. Metabolic reprogramming, characterized by high glycolysis and low oxidative phosphorylation, is critical for macrophage activation. 3,4-dihydroxyphenylacetic acid (3,4DHPAA) and 4-hydroxyphenylacetic acid (4HPAA), both microbiota-derived metabolites of flavonoids, have not been extensively studied although they exert antioxidant properties. The aim of this study was to determine the effect of hemin on the anticancer properties of macrophages and the role of 3,4DHPAA and 4HPAA in metabolic reprogramming and activation of macrophages leading to the elimination of cancer cells. The results showed that hemin inhibited glycolysis, glycolytic, and pentose phosphate pathway (PPP) enzyme activities and hypoxia-inducible factor-1 alpha (HIF-1α) stabilization, which interferes with macrophage activation (evidenced by decreased interferon-γ-inducible protein 10 (IP-10) release) and their ability to eliminate cancer cells (via cytotoxic mediators and phagocytosis). Hemin also reduced the mitochondrial membrane potential (MMP) and mitochondrial mass in macrophages. 3,4DHPAA and 4HPAA, by stimulating glycolysis and PPP, prevented the impairment of the macrophage anticancer activity induced by hemin. In conclusion, 3,4HPAA and 4HPAA administration could represent a promising strategy for preventing the reduction of macrophage activation induced by hemin.
Target Validation and Identification of Novel Boronate Inhibitors of the Plasmodium falciparum Proteasome
Publisher: American Chemical Society (ACS)
Date: 29-10-2018
Large-scale production of Plasmodium falciparum gametocytes for malaria drug discovery
Publisher: Springer Science and Business Media LLC
Date: 28-04-2016
Abstract: The tightly controlled induction of Plasmodium falciparum gametocytes in large-scale culture is a fundamental requirement for malaria drug discovery applications including, but not limited to, high-throughput screening. This protocol uses magnetic separation for isolation of hemozoin-containing parasites in order to (i) increase parasitemia, (ii) decrease hematocrit and (iii) introduce higher levels of young red blood cells in a culture simultaneously within 2-4 h. These parameters, along with red blood cell lysis products that are generated through schizont rupture, are highly relevant for enabling optimum induction of gametocytogenesis in vitro. No other previously published protocols have applied this particular approach for parasite isolation and maximization of fresh red blood cells before inducing gametocytogenesis, which is essential for obtaining highly synchronous gametocyte classical stages on a large scale. In summary, 500-1,000 million stage IV gametocytes can be obtained within 16 d from an initial 10 ml of asexual blood-stage culture.
Citronamides A and B, Tetrapeptides from the Australian Sponge Citronia astra
Publisher: American Chemical Society (ACS)
Date: 04-03-2009
DOI: 10.1021/NP800832W
Abstract: Two new linear tetrapeptides, citronamides A (1) and B (2), were isolated from the Australian sponge Citronia astra and their structures determined by 1D and 2D NMR spectroscopy. The peptides contain two previously unreported amino acids, 3-(2-oxo-2,3-dihydro-1H-imidazol-4-yl)serine and 6-amino-7-(4-methoxyphenyl)heptanoic acid, and alpha-iduronic acid modified at either C-3 or C-4 with a carbamate. Citronamide A showed moderate antifungal activity against Saccharomyces cerevisiae.
Sexual and Apomictic Seed Formation in Hieracium Requires the Plant Polycomb-Group Gene FERTILIZATION INDEPENDENT ENDOSPERM
Publisher: Oxford University Press (OUP)
Date: 09-2008
Abstract: A Polycomb-Group (PcG) complex, FERTILIZATION INDEPENDENT SEED (FIS), represses endosperm development in Arabidopsis thaliana until fertilization occurs. The Hieracium genus contains apomictic species that form viable seeds asexually. To investigate FIS function during apomictic seed formation, FERTILIZATION INDEPENDENT ENDOSPERM (FIE), encoding a WD-repeat member of the FIS complex, was isolated and downregulated in sexual and apomictic Hieracium species. General downregulation led to defects in leaf and seed development, consistent with a role in developmental transitions and cell fate. PcG-like activity of Hieracium FIE was also supported by its interaction in vitro with the Arabidopsis CURLY LEAF PcG protein. By contrast, specific downregulation of FIE in developing seeds of sexual Hieracium did not result in autonomous endosperm proliferation but led to seed abortion after cross-pollination. Furthermore, in apomictic Hieracium, specific FIE downregulation inhibited autonomous embryo and endosperm initiation, and most autonomous seeds displayed defective embryo and endosperm growth. Therefore, FIE is required for both apomictic and fertilization-induced seed initiation in Hieracium. Since Hieracium FIE failed to interact with FIS class proteins in vitro, its partner proteins might differ from those in the FIS complex of Arabidopsis. These differences in protein interaction were attributed to structural modifications predicted from comparisons of Arabidopsis and Hieracium FIE molecular models.
Plasmodium falciparum in vitro continuous culture conditions: A comparison of parasite susceptibility and tolerance to anti-malarial drugs throughout the asexual intra-erythrocytic life cycle
Publisher: Elsevier BV
Date: 12-2017
Successful Doctoral Training in Nursing and Health Sciences: A Guide for Supervisors, Students and Advisors
Publisher: Springer International Publishing
Date: 2022
Health-related quality of life in people with advanced dementia: a comparison of EQ-5D-5L and QUALID instruments.
Publisher: Springer Science and Business Media LLC
Date: 05-09-2019
DOI: 10.1007/S11136-018-1987-0
Abstract: Assessing health-related quality of life (HRQOL) in people with advanced dementia is challenging but important for informed decision-making. Proxy measurement of this construct is difficult and is often rated lower than self-report. Accurate proxy rating of quality of life in dementia is related to identification of concepts important to the person themselves, as well as the sensitivity of the measures used. The main aim of this study was to compare the performance of two instruments-QUALID and EQ-5D-5L-on measuring HRQOL in people with advanced dementia. In a sub-study nested within a cluster-RCT we collected proxy(nurse)-completed EQ-5D-5L and QUALID measures at baseline, 3, 6, 9 and 12 months' follow-up for people with advanced dementia, residing in 20 nursing homes across Australia. Spearman's rank correlations, partial correlations and linear regressions were used to assess the relationship between the HRQOL instrument scores and their changes over time. The mean weight from 284 people for the EQ-5D-5L and QUALID at baseline were 0.004 (95% CI - 0.026, 0.033) and 24.98 (95% CI 24.13, 25.82), respectively. At 12 months' follow-up, 115 participants remained alive. EQ-5D-5L weights and QUALID scores at baseline and at follow-up were moderately correlated (r = - 0.437 p < 0.001 at 12 months). Changes within QUALID and EQ-5D-5L across the same follow-up periods were also correlated (r = - 0.266 p = 0.005). The regression analyses support these findings. Whilst these quality of life instruments demonstrated moderate correlation, the EQ-5D-5L does not appear to capture all aspects of quality of life that are relevant to people with advanced dementia and we cannot recommend the use of this instrument for use within this population. The QUALID appears to be a more suitable instrument for measuring HRQOL in people with severe dementia, but is not preference-based, which limits its application in economic evaluations of dementia care.
Aminoazabenzimidazoles, a Novel Class of Orally Active Antimalarial Agents
Publisher: American Chemical Society (ACS)
Date: 24-06-2014
DOI: 10.1021/JM500535J
Pim2 Inhibitors from the Papua New Guinean Plant Cupaniopsis macropetala
Publisher: American Chemical Society (ACS)
Date: 25-10-0012
DOI: 10.1021/NP070431W
Abstract: Bioassay-guided fractionation of an organic extract from the leaves of Cupaniopsis macropetala resulted in the isolation of a new alkaloid, galloyl tyramine ( 1), together with the known flavonoid glycoside quercitrin ( 2). The structure of 1 was determined following 1D and 2D NMR, IR, UV, and MS data analysis. Compounds 1 and 2 displayed IC 50 values of 161 and 25 microM, respectively, in a Pim2 enzyme assay.
Cascade reactions of indigo with oxiranes and aziridines: efficient access to dihydropyrazinodiindoles and spiro-oxazocinodiindoles
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8OB00865E
Abstract: Cascade reactions of indigo with strained electrophiles affords access to previously unknown oxazocino, pyrazino, and diazepino diindoles with selective anti-plasmodial activity.
Sertraline in symptomatic chronic breathlessness: a double blind, randomised trial
Publisher: European Respiratory Society
Date: 15-09-2018
Aplysamine 6, an Alkaloidal Inhibitor of Isoprenylcysteine Carboxyl Methyltransferase from the Sponge Pseudoceratina sp.
Publisher: American Chemical Society (ACS)
Date: 05-04-2008
DOI: 10.1021/NP0706623
Abstract: The anticancer target isoprenylcysteine carboxyl methyltransferase (Icmt) was the focus of a natural product high-throughput screening c aign. The Australian marine sponge Pseudoceratina sp. yielded aplysamine 6, a new bromotyrosine derivative with an alpha,beta-unsaturated amide linkage, as the bioactive constituent. Its structure was determined by 1D and 2D NMR spectroscopy.
Chemokine receptor expression on integrin-mediated stellate projections of prostate cancer cells in 3D culture
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.CYTO.2013.07.012
Abstract: The chemokine receptor CXCR7 has emerged as a regulator of prostate tumor growth and invasion, along with the well-established role of its closely related receptor, CXCR4, and their shared ligand, SDF-1α. Consequently, inhibition of the CXCR7/CXCR4/SDF-1α axis may assist in controlling prostate tumor growth and progression. To facilitate the development of potential therapeutics, further clarification of CXCR7 function is required, specifically in relation to CXCR4. In this study, we report that CXCR7 and CXCR4 were co-expressed in LNCaP, DU145 and PC3 cell lines in 2D culture. When cultured in 3D using Matrigel, a marked up-regulation of both receptors was observed in PC3 cells. Interestingly, both CXCR7 and CXCR4 co-localized within radiating cellular structures, termed stellate projections, which protruded outward into the matrix. The stellate projections were rich in the expression of pro-invasive integrin β1, β-laminin and MMP-11 proteins. The development of the stellate projections was mediated by integrin β1-mediated interactions with the ECM, which also regulated the expression of CXCR7 and CXCR4. Taken together, these results demonstrate that integrin-mediated cell-ECM interactions can modulate tumor cell morphology, and regulate the expression of chemokine receptors which are associated with the invasive phenotype and progression of PCa.
A survey of critical care nurses’ knowledge of intra-abdominal hypertension and abdominal compartment syndrome
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.AUCC.2016.02.001
Abstract: Intra-abdominal hypertension and abdominal compartment syndrome are potentially life threatening conditions. Critical care nurses need to understand the factors that predispose patients to intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS). Predicting and managing IAH and ACS are important to improve health outcomes. The aim of this paper was to (1) assess the knowledge of Australian critical care nurses about current IAH and ACS practice guidelines, measurement techniques, predictors for the development of IAH and ACS and (2) identify barriers in recognizing IAH, ACS and measuring IAP. Between October 2014 and April 2015 86 registered nurses employed in the area of critical care were recruited via the form to participate in an on-line, 19-item questionnaire. The survey was distributed to critical care nurses via the Australian College of Critical Care Nurses (ACCCN) mailing list and directly to intensive care units via The majority of participants were women (n=62) all participants were registered nurses employed in critical care the response rate was 3.2%. The study design was used to establish demographic data, employment data, and in iduals' knowledge related to IAH and ACS. Participants had the option to write hand written responses in addition to selecting a closed question response. The results showed that most survey participants were able to identify some obvious causes of IAH. However, less than 20% were able to recognize less apparent indices of risk. A lack of education related to IAP monitoring was identified by nearly half (44.2%) of respondents as the primary barrier to monitoring IAP. Critical care clinicians' knowledge of IAH and ACS is generally low in the areas of presentation and outcomes of IAH and ACS requiring tailored and targeted educational interventions.
Convolutamines I and J, antitrypanosomal alkaloids from the bryozoan Amathia tortusa
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.BMC.2011.06.006
Abstract: Mass-directed isolation of the CH(2)Cl(2)/CH(3)OH extract from the marine bryozoan Amathia tortusa resulted in the purification of two new brominated alkaloids, convolutamines I (1) and J (2). The structures of 1 and 2 were determined following spectroscopic data analysis. Both compounds were isolated during a drug discovery program aimed at identifying new antitrypanosomal leads from a prefractionated natural product library. Compounds 1 and 2 were shown to be active toward the parasite Trypanosoma brucei brucei with IC(50) values of 1.1 and 13.7 μM, respectively. Preliminary toxicity profiling was also performed on both 1 and 2 using the human embryonic kidney cell line, HEK293. Compound 1 was shown to exhibit cytotoxicity against HEK293 with an IC(50) of 22.0 μM whilst 2 was inactive at 41.0 μM.
Screening the Medicines for Malaria Venture Pathogen Box across Multiple Pathogens Reclassifies Starting Points for Open-Source Drug Discovery
Publisher: American Society for Microbiology
Date: 09-2017
DOI: 10.1128/AAC.00379-17
Abstract: Open-access drug discovery provides a substantial resource for diseases primarily affecting the poor and disadvantaged. The open-access Pathogen Box collection is comprised of compounds with demonstrated biological activity against specific pathogenic organisms. The supply of this resource by the Medicines for Malaria Venture has the potential to provide new chemical starting points for a number of tropical and neglected diseases, through repurposing of these compounds for use in drug discovery c aigns for these additional pathogens. We tested the Pathogen Box against kinetoplastid parasites and malaria life cycle stages in vitro . Consequently, chemical starting points for malaria, human African trypanosomiasis, Chagas disease, and leishmaniasis drug discovery efforts have been identified. Inclusive of this in vitro biological evaluation, outcomes from extensive literature reviews and database searches are provided. This information encompasses commercial availability, literature reference citations, other aliases and ChEMBL number with associated biological activity, where available. The release of this new data for the Pathogen Box collection into the public domain will aid the open-source model of drug discovery. Importantly, this will provide novel chemical starting points for drug discovery and target identification in tropical disease research.
Ianthelliformisamines A-C, Antibacterial Bromotyrosine-Derived Metabolites from the Marine Sponge Suberea ianthelliformis
Publisher: American Chemical Society (ACS)
Date: 19-04-2012
DOI: 10.1021/NP300147D
Abstract: A high-throughput screening c aign using a prefractionated natural product library and an in vitro Pseudomonas aeruginosa (PAO200 strain) assay identified two antibacterial fractions derived from the marine sponge Suberea ianthelliformis. Mass-directed isolation of the CH(2)Cl(2)/CH(3)OH extract from S. ianthelliformis resulted in the purification of three new bromotyrosine-derived metabolites, ianthelliformisamines A-C (1-3), together with the known natural products aplysamine 1 (4) and araplysillin I (5). The structures of 1-3 were determined following analysis of 1D and 2D NMR and MS spectroscopic data. This is the first report of chemistry from the marine sponge S. ianthelliformis. Ianthelliformisamine A (1) showed inhibitory activity against the Gram-negative bacterium P. aeruginosa with an IC(50) value of 6.8 μM (MIC = 35 μM).
Design and Synthesis of Terephthalic Acid‐Based Histone Deacetylase Inhibitors with Dual‐Stage Anti‐Plasmodium Activity
Publisher: Wiley
Date: 13-09-2017
Abstract: In this work we aimed to develop parasite-selective histone deacetylase inhibitors (HDAC) inhibitors with activity against the disease-causing asexual blood stages of Plasmodium as well as causal prophylactic and/or transmission blocking properties. We report the design, synthesis, and biological testing of a series of 13 terephthalic acid-based HDAC inhibitors. All compounds showed low cytotoxicity against human embryonic kidney (HEK293) cells (IC
Leptoclinidamines A−C, Indole Alkaloids from the Australian Ascidian Leptoclinides durus
Publisher: American Chemical Society (ACS)
Date: 23-02-2009
DOI: 10.1021/NP800831Z
Abstract: Three new indole alkaloids, leptoclinidamines A-C (1-3), were isolated from the Australian ascidian Leptoclinides durus. Their structures were determined by analysis of 2D NMR spectra. Leptoclinidamines A and B both contain an indoleglyoxylic acid attached to an L-arginine. The structure of leptoclinidamine A was confirmed by total synthesis. Leptoclinidamine C contains the naturally rare 1,3-dimethyl-5-(methylthio)histidine attached to a 6-bromoindole-3-carboxylic acid. Leptoclinidamine C (3) and both enantiomers of leptoclinidamine A (1) were tested for antimalarial, antitrypanosomal, and cytotoxic activity, but none of the compounds were bioactive.
Euodenine A: A Small-Molecule Agonist of Human TLR4
Publisher: American Chemical Society (ACS)
Date: 07-02-2014
DOI: 10.1021/JM401321V
Abstract: A small-molecule natural product, euodenine A (1), was identified as an agonist of the human TLR4 receptor. Euodenine A was isolated from the leaves of Euodia asteridula (Rutaceae) found in Papua New Guinea and has an unusual U-shaped structure. It was synthesized along with a series of analogues that exhibit potent and selective agonism of the TLR4 receptor. SAR development around the cyclobutane ring resulted in a 10-fold increase in potency. The natural product demonstrated an extracellular site of action, which requires the extracellular domain of TLR4 to stimulate a NF-κB reporter response. 1 is a human-selective agonist that is CD14-independent, and it requires both TLR4 and MD-2 for full efficacy. Testing for immunomodulation in PBMC cells shows the induction of the cytokines IL-8, IL-10, TNF-α, and IL-12p40 as well as suppression of IL-5 from activated PBMCs, indicating that compounds like 1 could modulate the Th2 immune response without causing lung damage.
Small-molecule inhibitors of the cancer target, isoprenylcysteine carboxyl methyltransferase, from Hovea parvicalyx
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1016/J.PHYTOCHEM.2008.04.011
Abstract: Isoprenylcysteine carboxyl methyltransferase (Icmt) is enzyme target in anticancer drug discovery. An Icmt natural product high-throughput screening c aign was conducted and a hit extract from the roots of Hovea parvicalyx was identified. 2'-Methoxy-3'-prenyl-licodione and 2'-methoxy-3',3''-diprenyl-licodione, two prenylated beta-hydroxychalcone compounds, together with the known flavanone (S)-glabrol, were isolated and identified as bioactive constituents. Their structures were determined largely by 1D and 2D NMR spectroscopy.
Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility
Publisher: American Chemical Society (ACS)
Date: 05-11-2020
Antimalarial Benzylisoquinoline Alkaloid from the Rainforest Tree Doryphora sassafras
Publisher: American Chemical Society (ACS)
Date: 28-07-2009
DOI: 10.1021/NP9002564
Abstract: Mass-directed isolation of the CH(2)Cl(2)/MeOH extract of Doryphora sassafras resulted in the purification of a new benzylisoquinoline alkaloid, 1-(4-hydroxybenzyl)-6,7-methylenedioxy-2-methylisoquinolinium trifluoroacetate (1), and the known aporphine alkaloid (S)-isocorydine (2). The structures of 1 and 2 were determined by 1D and 2D NMR and MS data analyses. The compounds were isolated during a drug discovery program aimed at identifying new antimalarial leads from a prefractionated natural product library. When tested against two different strains of the parasite Plasmodium falciparum (3D7 and Dd2), 1 displayed IC(50) values of 3.0 and 4.4 microM, respectively. Compound 1 was tested for cytotoxicity toward a human embryonic kidney cell line (HEK293) and displayed no activity at 120 microM.
Identifying common metalloprotease inhibitors by protein fold types using Fourier Transform Mass Spectrometry
Publisher: Elsevier BV
Date: 12-2007
DOI: 10.1016/J.BMCL.2007.09.084
Abstract: Fourteen natural products, known to inhibit other proteins of the Zincin-like fold class, were screened for inhibition of the Zincin-like fold metalloprotease thermolysin using mass spectrometry. Fourier Transform Mass Spectrometry was successful in identifying actinonin, a known inhibitor of astacin and stromelysin, to be an inhibitor of thermolysin. Molecular modelling studies have shown that specificity within the Zincin-like fold is determined by Protein Fold Topology.
Quinolone-3-Diarylethers: A New Class of Antimalarial Drug
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-03-2013
DOI: 10.1126/SCITRANSLMED.3005029
Abstract: ELQ-300, an investigational drug for treating and preventing malaria, shows potent transmission-blocking activity in rodent models of malaria.
Advanced Cell Culture Techniques for Cancer Drug Discovery
Publisher: MDPI AG
Date: 30-05-2014
Repositioning and Characterization of 1-(Pyridin-4-yl)pyrrolidin-2-one Derivatives as Plasmodium Cytoplasmic Prolyl-tRNA Synthetase Inhibitors
Publisher: American Chemical Society (ACS)
Date: 30-04-2021
Progress toward establishing an open access molecular screening capability in the Australasian region
Publisher: American Chemical Society (ACS)
Date: 12-2007
DOI: 10.1021/CB7002384
A novel approach for the discovery of chemically diverse anti-malarial compounds targeting the Plasmodium falciparum Coenzyme A synthesis pathway
Publisher: Springer Science and Business Media LLC
Date: 31-08-2014
Identification of Compounds with Anti-Proliferative Activity against Trypanosoma brucei brucei Strain 427 by a Whole Cell Viability Based HTS Campaign
Publisher: Public Library of Science (PLoS)
Date: 29-11-2012
Splenic Retention of Plasmodium falciparum Gametocytes To Block the Transmission of Malaria
Publisher: American Society for Microbiology
Date: 07-2015
DOI: 10.1128/AAC.05030-14
Abstract: Plasmodium falciparum is transmitted from humans to Anopheles mosquito vectors via the sexual erythrocytic forms termed gametocytes. Erythrocyte filtration through microsphere layers (microsphiltration) had shown that circulating gametocytes are deformable. Compounds reducing gametocyte deformability would induce their splenic clearance, thus removing them from the blood circulation and blocking malaria transmission. The hand-made, single-s le prototype for microsphiltration was miniaturized to a 96-well microtiter plate format, and gametocyte retention in the microsphere filters was quantified by high-content imaging. The stiffening activity of 40 pharmacological compounds was assessed in microtiter plates, using a small molecule (calyculin) as a positive control. The stiffening activity of calyculin was assessed in spleen-mimetic microfluidic chips and in macrophage-depleted mice. Marked mechanical retention (80% to 90%) of mature gametocytes was obtained in microplates following exposure to calyculin at concentrations with no effect on parasite viability. Of the 40 compounds tested, including 20 antimalarials, only 5 endoperoxides significantly increased gametocyte retention (1.5- to 2.5-fold 24 h of exposure at 1 μM). Mature gametocytes exposed to calyculin accumulated in microfluidic chips and were cleared from the circulation of macrophage-depleted mice as rapidly as heat-stiffened erythrocytes, thus confirming results obtained using the microsphiltration assay. An automated miniaturized approach to select compounds for their gametocyte-stiffening effect has been established. Stiffening induces gametocyte clearance both in vitro and in vivo . Based on physiologically validated tools, this screening cascade can identify novel compounds and uncover new targets to block malaria transmission. Innovative applications in hematology are also envisioned.
Synthesis and evaluation of phenoxymethylbenzamide analogues as anti-trypanosomal agents
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4MD00406J
Abstract: The synthesis of a compound library based on a high throughput screening hit led to the discovery of several potent anti-trypanosomal agents.
Sulfide, sulfoxide and sulfone bridged acyclic nucleoside phosphonates as inhibitors of the Plasmodium falciparum and human 6-oxopurine phosphoribosyltransferases: Synthesis and evaluation
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.EJMECH.2019.111667
Abstract: Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is a recognized target for antimalarial chemotherapeutics. It synthesises all of the 6-oxopurine nucleoside monophosphates, IMP, GMP and XMP needed by the malarial parasite, Plasmodium falciparum (Pf). PfHGXPRT is also indirectly responsible for the synthesis of the adenosine monophosphate, AMP. The acyclic nucleoside phosphonates (ANPs) are a class of PfHGXPRT inhibitors. Prodrugs of these compounds are able to arrest the growth of Pf in cell culture. In the search for new inhibitors of PfHGXPRT, a series of sulfur containing ANPs (thia-ANPs) has been designed and synthesized. These compounds are based on the structure of 2-(phosphonoethoxy)ethylguanine (PEEG) and PEEHx which consist of a purine base (i.e. guanine or hypoxanthine) linked to a phosphonate group by five atoms i.e. four carbons and one oxygen. Here, PEEG and PEEHx were modified by substituting a sulfide, sulfoxide or a sulfone bridge for the oxygen atom in the linker. The effect of these substitutions on the K
Pseudoceramines A–D, new antibacterial bromotyrosine alkaloids from the marine sponge Pseudoceratina sp.
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C1OB05581J
Abstract: Bioassay-guided fractionation of the CH(2)Cl(2)/MeOH extract of the Australian marine sponge Pseudoceratina sp. resulted in the purification of four new bromotyrosine alkaloids, pseudoceramines A-D (1-4), along with a known natural product, spermatinamine (5). The structures of 1-5 were determined by spectroscopic methods. Pseudoceramines A (1) and B (2) feature a rare bromotyrosyl-spermine-bromotyrosyl sequence, and pseudoceramine C (3) is the first ex le of bromotyrosine coupled with an N-methyl derivative of spermidine. Compounds 1-5 were screened for inhibition of toxin secretion by the type III secretion (T3S) pathway in Yersinia pseudotuberculosis. Compounds 2 and 5 inhibited secretion of the Yersinia outer protein YopE (IC(50) = 19 and 6 μM, respectively) and the enzyme activity of YopH (IC(50) = 33 and 6 μM, respectively).
The Molecular Effects of Sulforaphane and Capsaicin on Metabolism upon Androgen and Tip60 Activation of Androgen Receptor
Publisher: MDPI AG
Date: 29-10-2019
DOI: 10.3390/IJMS20215384
Abstract: Androgen receptor (AR) stimulators, such as androgen and Tip60, play a pivotal role in prostatic carcinogenesis as androgen receptor signaling is critical for the growth and transformation of the prostate gland. Moreover, androgen and Tip60 promotes HIF-1α activation, involved in metabolic reprogramming by increasing glycolysis, a hallmark in cancer initiation and development. In this study we evaluated the effect of androgen and Tip60 stimulus in AR pathway activation and HIF-1α stabilization, in terms of proliferation and cell metabolism in androgen-sensitive LNCaP cells. The protective role of the bioactive compounds sulforaphane and capsaicin against the effect of these stimuli leading to pro-carcinogenic features was also addressed. Sulforaphane and capsaicin decreased nuclear AR, prostate specific antigen and Bcl-XL levels, and cell proliferation induced by androgen and Tip60 in LNCaP cells. These bioactive compounds prevented the increase in glycolysis, hexokinase and pyruvate kinase activity, and reduced HIF-1α stabilization induced by androgen and Tip60 in LNCaP cells. The protective role of sulforaphane and capsaicin on prostate cancer may rely on mechanisms involving the inhibition of Tip60, AR and HIF-1α effects.
8‐Aminoquinolines with an Aminoxyalkyl Side Chain Exert in vitro Dual‐Stage Antiplasmodial Activity
Publisher: Wiley
Date: 14-01-2019
Abstract: A series of novel 8-aminoquinolines (8-AQs) with an aminoxyalkyl side chain were synthesized and evaluated for in vitro antiplasmodial properties against asexual blood stages, liver stages, and sexual stages of Plasmodium falciparum. 8-AQs bearing 2-alkoxy and 5-phenoxy substituents on the quinoline ring system were found to be the most promising compounds under study, exhibiting potent blood schizontocidal and moderate tissue schizontocidal in vitro activity.
A Plasmodium vivax experimental human infection model for evaluating efficacy of interventions
Publisher: American Society for Clinical Investigation
Date: 27-04-2020
DOI: 10.1172/JCI134923
Health-Seeking Behaviors of Filipino Migrants in Australia: The Influence of Persisting Acculturative Stress and Depression
Publisher: Springer Science and Business Media LLC
Date: 07-06-2016
DOI: 10.1007/S10903-015-0233-X
Abstract: This study examined the relationships among the constructs of acculturative stress, depression, English language use, health literacy, and social support and the influence of these factors on health-seeking behaviors of Filipino Australians. Using a self-administered questionnaire, 552 respondents were recruited from November 2010 to June 2011. Structural equation modelling was used to examine relationships. A direct and negative relationship between health-seeking behaviors and depression, and an indirect relationship with acculturative stress, was observed mediated through depression. Social support had an important moderating influence on these effects. Although there was an inverse relationship between age and English language usage and depression, age was positively related to health-seeking behavior. Despite their long duration of stay, Filipino Australian migrants continue to experience acculturative stress and depression leading to lower health-seeking behaviors. This study highlights the importance of screening for acculturative stress and depression in migrants and fostering social support.
Isolation, structure elucidation and cytotoxic evaluation of endiandrin B from the Australian rainforest plant Endiandra anthropophagorum
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.BMC.2008.12.030
Abstract: Chemical investigations of the DCM extract from the roots of Endiandra anthropophagorum resulted in the isolation of a new cyclobutane lignan endiandrin B (1), together with the known natural products, endiandrin A (2), and (-)-dihydroguaiaretic acid (3). The structure of 1 was determined by extensive spectroscopic analyses, and confirmed by single crystal X-ray crystallography. Methylation of 1 using diazomethane afforded the previously reported natural product, cinbalansan (4). All compounds were evaluated for their cytotoxicity towards human lung carcinoma cells (A549) using high-content screening. (-)-Dihydroguaiaretic acid (3) was found to be the most potent cytotoxin against the A549 lung carcinoma cell line, with an IC(50) value of 7.49 microM.
A Meroisoprenoid, Heptenolides, and C-Benzylated Flavonoids from Sphaerocoryne gracilis ssp. gracilis
Publisher: American Chemical Society (ACS)
Date: 18-02-2020
PCaAnalyser: A 2D-image analysis based module for effective determination of prostate cancer progression in 3D culture
Publisher: Public Library of Science (PLoS)
Date: 20-11-2013
Negotiating health and chronic illness in Filipino-Australians: a qualitative study with implications for health promotion
Publisher: Informa UK Limited
Date: 08-03-2017
DOI: 10.1080/13557858.2017.1294656
Abstract: In spite of the healthy immigrant effect, the prevalence of lifestyle-related chronic diseases among migrants is reported to approximate that of the host country with longer duration of stay. For ex le, higher rates of chronic diseases such as Type 2 diabetes and hypertension have been observed among Filipino migrants and these have been linked to acculturation. The aim of this study was to explore the experiences of Filipino-Australian migrants in managing their chronic health conditions in a Western host country. This paper reports on qualitative findings of a mixed methods study that used an explanatory sequential design. Nine focus group discussions were undertaken with 58 Filipino-Australian migrants with chronic disease. Thematic analysis was undertaken using a five-stage general purpose thematic framework ensuring that themes closely identified key participants' experiences . Findings revealed that health benefits provided by the health system in Australia were considered advantageous. However, a lack of social and instrumental support compounded isolation and disempowerment, limiting self-management strategies for chronic illnesses. Cultural beliefs and practices influenced their knowledge, attitude to and management of chronic disease, which health service providers overlooked because of perceived acculturation and English language skills. Overall this study has clearly identified recognition of cultural beliefs, language needs and support as three core needs of Filipino-Australian migrants with the elderly the most vulnerable. This paper highlights that self-management of chronic disease among elderly Filipino immigrants may be adversely affected by host language difficulties, a lack of social support and cultural issues, impacting on access to services, health-seeking behaviours and participation in health promotion initiatives. Language, culture-specific health interventions and resources and enhancing social support are likely important strategies in promoting chronic disease self-management among the elderly. These interventions have the potential to empower and encourage in iduals to take control and better manage their chronic disease.
Induction of Reactive Bone Stromal Fibroblasts in 3D Models of Prostate Cancer Bone Metastases
Publisher: MDPI AG
Date: 15-06-2023
Abstract: A dynamic interplay between prostate cancer (PCa) cells and reactive bone stroma modulates the growth of metastases within the bone microenvironment. Of the stromal cells, metastasis-associated fibroblasts (MAFs) are known to contribute but are the least studied cell type in PCa tumour progression. It is the aim of the current study to establish a biologically relevant 3D in vitro model that mimics the cellular and molecular profiles of MAFs found in vivo. Using 3D in vitro cell culture models, the bone-derived fibroblast cell line, HS-5, was treated with conditioned media from metastatic-derived PCa cell lines, PC3 and MDA-PCa 2b, or mouse-derived fibroblasts 3T3. Two corresponding reactive cell lines were propagated: HS5-PC3 and HS5-MDA, and evaluated for alterations in morphology, phenotype, cellular behaviour, plus protein and genomic profiles. HS5-PC3 and HS5-MDA displayed distinct alterations in expression levels of N-Cadherin, non-functional E-Cadherin, alpha-smooth muscle actin (α-SMA), Tenascin C, and vimentin, along with transforming growth factor receptor expression (TGF β R1 and R2), consistent with subpopulations of MAFs reported in vivo. Transcriptomic analysis revealed a reversion of HS5-PC3 towards a metastatic phenotype with an upregulation in pathways known to regulate cancer invasion, proliferation, and angiogenesis. The exploitation of these engineered 3D models could help further unravel the novel biology regulating metastatic growth and the role fibroblasts play in the colonisation process.
Multidisciplinary perspectives on medication-related decision-making for people with advanced dementia living in long-term care: a critical incident analysis.
Publisher: Springer Science and Business Media LLC
Date: 14-01-2020
DOI: 10.1007/S00228-019-02820-Z
Abstract: This study aimed to explore medication-related decision-making by health professionals from different disciplines and specialties caring for people with advanced dementia living in long-term care facilities, focusing on dilemmas associated with starting, continuing or deprescribing medications commonly regarded as potentially inappropriate. Four focus groups were undertaken, each on a different medication type (antibiotics, lipid-lowering agents, opioids and acetylcholinesterase inhibitors). Transcripts underwent qualitative analysis using line by line inductive coding and then a person-centred framework to highlight themes across medication types. Sixteen participants participated in focus groups. Regardless of medication type or dilemma, results suggested decision-making for residents with advanced dementia should begin with discussing goals of care and engaging with families, and be viewed as an iterative process involving regular monitoring and adjustment. Decision-making was seen as requiring a dialectical approach involving multiple perspectives, with an emphasis on establishing communication between health professionals, family and the person with dementia to better understand goals references for care. Inter-professional collaboration enables sharing of clinical experience/expertise, differing disciplinary perspectives and knowledge about the resident. Continuing a medication should be considered an active decision that carries as much responsibility as starting or deprescribing.
One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites
Publisher: Elsevier BV
Date: 10-2018
(+)-7-Bromotrypargine: an antimalarial β-carboline from the Australian marine sponge Ancorina sp.
Publisher: Elsevier BV
Date: 2010
Naseseazine C, a new anti-plasmodial dimeric diketopiperazine from a marine sediment derived Streptomyces sp.
Publisher: Elsevier BV
Date: 12-2016
3-pyridyl inhibitors with novel activity against Trypanosoma cruzi reveal in vitro profiles can aid prediction of putative cytochrome P450 inhibition
Publisher: Springer Science and Business Media LLC
Date: 20-03-2018
DOI: 10.1038/S41598-018-22043-Z
Abstract: Using high throughput, high-content imaging, a proprietary library was screened against intracellular Trypanosoma cruzi amastigotes to identify compounds with novel activity against the parasite. Five inhibitors were discovered, which did not clear all of the parasites from 3T3 host cells following 48 hours exposure, and were identified as putative T . cruzi cytochrome P450 (TcCYP51) inhibitors. TcCYP51 inhibitors are not favourable for the drug discovery pipeline for treatment of Chagas Disease infection due to clinical and pre-clinical failures. To determine if there were in vitro inhibitory characteristics of these compounds that could aid the prediction of TcCYP51 inhibition further profiling using imaging and fluorescence based assays was undertaken. It was determined that in vitro profiles, coupled with analysis of chemical structure, could support the early prediction of putative TcCYP51 activity and thus enable early de-prioritisation of these compounds from progression through the drug discovery pipeline.
Expression of the thioredoxin system in an in vivo-like cancer cell environment upon auranofin treatment
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.EJCB.2016.08.003
Abstract: As essential elements of the tumor microenvironment, the variable oxygenation state of the tumor tissue, the extracellular matrix (ECM) and different cell types are important determinants of carcinogenesis. These elements may also influence how tumor cells respond to therapeutic treatments. In the present study, we assessed the anti-cancer activity of auranofin and its effect on the thioredoxin (Trx) system under conditions that closely resemble the in vivo tumor microenvironment with respect to the oxygen levels and tissue architecture. We utilised an oxygen scheme involving growth of cancer cells under normoxia (20%) and hypoxia (0.1%). We also preconditioned cells with intermittent hypoxia (IH) prior to a prolonged hypoxic incubation. This oxygen scheme did not affect the cytotoxicity of auranofin however, IH preconditioned cells were less sensitive towards the inhibition of thioredoxin reductase (TrxR) specific activity upon treatment with auranofin. IH preconditioning also upregulated Trx protein levels in auranofin treated cells. We also compared the activity of auranofin against cancer cells cultured in 2D monolayer and 3D spheroid-based culture models. Auranofin was less potent against cells grown under a more in vivo-like 3D environment. The results presented in this paper implicate the importance of the tumor oxygen environment and tissue architecture in influencing the response of cancer cells towards auranofin.
Synthesis of antimalarial amide analogues based on the plant serrulatane diterpenoid 3,7,8-trihydroxyserrulat-14-en-19-oic acid
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.BMCL.2017.07.039
Abstract: A plant-derived natural product scaffold, 3,7,8-trihydroxyserrulat-14-en-19-oic acid (1) was isolated in high yield from the aerial parts of the endemic Australian desert plant Eremophila microtheca. This scaffold (1) was subsequently used in the generation of a series of new amide analogues via a one-pot mixed anhydride amidation using pivaloyl chloride. The structures of all analogues were characterized using MS, NMR, and UV data. The major serrulatane natural products (1-3), isolated from the plant extract, and all amide analogues (6-15) together with several pivaloylated derivatives of 3,7,8-trihydroxyserrulat-14-en-19-oic acid (16-18) were evaluated for their antimalarial activity against 3D7 (chloroquine sensitive) and Dd2 (chloroquine resistant) Plasmodium falciparum strains, and preliminary cytotoxicity data were also acquired using the human embryonic kidney cell line HEK293. The natural product scaffold (1) did not display any antimalarial activity at 10µM. Replacing the carboxylic acid of 1 with various amides resulted in moderate activity against the P. falciparum 3D7 strain with IC
Desymmetrization Reactions of Indigo with Grignard Reagents for the Synthesis of Selective Antiplasmodial [1H,3′H]-3-Aryl-2,2′-diindol-3′-ones
Publisher: American Chemical Society (ACS)
Date: 08-2019
Abstract: The nucleophilic addition of organomagnesium and organolithium species to the cheap and robust natural dye indigo led to desymmetrization of the heterocyclic nucleus via a Grignard addition-dehydration procedure. Twenty-seven ersely functionalized [1
Spermatinamine, the first natural product inhibitor of isoprenylcysteine carboxyl methyltransferase, a new cancer target
Publisher: Elsevier BV
Date: 12-2007
DOI: 10.1016/J.BMCL.2007.10.021
Abstract: Isoprenylcysteine methyltransferase (Icmt) catalyzes the carboxyl methylation of oncogenic proteins in the final step of a series of post-translational modifications. The inhibition of Icmt provides an attractive and novel anticancer target. A natural product high-throughput screening c aign was conducted to discover inhibitors of Icmt. The Australian marine sponge, Pseudoceratina sp., yielded spermatinamine, a novel alkaloid with a bromotyrosyl-spermine-bromotyrosyl sequence, as the bioactive constituent. Its structure was determined by 1D and 2D NMR spectroscopy. Spermatinamine is the first natural product inhibitor of Icmt.
Bone-stromal cells up-regulate tumourigenic markers in a tumour-stromal 3D model of prostate cancer
Publisher: Springer Science and Business Media LLC
Date: 30-09-2013
Abstract: The cellular and molecular mechanisms that mediate interactions between tumour cells and the surrounding bone stroma are to date largely undetermined in prostate cancer (PCa) progression. The purpose of this study was to evaluate the role of alpha 6 and beta 1 integrin subunits in mediating tumour-stromal interactions. Utilising 3D in vitro assays we evaluated and compared 1. Monocultures of prostate metastatic PC3, bone stromal derived HS5 and prostate epithelial RWPE-1 cells and 2. Tumour-stromal co-cultures (PC3 + HS5) to ascertain changes in cellular phenotype, function and expression of metastatic markers. In comparison to 3D monocultures of PC3 or HS5 cells, when cultured together, these cells displayed up-regulated invasive and proliferative qualities, along with altered expression of epithelial-to-mesenchymal and chemokine protein constituents implicated in metastatic dissemination. When co-cultured, HS5 cells were found to re-express N-Cadherin and chemokine receptor CXCR7. Alterations in N-Cadherin expression were found to be mediated by soluble factors secreted by PC3 tumour cells, while chemokine receptor re-expression was dependent on direct cell-cell interactions. We have also shown that integrins beta 1 and alpha 6 play an integral role in maintaining cell homeostasis and mediating expression of E-Cadherin, N-Cadherin and vimentin, in addition to chemokine receptor CXCR7. Collectively our results suggest that both PC3 and HS5 cells provide a “protective” and reciprocal milieu that promotes tumour growth. As such 3D co-cultures may serve as a more complex and valid biological model in the drug discovery pipeline.
Development and Optimization of a Novel 384-Well Anti-Malarial Imaging Assay Validated for High-Throughput Screening
Publisher: American Society of Tropical Medicine and Hygiene
Date: 2012
Key elements of interventions for heart failure patients with mild cognitive impairment or dementia: A systematic review
Publisher: Oxford University Press (OUP)
Date: 26-07-2019
Abstract: The purpose of this systematic review was to (a) examine the effects of interventions delivered by a heart failure professional for mild cognitive impairment and dementia on cognitive function, memory, working memory, instrumental activities of daily living, heart failure knowledge, self-care, quality of life and depression and (b) identify the successful elements of these strategies for heart failure patients with mild cognitive impairment or dementia. During March 2018, an electronic search of databases including CINAHL, MEDLINE, EMBASE and PsycINFO was conducted. All randomised controlled trials, which examined an intervention strategy to help heart failure patients with mild cognitive impairment or dementia cope with self-care, were included. An initial search yielded 1622 citations, six studies were included ( N= 595 participants, mean age 68 years). There were no significant improvements in cognitive function and depression. However, significant improvements were seen in memory ( p=0.015), working memory ( p=0.029) and instrumental activities of daily living ( p=0.006). Nurse led interventions improved the patient’s heart failure knowledge ( p=0.001), self-care ( p .05) and quality of life ( p=0.029). Key elements of these interventions include brain exercises, for ex le, syllable stacks, in idualised assessment and customised education, personalised self-care schedule development, interactive problem-solving training on scenarios and association techniques to prompt self-care activities. Modest evidence for nurse led interventions among heart failure patients with mild cognitive impairment or dementia was identified. These results must be interpreted with caution in light of the limited number of available included studies.
DFS-generated pathways in GA crossover for protein structure prediction
Publisher: Elsevier BV
Date: 08-2010
Doxorubicin resistance in breast cancer cells is mediated by extracellular matrix proteins
Publisher: Springer Science and Business Media LLC
Date: 06-01-2018
HSQC–TOCSY Fingerprinting for Prioritization of Polyketide- and Peptide-Producing Microbial Isolates
Publisher: American Chemical Society (ACS)
Date: 02-03-2018
DOI: 10.1021/ACS.JNATPROD.7B01063
Abstract: Microbial products are a promising source for drug leads as a result of their unique structural ersity. However, reisolation of already known natural products significantly h ers the discovery process, and it is therefore important to incorporate effective microbial isolate selection and dereplication protocols early in microbial natural product studies. We have developed a systematic approach for prioritization of microbial isolates for natural product discovery based on heteronuclear single-quantum correlation-total correlation spectroscopy (HSQC-TOCSY) nuclear magnetic resonance profiles in combination with antiplasmodial activity of extracts. The HSQC-TOCSY experiments allowed for unfractionated microbial extracts containing polyketide and peptidic natural products to be rapidly identified. Here, we highlight how this approach was used to prioritize extracts derived from a library of 119 ascidian-associated actinomycetes that possess a higher potential to produce bioactive polyketides and peptides.
Antimalarial Bromotyrosine Derivatives from the Australian Marine Sponge Hyattella sp.
Publisher: American Chemical Society (ACS)
Date: 12-05-2010
DOI: 10.1021/NP900834G
Abstract: A drug discovery program aimed at identifying new antimalarial leads from a prefractionated natural product library has resulted in the identification of a new bromotyrosine alkaloid, psammaplysin G (1), along with the previously isolated compound, psammaplysin F (2). When tested against two different strains of the parasite Plasmodium falciparum (Dd2 and 3D7), 2 displayed IC(50) values of 1.4 and 0.87 microM, respectively, while 1 showed 98% inhibition at 40 microM against the chloroquine-resistant (Dd2) strain of P. falciparum.
Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei
Publisher: American Chemical Society (ACS)
Date: 17-07-2014
DOI: 10.1021/JM500191U
Abstract: A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC50 of 12 μM, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure-activity relationships. We determined that the physicochemical properties for this class are generally favorable with particular positions identified that appear to block metabolism when substituted and others that modulate solubility. Our most active compound is 79, which has an IC50 of 0.045 μM against the human pathogenic strain Trypanosoma brucei rhodesiense and is more than 4000 times less active against the mammalian L6 cell line.
Surface phagocytosis and host defence in the peritoneal cavity during continuous ambulatory peritoneal dialysis
Publisher: Springer Science and Business Media LLC
Date: 03-1990
DOI: 10.1007/BF01963836
Antimalarial Activity of Natural Product Extracts from Papua New Guinean and Australian Plants against Plasmodium falciparum
Publisher: Wiley
Date: 10-2008
DOI: 10.1002/PTR.2510
Abstract: In the search for new antimalarial compounds, a subset of a natural product extract library prepared from plant s les collected from Papua New Guinea and Australia was screened for in vitro activity against the chloroquine-sensitive 3D7 and chloroquine-resistant Dd2 strains of Plasmodium falciparum. Using the incorporation of ((3)H)-hypoxanthine into parasite nucleic acid as a marker of growth, 93 of the 794 extracts screened displayed >40% inhibition against 3D7 infected erythrocytes at 312 microge/mL. Antimalarial activity was confirmed in 48 of these extracts against both 3D7 and Dd2 infected erythrocytes at concentrations between 78 and 390 microge/mL, 14 of which caused >90% growth inhibition of 3D7 at the lowest concentration screened. Extracts were also tested for mammalian cell cytotoxicity to evaluate selectivity of action.
Clavatadines C−E, Guanidine Alkaloids from the Australian Sponge Suberea clavata
Publisher: American Chemical Society (ACS)
Date: 20-04-2009
DOI: 10.1021/NP8008013
Abstract: Three new marine alkaloids, clavatadines C-E (1-3), together with the three known compounds aerophobin 1 (4), purealdin L (5), and aplysinamisine II (6) were isolated from extracts of the sponge Suberea clavata by bioassay-guided fractionation using a serine protease factor XIa assay. Their structures were determined by 1D and 2D NMR spectroscopy. Compounds 1-6 exhibited weak inhibition of factor XIa.
7 ',8 '-Dihydroobolactone, a typanocidal alpha-pyrone from the rainforest tree Cryptocarya obovata
Publisher: Elsevier BV
Date: 07-2010
DOI: 10.1016/J.BMCL.2010.05.091
Abstract: Mass-directed isolation of the CH(2)Cl(2)/MeOH extract from the leaves of Cryptocarya obovata resulted in the purification of a new trypanocidal alpha-pyrone, 7',8'-dihydroobolactone (1). The chemical structure of 1 was determined by 1D/2D NMR, MS and CD data analysis. 7',8'-Dihydroobolactone was shown to inhibit Trypanosoma brucei brucei with an IC(50) of 2.8 microM.
Evaluation of chemotherapeutics in a three-dimensional breast cancer model
Publisher: Springer Science and Business Media LLC
Date: 15-03-2015
DOI: 10.1007/S00432-015-1950-1
Abstract: Utilization of miniaturized three-dimensional (3D) cell culture-based assays enables investigation into the anticancer activity of drug candidates and further elucidation of the anticancer profile of standard-of-care chemotherapeutic agents against tumor cells. Drug discovery assays established using 3D cell culture, which better recapitulate the tumor microenvironment, may more accurately reflect the antitumor activity of compounds. Several standard-of-care anticancer drugs, epirubicin, paclitaxel and vinorelbine, were evaluated against a panel of breast cancer cell lines grown in a 3D cell culture microenvironment in the presence of extracellular matrix. A comparison of this antitumor activity in 3D conditions was made with that observed in traditional two-dimensional (2D) monolayer conditions. Examination of the above mentioned drugs against breast tumor cells cultured in 3D conditions demonstrated significantly altered potency and efficacy in comparison with cells propagated in a 2D monolayer system. The differences observed were cell line-dependent and drug-specific the triple-negative cell line MDA-MB-231 and the endocrine receptor-positive cell line MCF-7 consistently displayed resistance to therapeutics with distinct modes of action (i.e., topoisomerase II and microtubules) in 3D cell culture in comparison with ErbB2 receptor-positive BT-474 cells. The data presented herein demonstrates the cellular viability and physical changes observed within the 3D spheroid following exposure to drug, which is not always reflected in 2D cell culture models.
Prenylated Flavonoids from the Roots of Tephrosia rhodesica
Publisher: American Chemical Society (ACS)
Date: 13-08-2020
Temporal and Wash-Out Studies Identify Medicines for Malaria Venture Pathogen Box Compounds with Fast-Acting Activity against Both Trypanosoma cruzi and Trypanosoma brucei
Publisher: MDPI AG
Date: 25-06-2022
DOI: 10.3390/MICROORGANISMS10071287
Abstract: Chagas disease caused by the protozoan Trypanosoma cruzi is endemic to 21 countries in the Americas, effects approximately 6 million people and on average results in 12,000 deaths annually. Human African Trypanosomiasis (HAT) is caused by the Trypanosoma brucei sub-species, endemic to 36 countries within sub-Saharan Africa. Treatment regimens for these parasitic diseases are complicated and not effective against all disease stages thus, there is a need to find improved treatments. To identify new molecules for the drug discovery pipelines for these diseases, we have utilised in vitro assays to identify compounds with selective activity against both T. cruzi and T.b. brucei from the Medicines for Malaria Venture (MMV) Pathogen Box compound collection. To prioritise these molecules for further investigation, temporal and wash off assays were utilised to identify the speed of action and cidality of compounds. For translational relevance, compounds were tested against clinically relevant T.b. brucei subspecies. Compounds with activity against T. cruzi cytochrome P450 (TcCYP51) have not previously been successful in clinical trials for chronic Chagas disease thus, to deprioritise compounds with this activity, they were tested against recombinant TcCYP51. Compounds with biological profiles warranting progression offer important tools for drug and target development against kinetoplastids.
Watsonianone A–C, anti-plasmodial β-triketones from the Australian tree, Corymbia watsoniana
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C2OB26931G
Abstract: Three new β-triketones, watsonianones A-C, and the known compound corymbone B were isolated from the flowers of the Australian eucalypt Corymbia watsoniana. Watsonianone A is the first naturally occurring methylene bridged bis-tetramethylcyclohexatrione, watsonianone B is only the fourth fused bisfurano β-triketone and watsonianone C is the first 4,4a,9,9a-tetrahydro-2H-xanthene-1,3,5,7(6H,8H)-tetraone to be reported in the literature. MS and NMR analysis established the structures of the new compounds. All three new compounds showed anti-plasmodial activity against chloroquine resistant (Dd2) and sensitive strains (3D7) of the parasite, Plasmodium falciparum, responsible for malarial infections. Watsonianone B was the most potent inhibitor (IC(50) 0.289 μM vs. Pf 3D7) demonstrating significant selectivity against the human cell line, HEK 293 (>400 ×). Stage specificity studies indicate that watsonianone B is predominantly active against young ring stages of P. falciparum.
Whole-organism high-throughput screening againstTrypanosoma brucei brucei
Publisher: Informa Healthcare
Date: 31-03-2013
DOI: 10.1517/17460441.2013.783816
Abstract: Human African trypanosomiasis (HAT) occurs as a result of infection with the protozoan parasites Trypanosoma brucei gambiense and T.b. rhodesiense and is nearly always fatal without treatment. However, current therapeutic options are severely limited and there is a desperate need for new compounds to treat the disease. Whole-cell high-throughput screening (HTS) is a technique frequently used to identify compounds with trypanocidal activity. The authors examine the development of whole-organism HTS assays for T.b. brucei. The authors describe the successes achieved through HTS and discuss the advantages and disadvantages of whole-organism HTS. Despite hundreds of trypanocidal molecules being identified by whole-organism HTS, very few have progressed into preclinical development. The failure of molecules identified by HTS to progress along the drug development pathway is due to a multitude of factors including undrug-like molecules and molecules having poor pharmacodynamics/kinetic properties. Future studies should focus on screening libraries that contain drug-like molecules that possess some of the properties required in the final compound.
Future treatment options for human African trypanosomiasis
Publisher: Informa UK Limited
Date: 28-09-2015
DOI: 10.1586/14787210.2015.1094374
Abstract: Over the past 17 years, the number of reported cases of human African trypanosomiasis (HAT) has declined by over 90%, a significant result since the disease was highlighted as a public health problem by the WHO in 1995. However, if the goal of eliminating HAT by 2020 is to be achieved, then new treatments need to be identified and developed. A plethora of compound collections has been screened against Trypanosoma brucei spp, the etiological agents of HAT, resulting in three compounds progressing to clinical development. However, due to the high attrition rates in drug discovery, it is essential that research continues to identify novel molecules. Failure to do so, will result in the absence of molecules in the pipeline to fall back on should the current clinical trials be unsuccessful. This could seriously compromise control efforts to date, resulting in a resurgence in the number of HAT cases.
Design, Synthesis, and Biological Evaluation of 2-Nitroimidazopyrazin-one/-es with Antitubercular and Antiparasitic Activity
Publisher: American Chemical Society (ACS)
Date: 23-11-2018
Antimalarial Activity of Azafluorenone Alkaloids from the Australian Tree Mitrephora diversifolia
Publisher: American Chemical Society (ACS)
Date: 10-07-2009
DOI: 10.1021/NP900247F
Abstract: Mass-directed isolation of the CH2Cl2/MeOH extract from the roots of the Australian tree Mitrephora ersifolia resulted in the purification of the new azafluorenone alkaloid 5,8-dihydroxy-6-methoxyonychine (1) together with the known natural product 5-hydroxy-6-methoxyonychine (2). The structures of 1 and 2 were determined by extensive 1D and 2D NMR and MS data analyses. Both compounds were isolated during a drug discovery program aimed at the identification of new antimalarial leads from a prefractionated natural product library. When tested against two different strains of the parasite Plasmodium falciparum (3D7 and Dd2), 2 displayed IC(50) values of 9.9 and 11.4 microM, respectively, while 1 showed minimal activity.
The isolation, structure determination and cytotoxicity of the new fungal metabolite, trichodermamide C
Publisher: Elsevier BV
Date: 05-2008
DOI: 10.1016/J.BMCL.2008.03.090
Abstract: Chemical investigations of a culture broth from the endophytic fungus Eupenicillium sp. afforded the new modified dipeptide trichodermamide C 1. The structure of 1 was established following the analysis of NMR, UV, IR, MS and X-ray diffraction data. Trichodermamide C was shown by high content screening to display cytotoxicity towards the human colorectal carcinoma HCT116 and human lung carcinoma A549 with IC(50) values of 0.68 and 4.28microg/ml, respectively.
Discovery and development of 2-aminobenzimidazoles as potent antimalarials
Publisher: Elsevier BV
Date: 10-2021
Secoiridoids and Iridoids from Morinda asteroscepa
Publisher: American Chemical Society (ACS)
Date: 27-08-2020
Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum
Publisher: Springer Science and Business Media LLC
Date: 25-11-2014
DOI: 10.1038/NCOMMS6521
Abstract: The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na + regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na + homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na + homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.
Assessing Drug Efficacy in a Miniaturized Pancreatic Cancer In Vitro 3D Cell Culture Model
Publisher: Mary Ann Liebert Inc
Date: 09-2016
DOI: 10.1089/ADT.2016.737
Abstract: Pancreatic cancer continues to have one of the poorest prognoses among all cancers. The drug discovery efforts for this disease have largely failed, with no significant improvement in survival outcomes for advanced pancreatic cancer patients over the past 20 years. Traditional in vitro cell culture techniques have been used extensively in both basic and early drug discovery however, these systems offer poor models to assess emerging therapeutics. More predictive cell-based models, which better capture the cellular heterogeneity and complexities of solid pancreatic tumors, are urgently needed not only to improve drug discovery success but also to provide insight into the tumor biology. Pancreatic tumors are characterized by a unique micro-environment that is surrounded by a dense stroma. A complex network of interactions between extracellular matrix (ECM) components and the effects of cell-to-cell contacts may enhance survival pathways within in vivo tumors. This biological and physical complexity is lost in traditional cell monolayer models. To explore the predictive potential of a more complex cellular system, a three-dimensional (3D) micro-tumor assay was evaluated. Efficacy of six current chemotherapeutics was determined against a panel of primary and metastatic pancreatic tumor cell lines in a miniaturized ECM-based 3D cell culture system. Suitability for potential use in high-throughput screening applications was assessed, including ascertaining the effects that miniaturization and automation had on assay robustness. Cellular health was determined by utilizing an indirect population-based metabolic activity assay and a direct imaging-based cell viability assay.
A New Benzopyranyl Cadenane Sesquiterpene and Other Antiplasmodial and Cytotoxic Metabolites from Cleistochlamys kirkii
Publisher: MDPI AG
Date: 29-07-2019
DOI: 10.3390/MOLECULES24152746
Abstract: Phytochemical investigations of ethanol root bark and stem bark extracts of Cleistochlamys kirkii (Benth.) Oliv. (Annonaceae) yielded a new benzopyranyl cadinane-type sesquiterpene (cleistonol, 1) alongside 12 known compounds (2–13). The structures of the isolated compounds were established from NMR spectroscopic and mass spectrometric analyses. Structures of compounds 5 and 10 were further confirmed by single crystal X-ray crystallographic analyses, which also established their absolute stereochemical configuration. The ethanolic crude extract of C. kirkii root bark gave 72% inhibition against the chloroquine-sensitive 3D7-strain malaria parasite Plasmodium falciparum at 0.01 μg/mL. The isolated metabolites dichamanetin, (E)-acetylmelodorinol, and cleistenolide showed IC50 = 9.3, 7.6 and 15.2 μM, respectively, against P. falciparum 3D7. Both the crude extract and the isolated compounds exhibited cytotoxicity against the triple-negative, aggressive breast cancer cell line, MDA-MB-231, with IC50 = 42.0 μg/mL (crude extract) and 9.6–30.7 μM (isolated compounds). Our findings demonstrate the potential applicability of C. kirkii as a source of antimalarial and anticancer agents.
Natural Products, Stylissadines A and B, Specific Antagonists of the P2X7 Receptor, an Important Inflammatory Target1
Publisher: American Chemical Society (ACS)
Date: 22-02-2007
DOI: 10.1021/JO062007Q
Abstract: The distribution of the P2X7 receptor in inflammatory cells suggests that P2X7 antagonists have a significant role to play in the treatment of inflammatory disease. We conducted a natural product high-throughput screening c aign to discover P2X7 receptor antagonists. The Australian marine sponge Stylissa flabellata yielded two new bisimidazo-pyrano-imidazole bromopyrrole ether alkaloids, stylissadines A (IC50 0.7 microM) and B (IC50 1.8 microM), as the specific bioactive constituents. The compounds inhibit BzATP-mediated pore formation in THP-1 cells. Also present in this extract was considerable nonspecific bioactivity in the hemeolysin specificity assay. A new pyrrole-imidazole alkaloid, konbu'acidin B, and the known pyrrole-imidazole alkaloids 4,5-dibromopalau'amine and massadine were also isolated and had nonspecific activity. ROESY and proton coupling constant data indicated that the stereochemistry at C12, C17, and C20 in 4,5-dibromopalau'amine should be revised to 12R, 17S, 20S. By analogy, the relative stereochemistry of palau'amine, 4-bromopalau'amine, styloguanidine, 3-bromostyloguanidine, and 2,3-dibromostyloguanidine should also be revised to 12R, 17S, 20S. Stylissadines A and B are the most potent natural product P2X7 antagonists to be isolated to date and provide a novel class of P2X7 receptor inhibitors. They are also the first ex les of tetrameric pyrrole-imidazole alkaloids.
Leishmaniasis drug discovery: recent progress and challenges in assay development
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.DRUDIS.2017.06.004
Abstract: Leishmaniasis, caused by the trypanosomatid protozoan Leishmania, is endemic in 98 countries worldwide, with morbidity and mortality increasing daily. Despite available drugs, leishmaniasis faces the challenge of emerging resistance and toxicity concerns for current drug regimes. Identification of anti-leishmanial compounds representing new chemistry and novel mechanisms of action is essential to populate the drug discovery pipeline. The in vitro assays currently available have shown poor translational outcomes, with high compound attrition rates. It is therefore imperative that more physiologically relevant assays are developed to identify anti-leishmanial compounds. This review provides an overview of the disease, current treatment options and compares the various technologies and assay formats currently available for leishmanial drug discovery.
In vivo biomarker expression patterns are preserved in 3D cultures of Prostate Cancer
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.YEXCR.2012.07.013
Abstract: Here we report that Prostate Cancer (PCa) cell-lines DU145, PC3, LNCaP and RWPE-1 grown in 3D matrices in contrast to conventional 2D monolayers, display distinct differences in cell morphology, proliferation and expression of important biomarker proteins associated with cancer progression. Consistent with in vivo growth rates, in 3D cultures, all PCa cell-lines were found to proliferate at significantly lower rates in comparison to their 2D counterparts. Moreover, when grown in a 3D matrix, metastatic PC3 cell-lines were found to mimic more precisely protein expression patterns of metastatic tumour formation as found in vivo. In comparison to the prostate epithelial cell-line RWPE-1, metastatic PC3 cell-lines exhibited a down-regulation of E-cadherin and α6 integrin expression and an up-regulation of N-cadherin, Vimentin and β1 integrin expression and re-expressed non-transcriptionally active AR. In comparison to the non-invasive LNCaP cell-lines, PC3 cells were found to have an up-regulation of chemokine receptor CXCR4, consistent with a metastatic phenotype. In 2D cultures, there was little distinction in protein expression between metastatic, non-invasive and epithelial cells. These results suggest that 3D cultures are more representative of in vivo morphology and may serve as a more biologically relevant model in the drug discovery pipeline.
Development and application of a sensitive, phenotypic, high-throughput image-based assay to identify compound activity against Trypanosoma cruzi amastigotes
Publisher: Elsevier BV
Date: 12-2015
Insights from Australians with respiratory disease living in the community with experience of self-managing through an emergency department 'near miss' for breathlessness: a strengths-based qualitative study.
Publisher: BMJ
Date: 12-2017
DOI: 10.1136/BMJOPEN-2017-017536
Abstract: Breathlessness ‘crises’ in people with chronic respiratory conditions are a common precipitant for emergency department (ED) presentations, many of which might be avoided through improved self-management and support. This study sought insights from people with experience of ED ‘near misses’ where they considered going to the ED but successfully self-managed instead. A qualitative approach was used with a phenomenological orientation. Participants were eligible if they reported breathlessness on most days from a diagnosed respiratory condition and experience of ≥1 ED near miss. Recruitment was through respiratory support groups and pulmonary rehabilitation clinics. Semistructured interviews were conducted with each participant via telephone or face-to-face. Questions focused on ED-related decision-making, information finding, breathlessness management and support. This analysis used an integrative approach and independent coding by two researchers. Lazarus and Cohen’s Transactional Model of Stress and Coping informed interpretive themes. Interviews were conducted with 20 participants, 15 of whom had chronic obstructive pulmonary disease. Nineteen interviews were conducted via telephone. Analysis identified important factors in avoiding ED presentation to include perceived control over breathlessness, self-efficacy in coping with a crisis and desire not to be hospitalised. Effective coping strategies included: taking a project management approach that involved goal setting, monitoring and risk management managing the affective dimension of breathlessness separately from the sensory perceptual and building three-way partnerships with primary care and respiratory services. In addition to teaching non-pharmacological and pharmacological management of breathlessness, interventions should aim to develop patients’ generic self-management skills. Interventions to improve self-efficacy should ensure this is substantiated by transfer of skills and support, including knowledge about when ED presentation is necessary. Complementary initiatives are needed to improve coordinated, person-centred care. Future research should seek ways to break the cyclical relationship between affective and sensory-perceptual dimensions of breathlessness.
Erratum: Corrigendum: A novel multiple-stage antimalarial agent that inhibits protein synthesis
Publisher: Springer Science and Business Media LLC
Date: 25-05-2016
DOI: 10.1038/NATURE18280
Synthesis and Antimalarial Evaluation of Halogenated Analogues of Thiaplakortone A
Publisher: MDPI AG
Date: 22-05-2023
DOI: 10.3390/MD21050317
Abstract: The incorporation of bromine, iodine or fluorine into the tricyclic core structure of thiaplakortone A (1), a potent antimalarial marine natural product, is reported. Although yields were low, it was possible to synthesise a small nine-membered library using the previously synthesised Boc-protected thiaplakortone A (2) as a scaffold for late-stage functionalisation. The new thiaplakortone A analogues (3–11) were generated using N-bromosuccinimide, N-iodosuccinimide or a Diversinate™ reagent. The chemical structures of all new analogues were fully characterised by 1D/2D NMR, UV, IR and MS data analyses. All compounds were evaluated for their antimalarial activity against Plasmodium falciparum 3D7 (drug-sensitive) and Dd2 (drug-resistant) strains. Incorporation of halogens at positions 2 and 7 of the thiaplakortone A scaffold was shown to reduce antimalarial activity compared to the natural product. Of the new compounds, the mono-brominated analogue (compound 5) displayed the best antimalarial activity with IC50 values of 0.559 and 0.058 μM against P. falciparum 3D7 and Dd2, respectively, with minimal toxicity against a human cell line (HEK293) observed at 80 μM. Of note, the majority of the halogenated compounds showed greater efficacy against the P. falciparum drug-resistant strain.
Metabolic Roles of Androgen Receptor and Tip60 in Androgen-Dependent Prostate Cancer
Publisher: MDPI AG
Date: 10-09-2020
DOI: 10.3390/IJMS21186622
Abstract: Androgen receptor (AR)-mediated signaling is essential for the growth and differentiation of the normal prostate and is the primary target for androgen deprivation therapy in prostate cancer. Tat interactive protein 60 kDa (Tip60) is a histone acetyltransferase that is critical for AR activation. It is well known that cancer cells rewire their metabolic pathways in order to sustain aberrant proliferation. Growing evidence demonstrates that the AR and Tip60 modulate key metabolic processes to promote the survival of prostate cancer cells, in addition to their classical roles. AR activation enhances glucose metabolism, including glycolysis, tricarboxylic acid cycle and oxidative phosphorylation, as well as lipid metabolism in prostate cancer. The AR also interacts with other metabolic regulators, including calcium/calmodulin-dependent kinase kinase 2 and mammalian target of rapamycin. Several studies have revealed the roles of Tip60 in determining cell fate indirectly by modulating metabolic regulators, such as c-Myc, hypoxia inducible factor 1α (HIF-1α) and p53 in various cancer types. Furthermore, Tip60 has been shown to regulate the activity of key enzymes in gluconeogenesis and glycolysis directly through acetylation. Overall, both the AR and Tip60 are master metabolic regulators that mediate cellular energy metabolism in prostate cancer, providing a framework for the development of novel therapeutic targets in androgen-dependent prostate cancer.
Identification and In-Vitro ADME Assessment of a Series of Novel Anti-Malarial Agents Suitable for Hit-to-Lead Chemistry
Publisher: American Chemical Society (ACS)
Date: 06-2012
DOI: 10.1021/ML300091C
3-Hydroxy-N′-arylidenepropanehydrazonamides with Halo-Substituted Phenanthrene Scaffolds Cure P. berghei Infected Mice When Administered Perorally
Publisher: American Chemical Society (ACS)
Date: 17-07-2017
DOI: 10.1021/ACS.JMEDCHEM.7B00140
Abstract: Structural optimization of 3-hydroxy-N'-arylidenepropanehydrazonamides provided new analogs with nanomolar to subnanomolar antiplasmodial activity against asexual blood stages of Plasmodium falciparum, excellent parasite selectivity, and nanomolar activity against the earliest forms of gametocyte development. Particularly, derivatives with a 1,3-dihalo-6-trifluoromethylphenanthrene moiety showed outstanding in vivo properties and demonstrated in part curative activity in the Plasmodium berghei mouse model when administered perorally.
Antiplasmodial β-triketones from the flowers of the Australian tree Angophora woodsiana
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.BMCL.2017.03.065
Abstract: Chemical investigations of the MeOH extract of air dried flowers of the Australian tree Angophora woodsiana (Myrtaceae) yielded two new β-triketones, woodsianones A and B (1, 2) and nine known β-triketones (3-11). Woodsianone A is a β-triketone-sesquiterpene adduct and woodsianone B is a β-triketone epoxide derivative. The structures of the new and known compounds were elucidated from the analysis of 1D/2D NMR and MS data. The relative configurations of the compounds were determined from analysis of
Microthecaline A, a Quinoline Serrulatane Alkaloid from the Roots of the Australian Desert Plant Eremophila microtheca
Publisher: American Chemical Society (ACS)
Date: 13-03-2018
DOI: 10.1021/ACS.JNATPROD.7B00992
Abstract: Chemical investigation of the roots of the Australian desert plant Eremophila microtheca yielded microthecaline A (1), a novel quinoline-serrulatane natural product. The structure of 1 was determined by spectroscopic analysis, and the absolute configuration was assigned by ECD. Compound 1 exhibited moderate antimalarial activity against Plasmodium falciparum (3D7 strain), with an IC
New graduate registered nurse transition into primary health care roles: an integrative literature review
Publisher: Wiley
Date: 27-06-2016
DOI: 10.1111/JOCN.13297
Abstract: To summarise the literature describing new graduate nurse transition to professional practice within the primary health care (PHC) setting. There is a plethora of research literature spanning several decades about new graduate nurse transition in the acute care setting. Yet, the experiences of new graduate nurse in the PHC setting is unremarkable particularly considering the increasing demand for skilled health care workers and focus of health reform to provide care where people work and live. Electronic data bases, Academic Search Complete, EBSCO, Medline, PsycINFO, CINHAL, and ERIC were searched using a combination of terms and synonyms arising from three key concepts which identify the phenomenon 'transition', 'new graduate registered nurse' and 'primary health care. An inclusive search strategy placed no limits on language or publication date. Of the 50 articles located and examined for relevance 40 were sourced through databases and 10 from Google Scholar/Alerts and hand-searching references. None of the 19 articles retained for analysis addressed all key concepts. Some challenges of researching the professional transition of graduate nurses in PHC settings included, an absence of definitive transition models, a dearth of literature and deference to acute care research. Nursing in PHC settings, particularly the client's home is notably different to hospital settings because of higher levels of isolation and autonomy. Societal changes, health reform and subsequent demand for skilled workers in PHC settings has caused health care providers to question the logic that such roles are only for experienced nurses. Implications arise for education and health service providers who desire to close the theory practice gap and mitigate risk for all stakeholders when next generation nurses have limited opportunities to experience PHC roles as undergraduates and newly graduated registered nurses are already transitioning in this setting.
Antitrypanosomal pyridoacridine alkaloids from the Australian ascidian Polysyncraton echinatum
Publisher: Elsevier BV
Date: 05-2010
‘I have only little English’: language anxiety of Filipino migrants with chronic disease
Publisher: Informa UK Limited
Date: 19-02-2016
DOI: 10.1080/13557858.2016.1143091
Abstract: This study investigates communication challenges faced by Filipino patients with chronic diseases when engaging with healthcare professionals (HCPs). Nine focus groups were conducted between November 2010 and June 2011. Two main categories of themes were identified: patient-related and HCP-related factors. Patient-related factors included three subthemes: (1) lack of confidence in their English language abilities in clinical situations (2) cultural attitudes and (3) strategies used to improve communication. Older Filipinos with chronic disease were anxious about their lack of ability to explain their symptoms in English and were concerned that asking questions was conveying distrust in the HCPs. Most of the elderly simply nodded their head to indicate they understood even if they did not, for fear of being thought 'stupid'. Many participants preferred Filipino GPs or have a relative interpret for them. Two subthemes were related to HCPs including (1) not being listened to and (2) assumptions of understanding. HCPs were thought to assume English language skills in Filipino patients and therefore were not careful about ensuring understanding. These findings highlighted the need for HCPs to be more aware of 'grey areas' in English-language proficiency and the cultural lens through which migrants understand health.
Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy
Publisher: American Chemical Society (ACS)
Date: 10-09-2016
The response of fenestrations, actin, and caveolin-1 to vascular endothelial growth factor in SK Hep1 cells
Publisher: American Physiological Society
Date: 07-2008
Abstract: To study the regulation of fenestrations by vascular endothelial growth factor in liver sinusoidal endothelial cells, SK Hep1 cells were transfected with green fluorescence protein (GFP)-actin and GFP-caveolin-1. SK Hep1 cells had pores some of which appeared to be fenestrations (diameter 55 ± 28 nm, porosity 2.0 ± 1.4%), rudimentary sieve plates, bristle-coated micropinocytotic vesicles and expressed caveolin-1, von Willebrand factor, vascular endothelial growth factor receptor-2, endothelial nitric oxide synthase and clathrin, but not CD31. There was avid uptake of formaldehyde serum albumin, consistent with endocytosis. Vascular endothelial growth factor caused an increase in porosity to 4.8 ± 2.6% ( P 0.01) and pore diameter to 104 ± 59 nm ( P 0.001). GFP-actin was expressed throughout the cells, whereas GFP-caveolin-1 had a punctate appearance both responded to vascular endothelial growth factor by contraction toward the nucleus over hours in parallel with the formation of fenestrations. SK Hep1 cells resemble liver sinusoidal endothelial cells, and the vascular endothelial growth factor-induced formation of fenestration-like pores is preceded by contraction of actin cytoskeleton and attached caveolin-1 toward the nucleus.
Frontispiece: Organometallic Conjugates of the Drug Sulfadoxine for Combatting Antimicrobial Resistance
Publisher: Wiley
Date: 17-07-2018
Selective anti-malarial minor groove binders
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.BMCL.2016.05.039
Abstract: A set of 31 DNA minor groove binders (MGBs) with erse structural features relating to both physical chemical properties and DNA binding sequence preference has been evaluated as potential drugs to treat Plasmodium falciparum infections using a chloroquine sensitive strain (3D7) and a chloroquine resistant strain (Dd2) in comparison with human embryonic kidney (HEK) cells as an indicator of mammalian cell toxicity. MGBs with an alkene link between the two N-terminal building blocks were demonstrated to be most active with IC50 values in the range 30-500nM and therapeutic ratios in the range 10->500. Many active compounds contained a C-alkylthiazole building block. Active compounds with logD7.4 values of approximately 3 or 7 were identified. Importantly the MGBs tested were essentially equally effective against both chloroquine sensitive and resistant strains. The results show that suitably designed MGBs have the potential for development into clinical candidates for antimalarial drugs effective against resistant strains of Plasmodia.
Pseudoceratinazole A: a novel bromotyrosine alkaloid from the Australian sponge Pseudoceratina sp.
Publisher: Elsevier BV
Date: 09-2010
2,4-Diaminothienopyrimidines as Orally Active Antimalarial Agents
Publisher: American Chemical Society (ACS)
Date: 28-01-2014
DOI: 10.1021/JM401760C
Abstract: A novel series of 2,4-diaminothienopyrimidines with potential as antimalarials was identified from whole-cell high-throughput screening of a SoftFocus ion channel library. Synthesis and structure-activity relationship studies identified compounds with potent antiplasmodial activity and low in vitro cytotoxicity. Several of these analogues exhibited in vivo activity in the Plasmodium berghei mouse model when administered orally. However, inhibition of the hERG potassium channel was identified as a liability for this series.
Solving the Supply of Resveratrol Tetramers from Papua New Guinean Rainforest Anisoptera Species That Inhibit Bacterial Type III Secretion Systems
Publisher: American Chemical Society (ACS)
Date: 18-11-2014
DOI: 10.1021/NP500433Z
Abstract: The supply of (-)-hopeaphenol (1) was achieved via enzymatic biotransformation in order to provide material for preclinical investigation. High-throughput screening of a prefractionated natural product library aimed to identify compounds that inhibit the bacterial virulence type III secretion system (T3SS) identified several fractions derived from two Papua New Guinean Anisoptera species, showing activity against Yersinia pseudotuberculosis outer proteins E and H (YopE and YopH). Bioassay-directed isolation from the leaves of A. thurifera, and similarly A. polyandra, resulted in three known resveratrol tetramers, (-)-hopeaphenol (1), vatalbinoside A (2), and vaticanol B (3). Compounds 1-3 displayed IC50 values of 8.8, 12.5, and 9.9 μM in a luminescent reporter-gene assay (YopE) and IC50 values of 2.9, 4.5, and 3.3 μM in an enzyme-based YopH assay, respectively, which suggested that they could potentially act against the T3SS in Yersinia. The structures of 1-3 were confirmed through a combination of spectrometric, chemical methods, and single-crystal X-ray structure determinations of the natural product 1 and the permethyl ether analogue of 3. The enzymatic hydrolysis of the β-glycoside 2 to the aglycone 1 was achieved through biotransformation using the endogenous leaf enzymes. This significantly enhanced the yield of the target bioactive natural product from 0.08% to 1.3% and facilitates ADMET studies of (-)-hopeaphenol (1).
Two-pronged attack: Dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors
Publisher: American Chemical Society (ACS)
Date: 24-10-2014
DOI: 10.1021/JM501323A
Abstract: Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics.
Related Organisations
Related Funding Activities
Linkage Projects - Grant ID: LP120200557
Start Date: 06-2013
End Date: 06-2017
Amount: $520,000.00
Funder: Australian Research Council
View Funded ActivityLinkage Projects - Grant ID: LP140100560
Start Date: 01-2015
End Date: 06-2017
Amount: $507,000.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE170100075
Start Date: 2017
End Date: 12-2017
Amount: $315,000.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE130100078
Start Date: 2013
End Date: 05-2014
Amount: $800,000.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP180102601
Start Date: 06-2018
End Date: 12-2021
Amount: $426,149.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE0775768
Start Date: 2007
End Date: 12-2007
Amount: $400,000.00
Funder: Australian Research Council
View Funded Activity