ORCID Profile
0000-0003-4291-7573
Current Organisation
Griffith University
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Infectious Diseases | Biologically active molecules | Biodiscovery | Biodiscovery | Environmental Biotechnology | Natural products and bioactive compounds | Environmental biotechnology |
Flora, Fauna and Biodiversity at Regional or Larger Scales | Infectious Diseases
Publisher: Springer Science and Business Media LLC
Date: 10-01-2018
Publisher: American Chemical Society (ACS)
Date: 26-05-2017
DOI: 10.1021/ACS.JNATPROD.7B00220
Abstract: Seven new dihydro-β-agarofurans, celastrofurans A-G (1-7), along with two known secondary metabolites, 9β-benzoyloxy-1α-furoyloxydihydro-β-agarofuran (8) and (1R,2R,4R,5S,7R,9S,10R)-2-acetoxy-9-benzoyloxy-1-furoyloxydihydro-β-agarofuran (9), were obtained from the leaves of the Australian rainforest vine, Celastrus subspicata. The structures of the new compounds were determined by detailed spectroscopic (1D/2D NMR) and MS data analysis. The absolute configurations of compounds 1-4 were defined by ECD and single-crystal X-ray diffraction studies. All compounds were found to exhibit inhibitory activity on leucine transport in the human prostate cancer cell line LNCaP with IC
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2OB00029F
Abstract: The plant-derived natural product 14-hydroxy-6,12-muuroloadien-15-oic acid (1) was identified as a unique scaffold that could be chemically elaborated to generate novel lead- or drug-like screening libraries. Prior to synthesis a virtual library was generated and prioritised based on drug-like physicochemical parameters such as log P, log D(5.5), hydrogen bond donors/acceptors, and molecular weight. The natural product scaffold (1) was isolated from the endemic Australian plant Eremophila mitchellii and then utilised in the parallel solution-phase generation of two series of analogues. The first library consisted of six semi-synthetic amide derivatives, whilst the second contained six carbamate analogues. These libraries have been evaluated for antimalarial activity using a chloroquine-sensitive Plasmodium falciparum line (3D7) and several compounds displayed low to moderate activity with IC(50) values ranging from 14 to 33 μM.
Publisher: Wiley
Date: 25-07-2016
DOI: 10.1002/MRC.4482
Abstract: Previous investigations of the aerial parts of the Australian plant Eremophila microtheca and Syzygium tierneyanum resulted in the isolation of the antimicrobial flavonoid jaceosidin (4) and 2',6'-dihydroxy-4'-methoxy-3',5'-dimethyl chalcone (7), respectively. In this current study, compounds 4 and 7 were derivatized by acetylation, pivaloylation, and methylation reactions. The final products, 5,7,4'-triacetoxy jaceosidin (10), 5,7,4'-tripivaloyloxy jaceosidin (11), 5,7,4'-trimethoxy jaceosidin (12), 2',6'-diacetoxy-4'-methoxy-3',5'-dimethyl chalcone (13), 2'-hydroxy-4'-methoxy-6'-pivaloyloxy-3',5'-dimethyl chalcone (14), and 2'-hydroxy-4',6'-dimethoxy-3',5'-dimethyl chalcone (15) were all fully characterized by NMR and MS. Derivatives 10 and 13 have been previously reported but were only partially characterized. This is the first reported synthesis of 11 and 14. The natural products and their derivatives were evaluated for their antibacterial and antifungal properties, and the natural product, jaceosidin (4) and the acetylated derivative, 5,7,4'-triacetoxy jaceosidin (10), showed modest antibacterial activity (32-128 µg/ml) against Staphylococcus aureus strains. Copyright © 2016 John Wiley & Sons, Ltd.
Publisher: MDPI AG
Date: 06-02-2023
Abstract: Impairing the motility of glioblastoma multiforme (GBM) cells is a compelling goal for new approaches to manage this highly invasive and rapidly lethal human brain cancer. Work here characterized an array of pharmacological inhibitors of membrane ion and water channels, alone and in combination, as tools for restraining glioblastoma spread in human GBM cell lines U87-MG and U251-MG. Aquaporins, AMPA glutamate receptors, and ion channel classes (shown to be upregulated in human GBM at the transcript level and linked to mechanisms of motility in other cell types) were selected as pharmacological targets for analyses. Effective compounds reduced the transwell invasiveness of U87-MG and U251-MG glioblastoma cells by 20–80% as compared with controls, without cytotoxicity. The compounds and doses used were: AqB013 (14 μM) nifedipine (25 µM) amiloride (10 µM) apamin (10 µM) 4-aminopyridine (250 µM) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione 30 µM). Invasiveness was quantified in vitro across transwell filter chambers layered with extracellular matrix. Co-application of each of the ion channel agents with the water channel inhibitor AqB013 augmented the inhibition of invasion (20 to 50% greater than either agent alone). The motility impairment achieved by co-application of pharmacological agents differed between the GBM proneural-like subtype U87-MG and classical-like subtype U251-MG, showing patterns consistent with relative levels of target channel expression (Human Protein Atlas database). In addition, two compounds, xanthurenic acid and caelestine C (from the Davis Open Access Natural Product-based Library, Griffith University QLD), were discovered to block invasion at micromolar doses in both GBM lines (IC50 values from 0.03 to 1 µM), without cytotoxicity, as measured by full mitochondrial activity under conditions matching those in transwell assays and by normal growth in spheroid assays. Mechanisms of action of these agents based on published work are likely to involve modulation of glutamatergic receptor signaling. Treating glioblastoma by the concurrent inhibition of multiple channel targets could be a powerful approach for slowing invasive cell spread without cytotoxic side effects, potentially enhancing the effectiveness of clinical interventions focused on eradicating primary tumors.
Publisher: Wiley
Date: 08-11-2019
DOI: 10.1002/MRC.4801
Abstract: Four new dihydro-β-agarofurans, denhaminols K-N (4-7), along with three known secondary metabolites, denhaminols A-C (1-3) were obtained from the large-scale isolation studies of the leaves of the Australian endemic rainforest plant, Denhamia celastroides. The structures of the previously undescribed compounds were determined by detailed 1D and 2D nuclear magnetic resonance spectroscopy, mass spectrometry, ultraviolet, and infrared data analysis. All compounds were found to inhibit the activity of leucine transport in a human prostate cancer cell line with IC
Publisher: Hindawi Limited
Date: 2014
DOI: 10.1155/2014/374079
Abstract: Natural product compound collections have proven an effective way to access chemical ersity and recent findings have identified phenolic, coumarin, and polyamine natural products as atypical chemotypes that inhibit carbonic anhydrases (CAs). CA enzymes are implicated as targets of variable drug therapeutic classes and the discovery of selective, drug-like CA inhibitors is essential. Just two natural product polyamines, spermine and spermidine, have until now been investigated as CA inhibitors. In this study, five more complex natural product polyamines 1–5 , derived from either marine sponge or fungi, were considered for inhibition of six different human CA isozymes of interest in therapeutic drug development. All compounds share a simple polyamine core fragment, either spermine or spermidine, yet display substantially different structure activity relationships for CA inhibition. Notably, polyamines 1–5 were submicromolar inhibitors of the cancer drug target CA IX, this is more potent than either spermine or spermidine.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.BMCL.2014.11.055
Abstract: Screening a series of natural product-based tetrahydroanthraquinones led to the identification of a novel molecule, (1S,3S)-austrocortirubin (2), which acts via inducing DNA damage. Compound 2 has a GI50 of 3μM against HCT116 and induces apoptosis. Mechanism of action studies indicate that it causes significant DNA damage during G0/G1, S, and G2 cell cycle phases. Cells are stopped at the G2/M phase checkpoint, and do not reach mitosis due to large amounts of DNA damage. Thus, compound 2 exhibits a unique mechanism of action, one that is distinct from doxorubicin, despite the high degree of structural homology between these two quinone-based structures.
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.
Publisher: MDPI AG
Date: 15-09-2015
DOI: 10.3390/MD13095784
Publisher: MDPI AG
Date: 04-01-2019
DOI: 10.3390/MD17010026
Abstract: Capillasterin A (1), a novel pyrano[2,3-f]chromene, together with seven known naphthopyrones including comaparvin (2), TMC-256C1 (3), 6-methoxycomaparvin-5- methyl ether (4), 5,8-dihydroxy-6-methoxy-2-propyl-4H-naphtho[2,3-b]pyran-4-one (5), 5,8-dihydroxy-6,10-dimethoxy-2-propyl-4H-naphtho[2,3-b]pyran-4-one (6), TMC-256A1 (7) and 6-methoxycomaparvin (8) were isolated from an EtOH/H2O extract from the Australian crinoid Capillaster multiradiatus. The structures of all the compounds were determined by detailed spectroscopic (1D/2D NMR and MS) data analysis. This is the first report of a natural product that contains the pyrano[2,3-f]chromene skeleton. Compounds 2–6 were observed to display moderate inhibition of in vitro HIV-1 replication in a T cell line with EC50 values ranging from 7.5 to 25.5 µM without concomitant cytotoxicity.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2018
DOI: 10.1038/S41598-018-28551-2
Abstract: Olfactory ensheathing cells (OECs) are being trialled for cell transplantation therapies for neural repair as they have unique properties which can enhance neuron regeneration. However, improvements in cell viability, proliferation and migration are needed to enhance therapeutic outcomes. Growth factors can enhance cell activity, but they can also induce side effects as they can act on numerous cell types. An alternative approach is to identify natural products (NPs) that more selectively activate specific cell functions. We have examined two pure NPs, 3-acetoxy-7,8-dihydroxyserrulat-14-en-19-oic acid (RAD288) and 3,7,8-trihydroxyserrulat-14-en-19-oic acid (RAD289) isolated from the Australian plant Eremophila microtheca . We determined that RAD288 and RAD289 stimulated the viability and proliferation of OECs in two-dimensional cultures and increased cell viability in three-dimensional spheroids. Both compounds also enhanced OEC-mediated phagocytosis of neural debris. However, only RAD288 stimulated migration of OECs, demonstrating that key structural changes to the compound can dramatically affect the resultant cellular action. In addition, cell-type specific action is highlighted by the result that neither compound stimulated the viability of Schwann cells which are a closely-related glial cell type. Therefore, these small molecules may have high potential for selective activation of specific therapeutically-useful activities of OECs for transplantation therapies to repair the nervous system.
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.BMCL.2014.05.104
Abstract: Mass-guided fractionation of the MeOH extract from a specimen of the Australian marine sponge Hyrtios sp. resulted in the isolation of two new tryptophan alkaloids, 6-oxofascaplysin (2), and secofascaplysic acid (3), in addition to the known metabolites fascaplysin (1) and reticulatate (4). The structures of all molecules were determined following NMR and MS data analysis. Structural ambiguities in 2 were addressed through comparison of experimental and DFT-generated theoretical NMR spectral values. Compounds 1-4 were evaluated for their cytotoxicity against a prostate cancer cell line (LNCaP) and were shown to display IC50 values ranging from 0.54 to 44.9 μM.
Publisher: American Chemical Society (ACS)
Date: 06-12-2012
DOI: 10.1021/NP300560B
Abstract: Twenty-one new psammaplysin derivatives (4-24) exhibiting a variety of side chains, as well as six previously known psammaplysins, were identified from the Indonesian marine sponge Aplysinella strongylata. The double bond on the side chain of the fatty acid-containing psammaplysins was located by GC-MS analysis of the fatty acid methyl esters and their pyrrolidide derivatives. HPLC and Mosher ester studies confirmed that the isolated metabolites possessing a 19-OH substituent were mixtures of diastereomers. Selected compounds (4, 5, 7, 8, 12, 18, and 22) were screened for in vitro activity against chloroquine-sensitive (3D7) P. falciparum malaria parasites. Of the new psammaplysins, 19-hydroxypsammaplysin E (4) showed the best antimalarial activity, with an IC(50) value of 6.4 μM.
Publisher: Wiley
Date: 23-04-2013
DOI: 10.1002/MRC.3958
Abstract: A focused library based on the marine natural products polyandrocarpamines A (1) and B (2) has been designed and synthesised using parallel solution-phase chemistry. In silico physicochemical property calculations were performed on synthetic candidates in order to optimise the library for drug discovery and chemical biology. A library of ten 2-aminoimidazolone products (3-12) was prepared by coupling glycocyamidine and a variety of aldehydes using a one-step stereoselective aldol condensation reaction under microwave conditions. All analogues were characterised by NMR, UV, IR and MS. The library was evaluated for cytotoxicity towards the prostate cancer cell lines, LNCaP, PC-3 and 22Rv1.
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0NP00089B
Abstract: A comprehensive review of 1490 new MNPs including looekeyolides A and B, which are associated with coral black band disease.
Publisher: American Chemical Society (ACS)
Date: 26-01-1999
DOI: 10.1021/NP9803530
Publisher: Wiley
Date: 04-2013
Abstract: In the period from January 1981 to December 2010, 1068 small-molecule new chemical entities (NCEs) were introduced, of which ca. 34% are either a natural product or a close analogue. While this metric reflects the impact natural products have played in delivering new chemical starting points (leads) for the pharmaceutical industry, it does not capture the decline this approach has suffered over the last 20 years as the high-throughput screening (HTS) of pure compound libraries has become more popular. An impediment to natural-product drug discovery in the HTS paradigm is the lack of a clear strategy that enables front-loading of an extract or fraction's chemical constituents so that they are compliant with lead- and drug-like chemical space. To address this imbalance, an approach based on lipophilicity, as measured by clog P has been developed that, together with advances being made in isolation and structural elucidation, can afford natural product leads in timelines compatible with pure compound screening.
Publisher: Elsevier BV
Date: 11-2009
Publisher: MDPI AG
Date: 31-10-2019
DOI: 10.3390/MOLECULES24213938
Abstract: The reaction of papaverine with a series of Baran DiversinatesTM is reported. Although the yields were low, it was possible to synthesize a small biodiscovery library using this plant alkaloid as a scaffold for late-stage C–H functionalization. Ten papaverine analogues (2–11), including seven new compounds, were synthesized. An unexpected radical-induced exchange reaction is reported where the dimethoxybenzyl group of papaverine was replaced by an alkyl group. This side reaction enabled the synthesis of additional novel fragments based on the isoquinoline scaffold, which is present in numerous natural products. Possible reasons for the poor yields in the DiversinateTM reactions with this particular scaffold are discussed.
Publisher: Wiley
Date: 12-2016
Publisher: Wiley
Date: 07-07-2017
Publisher: MDPI AG
Date: 17-10-2017
DOI: 10.3390/MD15100316
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C7NP00052A
Abstract: This review of 2016 literature describes the structures and biological activities of 1277 new marine natural products and the structure revision and absolute configuration of previously reported MNPs. The chemical ersity of 28 609 MNPs reported since 1957 is also investigated and compared to that of approved drugs.
Publisher: Elsevier BV
Date: 2010
DOI: 10.1016/J.BMC.2009.11.021
Abstract: We have investigated the enzyme inhibition characteristics of a natural product (NP)-based phenolic library against a panel of human carbonic anhydrases (hCAs, EC 4.2.1.1) which included hCAs I and II (cytosolic) and hCA VA/VB (mitochondrial isoforms). Most of these compounds were weak, micromolar inhibitors of the two cytosolic hCAs (K(I)s >10 microM) but showed good hCA VA/VB inhibitory activity with inhibition constants in the range of 70-125 nM. The selectivity ratios for inhibiting the mitochondrial over the cytosolic isoforms for these phenol derivatives were in the range of 120-3800, making them the most isoform-selective compounds for inhibiting hCA VA/VB known to date. The CA VA/VB enzymes are involved in biosynthetic processes such as gluconeogenesis, lipogenesis and ureagenesis, and no pharmacological inhibitors with good selectivity are currently available. Thus the NP inhibitors identified during these studies are excellent leads for obtaining even more effective compounds that selectively target mitochondrial hCAs, and also have the potential to be used as tools for understanding the physiological processes that are regulated by the two mitochondrial CA isoforms.
Publisher: MDPI AG
Date: 16-06-2023
Abstract: Pseudomonas aeruginosa forms stable biofilms, providing a major barrier for multiple classes of antibiotics and severely impairing treatment of infected patients. The biofilm matrix of this Gram-negative bacterium is primarily composed of three major exopolysaccharides: alginate, Psl, and Pel. Here, we studied the antibiofilm properties of sponge-derived natural products ianthelliformisamines A–C and their combinations with clinically used antibiotics. Wild-type P. aeruginosa strain and its isogenic exopolysaccharide-deficient mutants were employed to determine the interference of the compounds with biofilm matrix components. We identified that ianthelliformisamines A and B worked synergistically with ciprofloxacin to kill planktonic and biofilm cells. Ianthelliformisamines A and B reduced the minimum inhibitory concentration (MIC) of ciprofloxacin to 1/3 and 1/4 MICs, respectively. In contrast, ianthelliformisamine C (MIC = 53.1 µg/mL) alone exhibited bactericidal effects dose-dependently on both free-living and biofilm populations of wild-type PAO1, PAO1ΔpslA (Psl deficient), PDO300 (alginate overproducing and mimicking clinical isolates), and PDO300Δalg8 (alginate deficient). Interestingly, the biofilm of the clinically relevant mucoid variant PDO300 was more susceptible to ianthelliformisamine C than strains with impaired polysaccharide synthesis. Ianthelliformisamines exhibited low cytotoxicity towards HEK293 cells in the resazurin viability assay. Mechanism of action studies showed that ianthelliformisamine C inhibited the efflux pump of P. aeruginosa. Metabolic stability analyses indicated that ianthelliformisamine C is stable and ianthelliformisamines A and B are rapidly degraded. Overall, these findings suggest that the ianthelliformisamine chemotype could be a promising candidate for the treatment of P. aeruginosa biofilms.
Publisher: Elsevier BV
Date: 09-2013
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.
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.BMC.2012.09.052
Abstract: As part of a research program aimed at discovering new antimalarial leads from Australian macrofungi a unique fungi-derived prefractionated library was screened against a chloroquine-sensitive Plasmodium falciparum line (3D7) using a radiometric growth inhibition assay. A library fraction derived from a Cortinarius species displayed promising antimalarial activity. UV-guided fractionation on the CH(2)Cl(2)/MeOH extract from this fungus resulted in the isolation of four known compounds: (1S,3R)-austrocortirubin (1), (1S,3S)-austrocortirubin (2), 1-deoxyaustrocortirubin (3), and austrocortinin (4). Compound 2 was used as a natural product scaffold in the parallel solution-phase synthesis of a small library of N-substituted tetrahydroanthraquinones (5-15). All compounds (1-15) were tested in vitro against P. falciparum 3D7 parasites and (1S,3S)-austrocortirubin (2), the major fungal constituent, was shown to be the most active compound with an IC(50) of 1.9 μM. This compound displayed moderate cytotoxicity against neonatal foreskin fibroblast (NFF) cells with an IC(50) of 15.6 μM.
Publisher: American Chemical Society (ACS)
Date: 27-04-2016
DOI: 10.1021/ACS.JNATPROD.6B00190
Abstract: Chemical investigations of the CH2Cl2 extract obtained from the leaves of the Australian rainforest tree Maytenus bilocularis afforded three new dihydro-β-agarofurans, bilocularins A-C (1-3), and six known congeners, namely, celastrine A (4), 1α,6β,8α-triacetoxy-9α-benzoyloxydihydro-β-agarofuran (5), 1α,6β-diacetoxy-9α-benzoyloxy-8α-hydroxydihydro-β-agarofuran (6), Ejap-10 (11), 1α,6β-diacetoxy-9β-benzoyloxydihydro-β-agarofuran (12), and Ejap-2 (13). The major compound 1 was used in semisynthetic studies to afford four ester derivatives (7-10). The chemical structures of 1-3 were elucidated following analysis of 1D/2D NMR and MS data. The absolute configurations of bilocularins A (1) and B (2) were determined by single-crystal X-ray diffraction analysis. All compounds were evaluated for cytotoxic activity against the human prostate cancer cell line LNCaP none of the compounds were active. However, several compounds showed similar potency to the drug efflux pump inhibitor verapamil in reversing the drug resistance of the human leukemia CEM/VCR R cell line. In addition, similar to verapamil, compound 5 was found to inhibit leucine uptake in LNCaP cells (IC50 = 15.5 μM), which was more potent than the leucine analogue 2-aminobicyclo[2.2.1]heptane-2-carbocyclic acid. This is the first report of secondary metabolites from Maytenus bilocularis.
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.
Publisher: Elsevier BV
Date: 09-2015
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).
Publisher: Elsevier BV
Date: 10-2021
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C2OB26879E
Abstract: Four new acylated pteridine alkaloids, duramidines A-D, two new acylated thymidine alkaloids, leptoclinidines A and B, two new 1-acylglyceryl-3-(O-carboxyhydroxymethylcholine) alkaloids, durabetaines A and B, three new 1,3-dimethyl-5-methylsulfanylimidazole alkaloids, leptoclinidamines D-F, and the known alkaloids leptoclinidamines B and C and 6-bromo-1H-indolo-3-yl-oxoacetic acid methyl ester were isolated from the Australian ascidian Leptoclinides durus. The duramidines are the first pteridine alkaloids, possessing a three carbon side chain esterified at C-1' with a 4-hydroxy-2'-methoxycinnamic acid, and are either hydroxylated or sulfated at C-2'. The leptoclinidines are the first 3'-indole-3-carboxylic acid ester derivatives of thymidine to be reported in the literature. The durabetaines are the first glyceryl-3-(O-carboxyhydroxymethylcholine) alkaloids to be reported from an animal source and are also the only known derivatives from this class to be acylated with aromatic carboxylic acids. MS and NMR data analysis established the structures of the new compounds. All compounds were shown to be inactive when tested for cytotoxic activity against prostate (LNCaP) and breast (MDA-MB-231) cancer cell lines and antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus.
Publisher: American Chemical Society (ACS)
Date: 17-02-2023
Publisher: American Chemical Society (ACS)
Date: 21-06-2022
DOI: 10.1021/ACS.JNATPROD.2C00229
Abstract: High-throughput screening of the NatureBank marine extract library (7616 s les) identified an extract derived from the Australian marine sponge
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.BMC.2005.08.030
Abstract: This manuscript reports the use of Fourier transform ion cyclotron resonance mass spectrometry to screen a combinatorially generated natural product-based library for binding affinity to bovine carbonic anhydrase II (bCAII). The fungal natural product 3-chloro-4-hydroxyphenylacetamide was the library template, with 11 secondary amide analogues of this template constituting the combinatorial library. 2-(3-Chloro-4-hydroxyphenyl)-N-(4-sulfamoylphenethyl)acetamide (compound 11) of this library was identified as a tight binding inhibitor of bCAII, by detection of a noncovalent complex corresponding to [bCAII+11] in the mass spectrum. A competitive bCAII enzyme binding assay validated the mass spectrometry screening result. The equilibrium dissociation constant (K(i)) for 11 was measured as 77.4 nM. Preliminary structure-activity investigations of the bioactive natural product analogue are also reported.
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.
Publisher: Elsevier BV
Date: 12-2011
Publisher: Public Library of Science (PLoS)
Date: 11-08-2010
Publisher: MDPI AG
Date: 04-03-2014
DOI: 10.3390/MD12031169
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.
Publisher: American Chemical Society (ACS)
Date: 05-04-2016
DOI: 10.1021/ACS.JNATPROD.5B01029
Abstract: Chemical investigations of an Australian sponge, Clathria hirsuta, from the Great Barrier Reef, have resulted in the isolation of two known anthraquinones, rhodocomatulin 5,7-dimethyl ether (1) and rhodocomatulin 7-methyl ether (2). Additionally, four new anthraquinone metabolites, 6-methoxyrhodocomatulin 7-methyl ether, 3-bromo-6-methoxy-12-desethylrhodocomatulin 7-methyl ether, 3-bromo-6-methoxyrhodocomatulin 7-methyl ether, and 3-bromorhodocomatulin 7-methyl ether (3-6), were also isolated and characterized. This is the first report of the rhodocomatulin-type anthraquinones from a marine sponge, as 1 and 2 were previously isolated from the marine crinoid genus Comatula. An additional chemical investigation of the marine crinoid Comatula rotalaria enabled the isolation of further quantities of 1 and 2, as well as two additional new crinoid metabolites, 12-desethylrhodocomatulin 5,7-dimethyl ether and 12-desethylrhodocomatulin 7-methyl ether (7 and 8). An NMR spectroscopic analysis of compounds 7 and 8 provided further insight into the rhodocomatulin planar structure and, together with the successful implementation of DFT-NMR calculations, confirmed that the rhodocomatulin metabolites existed as para rather than ortho quinones.
Publisher: American Chemical Society (ACS)
Date: 18-02-2011
DOI: 10.1021/JM1013242
Abstract: In order to discover novel probes that may help in the investigation and control of infectious diseases through a new mechanism of action, we have evaluated a library of phenol-based natural products (NPs) for enzyme inhibition against four recently characterized pathogen β-family carbonic anhydrases (CAs). These include CAs from Mycobacterium tuberculosis, Candida albicans, and Cryptococcus neoformans as well as α-family human CA I and CA II for comparison. Many of the NPs selectively inhibited the mycobacterial and fungal β-CAs, with the two best performing compounds displaying submicromolar inhibition with a preference for fungal over human CA inhibition of more than 2 orders of magnitude. These compounds provide the first ex le of non-sulfonamide inhibitors that display β over α CA enzyme selectivity. Structural characterization of the library compounds in complex with human CA II revealed a novel binding mode whereby a methyl ester interacts via a water molecule with the active site zinc.
Publisher: Elsevier BV
Date: 04-2011
Publisher: American Chemical Society (ACS)
Date: 24-11-2015
DOI: 10.1021/ACS.JNATPROD.5B00509
Abstract: In order to identify new anticancer compounds from nature, a prefractionated library derived from Australian endemic plants was generated and screened against the prostate cancer cell line LNCaP using a metabolic assay. Fractions from the seeds, leaves, and wood of Anopterus macleayanus showed cytotoxic activity and were subsequently investigated using a combination of bioassay-guided fractionation and mass-directed isolation. This led to the identification of four new diterpenoid alkaloids, 6α-acetoxyanopterine (1), 4'-hydroxy-6α-acetoxyanopterine (2), 4'-hydroxyanopterine (3), and 11α-benzoylanopterine (4), along with four known compounds, anopterine (5), 7β-hydroxyanopterine (6), 7β,4'-dihydroxyanopterine (7), and 7β-hydroxy-11α-benzoylanopterine (8) all compounds were purified as their trifluoroacetate salt. The chemical structures of 1-8 were elucidated after analysis of 1D/2D NMR and MS data. Compounds 1-8 were evaluated for cytotoxic activity against a panel of human prostate cancer cells (LNCaP, C4-2B, and DuCaP) and nonmalignant cell lines (BPH-1 and WPMY-1), using a live-cell imaging system and a metabolic assay. All compounds showed potent cytotoxicity with IC50 values of <400 nM compound 1 was the most active natural product from this series, with an IC50 value of 3.1 nM toward the LNCaP cell line. The live-cell imaging assay on 1-8 showed a concentration- and time-dependent effect on the cell morphology and proliferation of LNCaP cells.
Publisher: Elsevier BV
Date: 06-2010
Publisher: American Chemical Society (ACS)
Date: 12-01-2015
DOI: 10.1021/NP500740F
Abstract: Eight new dihydro-β-agarofurans, denhaminols A-H (1-8), were isolated from the leaves of the Australian rainforest tree Denhamia celastroides. The chemical structures of 1-8 were elucidated following analysis of 1D/2D NMR and MS data. The absolute configuration of denhaminol A (1) was determined by single-crystal X-ray crystallography. All compounds were evaluated for cytotoxic activity against the human prostate cancer cell line LNCaP, using live-cell imaging and metabolic assays. Denhaminols A (1) and G (7) were also tested for their effects on the lipid content of LNCaP cells. This is the first report of secondary metabolites from D. celastroides.
Publisher: International Union of Crystallography (IUCr)
Date: 06-12-2006
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).
Publisher: Elsevier BV
Date: 04-2019
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.PHYTOCHEM.2015.12.014
Abstract: Eighteen natural products sourced from Australian micro- or macro-fungi were screened for antibacterial and antifungal activity. This focused library was comprised of caprolactams, polyamines, quinones, and polyketides, with additional large-scale isolation studies undertaken in order to resupply previously identified compounds. Chemical investigations of the re-fermented culture from the endophytic fungus Pestalotiopsis sp. yielded three caprolactam analogues, pestalactams D-F, along with larger quantities of the known metabolite pestalactam A, which was methylated using diazomethane to yield 4-O-methylpestalactam A. The chemical structures of the previously undescribed fungal metabolites were determined by analysis of 1D/2D NMR and MS data. The structure of 4-O-methylpestalactam A was confirmed following single crystal X-ray diffraction analysis. The antibacterial and antifungal activity of all compounds was assessed, which identified three compounds, (1S,3R)-austrocortirubin, (1S,3S)-austrocortirubin, and 1-deoxyaustrocortirubin with mild activity (100 μM) against Gram-positive isolates and one compound, 2-hydroxy-6-methyl-8-methoxy-9-oxo-9H-xanthene-1-carboxylic acid, with activity against Cryptococcus neoformans and Cryptococcus gattii at 50 μM.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.VETPAR.2017.07.005
Abstract: The control of parasitic roundworms (nematodes) is heavily reliant on the use of a limited number of anthelmintic drugs. However, drug resistance is now very widespread and no vaccines are available, such that the discovery of new chemical entities is crucial. Within this context, we screened a library of pure natural products (n=400) against exsheathed third-stage (xL3) larvae of the parasitic nematode Haemonchus contortus using a whole-organism screening method. We identified two plant-derived rotenoids, deguelin and rotenone, with inhibitory activity on xL3 motility. Rotenone was not investigated further, because of its toxicity to some vertebrates. The dose response and cytotoxicity studies showed potent and selective inhibitory activity of deguelin on motility of xL3 larvae of H. contortus. Detailed future work needs to be conducted to explore the mode of action of this compound on H. contortus and related nematodes, and to assess its potential as an anthelmintic candidate.
Publisher: Wiley
Date: 10-09-2012
DOI: 10.1002/MRC.3868
Abstract: Bromotyrosine-derived compounds are commonly isolated from Verongida sponges and are a major class of marine natural products. Here we report on the unequivocal (13)C NMR assignment of the brominated carbons at positions C-2 and C-4 of the cyclohexadiene ring, two carbons whose resonances are often incorrectly assigned. Interpretation of HMBC data acquired for a series of known bromotyrosine analogues, which included ianthesine E(1), aerothionin (2), 11-hydroxyaerothionin (3), and 11,19-dideoxyfistularin-3 (4), allowed us to unequivocally assign the carbons in question, C-2 and C-4, through the observance of unique HMBC correlations from the C-1 hydroxyl proton. Here we present the complete 2D NMR data sets recorded in DMSO-d(6) for 2-4 that were used to confirm the assignment and establish the working model. Using this model, a survey of the literature revealed that many members of this structure class had been wrongly assigned. This paper serves to reassign those compounds whose (13)C NMR assignment at positions C-2 and C-4 of the cyclohexadiene ring should be reversed.
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8CC00090E
Abstract: Selective protein unfolding was combined with high-throughput differential scanning fluorimetry of GFP-tagged proteins for the identification of irreversible enzyme inhibitors.
Publisher: American Chemical Society (ACS)
Date: 06-2020
Publisher: American Chemical Society (ACS)
Date: 28-12-2011
DOI: 10.1021/NP200687V
Abstract: While natural products or their derivatives and mimics have contributed around 50% of current drugs, there has been no approach allowing front-loading of chemical space compliant with lead- and drug-like properties. The importance of physicochemical properties of molecules in the development of orally bioavailable drugs has been recognized. Classical natural product drug discovery has only been able to undertake this analysis retrospectively after compounds are isolated and structures elucidated. The present approach addresses front-loading of both extracts and subsequent fractions with desired physicochemical properties prior to screening for drug discovery. The physicochemical profiles of natural products active against two neglected disease targets, malaria and African trypanosomiasis, are presented based on this strategy. This approach can ensure timely development of natural product leads at a hitherto unachievable rate.
Publisher: Wiley
Date: 18-05-2015
DOI: 10.1111/FEBS.13313
Abstract: The mycobacterial enzyme Rv1284 is a member of the β-carbonic anhydrase family that is considered essential for survival of the pathogen. The active site cavity of this dimeric protein is characterized by an exceptionally small volume and harbours a catalytic zinc ion coordinated by two cysteine and one histidine residue side chains. Using the natural products polycarpine and emodin as chemical probes in crystallographic experiments and stopped-flow enzyme assays, we report that the catalytic activity can be reversibly inhibited by oxidation. Oxidative conditions lead to the removal of one of the active site cysteine residues from the coordination sphere of the catalytic metal ion by engagement in a disulfide bond with another cysteine residue close by. The subsequent loss of the metal ion, which is supported by crystallographic analysis, may thus render the protein catalytically inactive. The oxidative inhibition of Rv1284 can be reversed by exposing the protein to reducing conditions. Because the physical size of the chemical probes used in the present study substantially exceeds the active site volume, we hypothesized that these compounds exert their effects from a surface-bound location and identified Tyr120 as a critical residue for oxidative inactivation. These findings link conditions of oxidative stress to pH homeostasis of the pathogen. Because oxidative stress and acidification are defence mechanisms employed by the innate immune system of the host, we suggest that Rv1284 may be a component of the mycobacterial survival strategy. Atomic coordinates and structure factors have been deposited in the Protein Data Bank under accession numbers 4yf4, 4yf5 and 4yf6.
Publisher: American Chemical Society (ACS)
Date: 04-11-2013
DOI: 10.1021/NP400617H
Abstract: Chemical investigations of two specimens of Trikentrion flabelliforme collected from Australian waters have resulted in the identification of four new indole alkaloids, trikentramides A-D (9-12). The planar chemical structures for 9-12 were established following analysis of 1D/2D NMR and MS data. The relative configurations for 9-12 were determined following the comparison of (1)H NMR data with data previously reported for related natural products. The application of a quantum mechanical modeling method, density functional theory, confirmed the relative configurations and also validated the downfield carbon chemical shift observed for one of the quaternary carbons (C-5a) in the cyclopenta[g]indole series. The indole-2,3-dione motif present in trikentramides A-C is rare in nature, and this is the first report of these oxidized indole derivatives from a marine sponge.
Publisher: Future Science Ltd
Date: 06-2012
DOI: 10.4155/FMC.12.55
Abstract: Natural products (NPs) have historically been a fertile source of new drugs for the pharmaceutical industry. However, this once-popular approach has waned considerably over the past two decades as the high-throughput screening of megalibraries comprised mainly of molecules with non-natural (synthetic) motifs has unfolded. Contemporary high-throughput screening libraries contain molecules compliant with physicochemical profiles considered essential for downstream development. Until recently, there was no strategy that aligned NP screening with the same physicochemical profiles. An approach based on Log P has addressed these concerns and, together with advances in isolation, afforded NP leads in timelines compatible with pure compound screening. Concomitant progress related to access of biological resources has provided long-awaited legal certainty to further facilitate NP drug discovery.
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D1NP00076D
Abstract: A comprehensive review of 1407 new MNPs including turbinmicin, a potent antifungal lead isolated from a marine bacterium.
Publisher: MDPI AG
Date: 12-10-2017
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.
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.BMC.2012.07.021
Abstract: Natural products (NPs) have proven to be an invaluable source of new chemotherapies yet very few have been explored to source small molecule carbonic anhydrase (CA) inhibitors. CA enzymes underpin physiological pH and are critical to the progression of several diseases including cancer. The present study is the first to more widely investigate NP coumarins for CA inhibition following the recent discovery of a NP coumarin CA inhibitor. We assembled a NP library comprising 24 plant coumarins (compounds 4-27) and three ascidian coumarins (compounds 28-30) that together provide a erse collection of structures containing the coumarin pharmacophore. This library was then evaluated for inhibition of six human CA isozymes (CAs I, II, VII, IX, XII and XIII) and a broad range of inhibition and isozyme selectivity profiles were evident. Our findings provide a platform to support further evaluation of NPs for the discovery of new chemotypes that inhibit disease relevant CA enzymes.
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C6NP00093B
Abstract: This review summarises known crinoid chemistry from 1877 to the present day, and discusses some of the problems (and potential solutions) with establishing crinoid natural product structures, as well as future directions for crinoid research.
Publisher: Elsevier BV
Date: 2010
Publisher: American Association for Cancer Research (AACR)
Date: 2017
DOI: 10.1158/1535-7163.MCT-16-0325
Abstract: The lack of a cure for metastatic castrate-resistant prostate cancer (mCRPC) highlights the urgent need for more efficient drugs to fight this disease. Here, we report the mechanism of action of the natural product 6α-acetoxyanopterine (6-AA) in prostate cancer cells. At low nanomolar doses, this potent cytotoxic alkaloid from the Australian endemic tree Anopterus macleayanus induced a strong accumulation of LNCaP and PC-3 (prostate cancer) cells as well as HeLa (cervical cancer) cells in mitosis, severe mitotic spindle defects, and asymmetric cell isions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. DNA microarray of 6-AA–treated LNCaP cells combined with pathway analysis identified very similar transcriptional changes when compared with the anticancer drug vinblastine, which included pathways involved in mitosis, microtubule spindle organization, and microtubule binding. Like vinblastine, 6-AA inhibited microtubule polymerization in a cell-free system and reduced cellular microtubule polymer mass. Yet, microtubule alterations that are associated with resistance to microtubule-destabilizing drugs like vinca alkaloids (vinblastine/vincristine) or 2-methoxyestradiol did not confer resistance to 6-AA, suggesting a different mechanism of microtubule interaction. 6-AA is a first-in-class microtubule inhibitor that features the unique anopterine scaffold. This study provides a strong rationale to further develop this novel structure class of microtubule inhibitor for the treatment of malignant disease. Mol Cancer Ther 16(1) 3–15. ©2016 AACR.
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4MD00310A
Abstract: Mycobacterial carbonic anhydrases, such as the essential protein Rv3588c, are attractive drug targets since they constitute a different class of carbonic anhydrases than those found in humans.
Publisher: MDPI AG
Date: 27-09-2021
DOI: 10.3390/MOLECULES26195846
Abstract: Widespread resistance in parasitic nematodes to most classes of anthelmintic drugs demands the discovery and development of novel compounds with distinct mechanisms of action to complement strategic or integrated parasite control programs. Products from nature—which assume a erse ‘chemical space’—have significant potential as a source of anthelmintic compounds. In the present study, we screened a collection of extracts (n = 7616) derived from marine invertebrates s led from Australian waters in a high throughput bioassay for in vitro anti-parasitic activity against the barber’s pole worm (Haemonchus contortus)—an economically important parasitic nematode of livestock animals. In this high throughput screen (HTS), we identified 58 active extracts that reduced larval motility by ≥70% (at 90 h), equating to an overall ‘hit rate’ of ~0.8%. Of these 58 extracts, 16 also inhibited larval development by ≥80% (at 168 h) and/or induced ‘non-wild-type’ (abnormal) larval phenotypes with reference to ‘wild-type’ (normal) larvae not exposed to extract (negative controls). Most active extracts (54 of 58) originated from sponges, three from chordates (tunicates) and one from a coral these extracts represented 37 distinct species/taxa of 23 families. An analysis of s les by 1H NMR fingerprinting was utilised to dereplicate hits and to prioritise a set of 29 sponge s les for future chemical investigation. Overall, these results indicate that a range of sponge species from Australian waters represents a rich source of natural compounds with nematocidal or nematostatic properties. Our plan now is to focus on in-depth chemical investigations of the s le set prioritised herein.
Publisher: Springer Netherlands
Date: 17-09-2013
DOI: 10.1007/978-94-007-7359-2_16
Abstract: The chemical ersity, binding specificity and propensity to interact with biological targets has inspired many researchers to utilize natural products as molecular probes. Almost all reported carbonic anhydrase inhibitors comprise a zinc binding group in their structure of which the primary sulfonamide moiety (-SO2NH2) is the foremost ex le and to a lesser extent the primary sulfamate (-O-SO2NH2) and sulfamide (-NH-SO2NH2) groups. Natural products that comprise these zinc binding groups in their structure are however rare and relatively few natural products have been explored as a source for novel carbonic anhydrase inhibitors. This chapter will highlight the recent and growing interest in carbonic anhydrase inhibitors sourced from nature, demonstrating that natural product chemical space presents a rich source of potential alternate chemotypes for the discovery of novel drug-like carbonic anhydrase inhibitors.
Publisher: Wiley
Date: 16-11-2016
Publisher: Springer Science and Business Media LLC
Date: 14-08-2017
DOI: 10.1038/S41598-017-08404-0
Abstract: The human cytochrome P450 2D6 (CYP2D6) enzyme is part of phase-I metabolism and metabolizes at least 20% of all clinically relevant drugs. Therefore, it is an important target for drug-drug interaction (DDI) studies. High-throughput screening (HTS) assays are commonly used tools to examine DDI, but show certain drawbacks with regard to their applicability to natural products. We propose an in silico – in vitro workflow for the reliable identification of natural products with CYP2D6 inhibitory potential. In order to identify candidates from natural product-based databases that share similar structural features with established inhibitors, a pharmacophore model was applied. The virtual hits were tested for the inhibition of recombinant human CYP2D6 in a bioluminescence-based assay. By controlling for unspecific interferences of the test compounds with the detection reaction, the number of false positives were reduced. The success rate of the reported workflow was 76%, as most of the candidates identified in the in silico approach were able to inhibit CYP2D6 activity. In summary, the workflow presented here is a suitable and cost-efficient strategy for the discovery of new CYP2D6 inhibitors with natural product libraries.
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/B924169H
Abstract: Chemical investigations of a fermentation culture from the endophytic fungus Pestalotiopsis sp. yielded three novel caprolactams, pestalactams A-C (). The structures of were determined by analysis of 1D and 2D-NMR, UV, IR, and MS data. The structure of pestalactam A was confirmed following single crystal X-ray diffraction analysis. Pestalactams A-C are the first C-7 alkylated caprolactam natural products to be reported. Pestalactams A () and B () were tested against two different strains of the malaria parasite Plasmodium falciparum (3D7 and Dd2), and the mammalian cell lines, MCF-7 and NFF, and showed modest in vitro activity in all assays.
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
Publisher: Springer Science and Business Media LLC
Date: 23-08-2014
DOI: 10.1007/S00284-013-0415-5
Abstract: Limited knowledge currently exists regarding species ersity and antimicrobial activity of endophytic isolates of Preussia within Australia. This report describes endophytic Preussia species that were identified through molecular analysis of the internal transcribed spacer region. Screening for antimicrobial secondary metabolites was determined by testing crude ethyl acetate (EtOAc) extracts derived from fungal mycelia against a panel of ATCC type strains which included Bacillus cereus, Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, Serratia marcescens, methicillin-resistant Staphylococcus aureus (MRSA) and the opportunist yeast pathogen Candida albicans. Subsequently, high-performance liquid chromatography generated fractions of bioactive EtOAc extracts which were subject to confirmatory testing using the Clinical and Laboratory Standards Institute reference microdilution antimicrobial activity assay. A total of 18 Preussia were isolated from nine host plants with 6/18 having a <97 % sequence similarity to other known species in Genbank, suggesting that they are new species. In preliminary screening, 13/18 Preussia isolates revealed antimicrobial activity against at least one of the microbes tested, whilst 6/18 isolates, including 4/6 putative new species showed specific antimicrobial activity against MRSA and C. albicans. These results highlight the antimicrobial potential of Australian Preussia spp. and also the importance of Australian dry rainforests as an untapped repository of potentially significant bioactive compounds.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.BMCL.2017.05.021
Abstract: The plant natural product, valerenic acid (1) was chosen as a desirable scaffold for the generation of a novel screening library due to its drug-like physicochemical parameters (such as LogP, hydrogen bond donor/acceptor counts, and molecular weight). An 11-membered amide library (2-12) was subsequently generated using parallel solution-phase synthesis and Ghosez's reagent. The chemical structures of all semi-synthetic analogues (2-12) were elucidated following analysis of the NMR, MS, UV and IR data. The structures of compounds 8 and 11 were also confirmed by X-ray crystallographic analysis. All library members were evaluated for their ability to inhibit the release of IL-8 and TNF-α. Six analogues showed moderate activity in the IL-8 assay with IC
Publisher: Informa UK Limited
Date: 12-10-2023
Publisher: MDPI AG
Date: 23-10-2019
DOI: 10.3390/MD17110598
Abstract: There is an urgent need to discover and develop new anthelmintics for the treatment of parasitic nematodes of veterinary importance to circumvent challenges linked to drug resistant parasites. Being one of the most erse natural ecosystems, the marine environment represents a rich resource of novel chemical entities. This study investigated 2000 extracts from marine invertebrates, collected from Australian waters, for anthelmintic activity. Using a well-established in vitro bioassay, these extracts were screened for nematocidal activity against Haemonchus contortus — a socioeconomically important parasitic nematode of livestock animals. Extracts (designated Mu-1, Ha-1 and Ha-2) from two marine sponges (Monanchora unguiculata and Haliclona sp.) each significantly affected larvae of H. contortus. In idual extracts displayed a dose-dependent inhibition of both the motility of exsheathed third-stage larvae (xL3s) and the development of xL3s to fourth-stage larvae (L4s). Active fractions in each of the three extracts were identified using bioassay-guided fractionation. From the active fractions from Monanchora unguiculata, a known pentacyclic guanidine alkaloid, fromiamycalin (1), was purified. This alkaloid was shown to be a moderately potent inhibitor of L4 development (half-maximum inhibitory concentration (IC50) = 26.6 ± 0.74 µM) and L4 motility (IC50 = 39.4 ± 4.83 µM), although it had a relatively low potency at inhibiting of xL3 motility (IC50 ≥ 100 µM). Investigation of the active fractions from the two Haliclona collections led to identification of a mixture of amino alcohol lipids, and, subsequently, a known natural product halaminol A (5). Anthelmintic profiling showed that 5 had limited potency at inhibiting larval development and motility. These data indicate that fromiamycalin, other related pentacyclic guanidine alkaloids and/or halaminols could have potential as anthelmintics following future medicinal chemistry efforts.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.DRUDIS.2016.01.002
Abstract: The treatment of major human parasitic infections is dependent on drugs that are plagued by issues of drug resistance. New chemotherapeutics with novel mechanisms of action (MOA) are desperately needed to combat multi-drug-resistant parasites. Although widespread screening strategies are identifying potential new hits for development against most major human parasitic diseases, in many cases such efforts are hindered by limited MOA data. Although MOA data are not essential for drug development, they can facilitate compound triage and provide a mechanism to combat drug resistance. Here we describe and discuss methods currently used to identify the targets of antiparasitic compounds, which could circumvent this bottleneck and facilitate the development of new antiparasitic drugs.
Publisher: MDPI AG
Date: 09-12-2021
DOI: 10.3390/MD19120698
Abstract: High-throughput screening of the NatureBank marine extract library (n = 7616) using a phenotypic assay for the parasitic nematode Haemonchus contortus identified an active extract derived from the Australian marine sponge Citronia sp. Bioassay-guided fractionation of the CH2Cl2/MeOH extract from Citronia sp. resulted in the purification of two known hexachlorinated peptides, dysidenin (1) and dysideathiazole (2). Compound 1 inhibited the growth/development of H. contortus larvae and induced multiple phenotypic changes, including a lethal evisceration (Evi) phenotype and/or somatic cell and tissue destruction. This is the first report of anthelmintic activity for these rare and unique polychlorinated peptides.
Publisher: International Union of Crystallography (IUCr)
Date: 08-09-2010
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4OB01849D
Abstract: A series of amide and urea analogues based on the thiaplakortone A natural product scaffold were synthesised and screened for in vitro antimalarial activity.
Publisher: Public Library of Science (PLoS)
Date: 13-11-2012
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.
Publisher: Informa UK Limited
Date: 04-03-2018
Publisher: American Chemical Society (ACS)
Date: 30-08-2011
DOI: 10.1021/NP2003676
Abstract: Chemical investigations of the Australian plant Eremophila mitchellii resulted in the isolation of the novel tetracyclic sesquiterpene lactones mitchellenes A-C (1-3), the new sesquiterpene acids mitchellenes D and E (4 and 5), and the previously reported natural products 14-hydroxy-6,12-muuroloadien-15-oic acid (6), casticin, and centaureidin. The chemical structures of all compounds were determined by extensive 1D/2D NMR and MS data analysis. Mitchellenes A-C are the first tetracyclic sesquiterpene lactones to be reported a biosynthetic pathway is proposed for these unique secondary metabolites.
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).
Publisher: American Chemical Society (ACS)
Date: 02-01-2013
DOI: 10.1021/ML400447V
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C5NP00121H
Abstract: This Highlight examines the use of isolated natural products as scaffolds in the semi-synthesis of drug discovery libraries, and the potential of this rarely used method to contribute to successful natural product library generation strategies.
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D2NP00083K
Abstract: A comprehensive review of 1425 new MNPs including a novel cyanobacterial cyclodepsipeptide, gatorbulin-1, that targets a 7th tubulin binding site.
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1016/J.BMC.2011.12.037
Abstract: 5-Methoxyflavenes and 6-methoxyflavenes were found to undergo stereoselective acid-catalyzed rearrangement to generate a range of novel chromeno[2,3-b]chromene derivatives. When subjected to an in vitro antiplasmodial growth inhibition assay using Plasmodium falciparum (3D7 line) the chromene analogues were shown to display IC(50) values ranging from 6.8 to 39.8 μM.
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.PHYTOCHEM.2018.01.009
Abstract: Phytochemical studies of the roots of the Australian plant, Maytenus bilocularis, resulted in the identification of six previously undescribed dihydro-β-agarofuran sesquiterpenoids, bilocularins D-I, along with three known natural products, namely 1α,2α,6β,15-tetraacetoxy-9β-benzoyloxydihydro-β-agarofuran, pristimerin, and celastrol. The structures of all compounds were characterized via analysis of 1D/2D NMR and MS data. The absolute configuration of bilocularin D was defined by X-ray crystallography analysis. Bilocularins D and G, 1α,2α,6β,15-tetraacetoxy-9β-benzoyloxydihydro-β-agarofuran, and celastrol inhibited leucine transport in the human prostate cancer cell line LNCaP with IC
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.
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.
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.BMCL.2010.11.081
Abstract: Mass-directed isolation of the CH(2)Cl(2)/CH(3)OH extract from a marine sponge of the genus Pseudoceratina resulted in the purification of a new antimalarial bromotyrosine alkaloid, psammaplysin H (1), along with the previously isolated analogs psammaplysins G (2) and F (3). The structure of 1 was elucidated following 1D and 2D NMR, and MS data analysis. All compounds were tested in vitro against the 3D7 line of Plasmodium falciparum and mammalian cell lines (HEK293 and HepG2), with 1 having the most potent (IC(50) 0.41μM) and selective (>97-fold) antimalarial activity.
Publisher: American Chemical Society (ACS)
Date: 21-07-2020
Publisher: Wiley
Date: 19-03-2007
DOI: 10.1002/MRC.1984
Abstract: Parallel solution-phase chemistry has yielded a series of secondary amide analogues of the fungal natural product 3-chloro-4-hydroxyphenylacetamide. 3-Chloro-4-hydroxyphenylacetic acid was coupled to a variety of primary amines using 1-ethyl-3-(3'-dimethylamino- propyl)-carbodiimide hydrochloride. The desired products were obtained in good yield and high purity following rapid silica purification. All analogues were spectroscopically characterised using NMR, UV, IR and MS data. One compound displayed moderate cytotoxicity against the human melanoma and prostate cell lines, MM96L and DU145.
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.
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.
Publisher: American Chemical Society (ACS)
Date: 20-03-2017
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.
Publisher: MDPI AG
Date: 28-02-2019
DOI: 10.3390/MOLECULES24050859
Abstract: An analytical method using UHPLC-MS was developed and applied to 16 crude CH2Cl2 extracts from Australian Celastraceae plants the endemic plant materials were accessed from Griffith University’s NatureBank resource and included bark, fruit, leaf, root, twig and mixed s les, all of which were collected from Queensland, Australia. The generated UHPLC-MS data were analysed and dereplicated using the scientific databases Dictionary of Natural Products and SciFinder Scholar in order to potentially identify new dihydro-β-agarofurans from local Celastraceae plants. These investigations led to the large-scale extraction and isolation work on a prioritised fruit s le that belonged to the rainforest plant Denhamia celastroides. Chemical investigations resulted in the purification of four new natural products, denhaminols O–R (1–4), along with the related and known compound, denhaminol G (5). The structures of all the new compounds were determined via detailed analysis of NMR and MS data.
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.BMCL.2013.06.082
Abstract: Described is the antibiotic activity of a marine natural product. Psammaplysin F (1) inhibited the growth of four Gram-positive strains by >80% at 50μM, and the amine at position C-20 is responsible for the observed antibacterial activity. When tested against two strains of methicillin resistant Staphylococcus aureus (MRSA), the minimum inhibitory concentrations (MICs) for psammaplysin F (40-80μM) were similar to the structurally-related alkaloid psammaplysin H (2). Psammaplysin F (1) increased membrane permeability by two to four-fold compared to psammaplysin H (2) or control-treated bacteria, respectively. Unlike psammaplysin H (2), we show that psammaplysin F (1) inhibits equal partitioning of DNA into each daughter cell, suggesting that this natural product is a unique prokaryotic cell ision inhibitor.
Publisher: Public Library of Science (PLoS)
Date: 04-12-2013
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.
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).
Publisher: Elsevier BV
Date: 04-2003
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.PHYTOCHEM.2013.02.021
Abstract: Chemical investigations of the aerial parts of the Australian plant Eremophila microtheca resulted in the isolation of three serrulatane diterpenoids, 3-acetoxy-7,8-dihydroxyserrulat-14-en-19-oic acid (1), 3,7,8-trihydroxyserrulat-14-en-19-oic acid (2) and 3,19-diacetoxy-8-hydroxyserrulat-14-ene (3) as well as the previously reported compounds verbascoside (4) and jaceosidin (5). Acetylation and methylation of the major serrulatane diterpenoid 2 afforded 3,8-diacetoxy-7-hydroxyserrulat-14-en-19-oic acid (6) and 3,7,8-trihydroxyserrulat-14-en-19-oic acid methyl ester (7), respectively. The antibacterial activity of 1-7 was assessed against a panel of Gram-positive and Gram-negative bacterial isolates. All of the serrulatane compounds exhibited moderate activity against Streptococcus pyogenes (ATCC 12344) with minimum inhibitory concentrations (MICs) ranging from 64-128 μg/mL. Serrulatane 1 demonstrated activity against all Gram-positive bacterial strains (MICs 64-128 μg/mL) except for Enterococcus faecalis and Enterococcus faecium. This is the first report of natural products from E. microtheca.
Publisher: Elsevier BV
Date: 09-2011
DOI: 10.1016/J.BMC.2011.07.009
Abstract: 7-Methoxyflavenes and 5,7,8-trimethoxyflavenes were found to undergo stereoselective acid-catalyzed rearrangement to generate the benzopyrano[4,3-b]benzopyran ring system present in the natural product, dependensin. Dependensin and its analogs were subjected to antimalarial growth inhibition assays against Plasmodium falciparum and found to have IC(50) values ranging between 1.9 and 3.9 μM.
Publisher: MDPI AG
Date: 12-10-2023
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.PHYTOCHEM.2012.09.019
Abstract: Chemical investigation of the CH(2)Cl(2)/CH(3)OH extracts from aerial parts of the Australian plant Goniothalamus australis has resulted in the isolation of two pyridocoumarin alkaloids, goniothalines A (1) and B (2) as well as eight known natural products, aristolactam AII (3), enterocarpam II (4), caldensine (5), sauristolactam (6), (-)-anonaine (7), asimilobine (8), altholactone (9) and (+)-goniofufurone (10). The chemical structures of all compounds were determined by extensive spectroscopic and spectrometric analysis. Methylation of 2 using TMS-diazomethane afforded 1, which unequivocally established that both 1 and 2 possessed a 10-methyl-2H-pyrano[2,3-f]quinolin-2-one skeleton. These pyridocoumarin alkaloids are putatively proposed to arise biosynthetically from an aporphinoid precursor. Compounds 1-10 were evaluated for in vitro antimalarial activity against a chloroquine-sensitive Plasmodium falciparum line (3D7). Sauristolactam (6) and (-)-anonaine (7) exhibited the most potent antiparasitic activity with IC(50) values of 9 and 7 μM, respectively.
Publisher: Wiley
Date: 06-07-2006
DOI: 10.1002/MRC.1872
Abstract: The complete 1H and 13C NMR assignments are reported for the new natural products, 7-hydroxy-3-(hydroxymethyl)-1-methoxy-9H-xanthen-9-one (1) and 2,5-dihydroxy-8-methoxy-6-methyl-9-oxo-9H-xanthene -1-carboxylic acid (2). Both of these secondary metabolites were isolated from the fermentation culture of the endophytic fungus Xylaria sp. FRR 5657. 1D and 2D NMR experiments that included 1H, gCOSY, gHSQC and gHMBC were used for the determination of the structure and assignment of these xanthones.
Publisher: American Chemical Society (ACS)
Date: 23-02-2018
DOI: 10.1021/ACS.JNATPROD.7B00929
Abstract: The naturally occurring pentacyclic diterpenoid gibberellic acid (1) was used in the generation of a drug-like amide library using parallel-solution-phase synthesis. Prior to the synthesis, a virtual library was generated and prioritized based on drug-like physicochemical parameters such as log P, hydrogen bond donor/acceptor counts, and molecular weight. The structures of the synthesized analogues (2-13) were elucidated following analysis of the NMR, MS, UV, and IR data. Compound 12 afforded crystalline material, and its structure was confirmed by X-ray crystallographic analysis. All compounds were evaluated in vitro for cytotoxicity and deregulation of lipid metabolism in LNCaP prostate cancer cells. While no cytotoxic activity was identified at the concentrations tested, synthesized analogues 3, 5, 7, 10, and 11 substantially reduced cellular uptake of free cholesterol in prostate cancer cells, suggesting a novel role of gibberellic acid derivatives in deregulating cholesterol metabolism.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/C9NP00069K
Abstract: A comprehensive review of 1554 new MNPs, including numerous novel and bioactive compounds from marine bacteria.
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.
Publisher: Wiley
Date: 19-10-2018
DOI: 10.1111/MPP.12736
Abstract: The identification of chemical compounds that prevent and combat bacterial diseases is fundamental for crop production. Bacterial virulence inhibitors are a promising alternative to classical control treatments, because they have a low environmental impact and are less likely to generate bacterial resistance. The major virulence determinant of most animal and plant bacterial pathogens is the type III secretion system (T3SS). In this work, we screened nine plant extracts and 12 isolated compounds—including molecules effective against human pathogens—for their capacity to inhibit the T3SS of plant pathogens and for their applicability as virulence inhibitors for crop protection. The screen was performed using a luminescent reporter system developed in the model pathogenic bacterium Ralstonia solanacearum . Five synthetic molecules, one natural product and two plant extracts were found to down‐regulate T3SS transcription, most through the inhibition of the regulator hrpB. In addition, for three of the molecules, corresponding to salicylidene acylhydrazide derivatives, the inhibitory effect caused a dramatic decrease in the secretion capacity, which was translated into impaired plant responses. These candidate virulence inhibitors were then tested for their ability to protect plants. We demonstrated that salicylidene acylhydrazides can limit R. solanacearum multiplication in planta and protect tomato plants from bacterial speck caused by Pseudomonas syringae pv. tomato . Our work validates the efficiency of transcription reporters to discover compounds or natural product extracts that can be potentially applied to prevent bacterial plant diseases.
Publisher: Elsevier BV
Date: 07-2015
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).
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.
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
Publisher: American Chemical Society (ACS)
Date: 19-05-2010
DOI: 10.1021/NP100010Z
Abstract: Three new bastadins, bastadin 25 (1), 15-O-sulfonatobastadin 11 (2), and bastadin 26 (3), were isolated from a MeOH extract of the Australian marine sponge Ianthella flabelliformis. Their structures were determined by interpretation of 1D and 2D NMR spectra and mass spectrometry. Bastadin 26 (3) showed potent affinity for the guinea pig delta-opioid receptors with a K(i) value of 100 nM. The other two bastadins had a 100-fold lower affinity. The three compounds were also tested for their affinity to guinea pig micro- and kappa-opioid receptors and shown to have either no affinity or only very weak affinity toward both of these opioid receptors.
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7MD00090A
Abstract: This study reports the most active non-sulfonamide mycobacterial CA inhibitor to date.
Publisher: Elsevier BV
Date: 05-2010
Publisher: Public Library of Science (PLoS)
Date: 06-11-2014
Publisher: Beilstein Institut
Date: 15-11-2022
DOI: 10.3762/BJOC.18.164
Abstract: In order to further expand the NatureBank open access compound library, chemical investigations of the Australian marine sponge, Ianthella basta, were undertaken since UHPLC–MS analysis of the extract from this sponge indicated the presence of a new alkaloid. Large-scale extraction and mass-directed isolation studies on the CH 2 Cl 2 /MeOH I. basta extract resulted in the purification of a new bromotyrosine-derived alkaloid, 5-debromopurealidin H ( 1 ), along with the known marine natural product, ianthesine E ( 2 ). The chemical structure of the new compound was determined following detailed spectroscopic and spectrometric data analysis. These two compounds ( 1 and 2 ) along with seven previously reported marine bromotyrosine alkaloids from the NatureBank open access library, which included psammaplysins F ( 3 ) and H ( 4 ), bastadins 4 ( 5 ), 8 ( 6 ) and 13 ( 7 ), aerothionin ( 8 ) and hexadellin A ( 9 ), were evaluated for their nematocidal activity against exsheathed third-stage larvae of Haemonchus contortus , a highly pathogenic parasite of ruminants. Of the nine compounds, bastadin 8 ( 6 ), hexadellin A ( 9 ) and bastadin 4 ( 5 ) showed inhibition towards larval motility after 72 h of exposure with IC 50 values of 1.6 µM, 10.0 µM and 33.3 µM, respectively.
Publisher: Informa UK Limited
Date: 12-2006
DOI: 10.1080/14786410601101811
Abstract: The absolute stereochemistry of longithorone J (1) from the ascidian Aplidium longithorax has been determined using the advanced Mosher method. Based on biosynthetic reasoning and chiroptical data comparison the absolute stereochemistry for longithorone K (2) was also assigned. Longithorone J was tested for cytotoxicity against the cell lines SHSY5Y, HEK293T and A549. Compound 1 showed minimal cytotoxicity towards the SHSY5Y and HEK293T cell lines.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C8NP00092A
Abstract: A comprehensive review of 1490 new MNPs including the first naturally occurring blue zwitterionic quinoids dactylocyanines A–H is presented.
Publisher: MDPI AG
Date: 17-10-2014
DOI: 10.3390/MD12105222
Publisher: Elsevier BV
Date: 09-2010
Publisher: Frontiers Media SA
Date: 18-12-2018
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).
Start Date: 2012
End Date: 2015
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2012
End Date: 2015
Funder: Australian Research Council
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End Date: 2021
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2017
End Date: 2018
Funder: Prostate Cancer Foundation of Australia
View Funded ActivityStart Date: 2005
End Date: 2006
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 11-2012
End Date: 01-2014
Amount: $279,000.00
Funder: Australian Research Council
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End Date: 02-2024
Amount: $1,078,770.00
Funder: Australian Research Council
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