ORCID Profile
0000-0002-7537-247X
Current Organisations
University of Bristol
,
University of Western Australia
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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)
Organic Chemical Synthesis | Analytical Chemistry | Biochemistry and cell biology | Natural products and bioactive compounds | Analytical Spectrometry | Structural Chemistry | Organometallic chemistry | Organic Chemistry | Synthetic biology | Structural biology (incl. macromolecular modelling) | Physical Chemistry (Incl. Structural) | Other Instrumental Methods | Inorganic chemistry | Industrial Chemistry | Supramolecular Chemistry | Transition metal chemistry | Materials Engineering Not Elsewhere Classified | Condensed Matter Physics—Structural Properties
ANZSRC Socio-Economic Objective (SEO)
Organic industrial chemicals not classified elsewhere | Field crops | Chemical sciences | Physical sciences | Industrial chemicals and related products | Ceramics, glass and industrial mineral products not elsewhere classified | Manufactured products not elsewhere classified | Treatments (e.g. chemicals, antibiotics) |
Related Links
Publications
Domino or Single‐Step Tsuji–Trost/Heck Reactions and Their Application in the Synthesis of 3‐Benzazepines and Azepino[4,5‐b]indole Ring Systems
Publisher: Wiley
Date: 30-03-2009
Abstract: A series of methods for palladium‐mediated single‐step and domino Tsuji–Trost/Heck reactions are described. These methods are applied to the synthesis of both 3‐benzazepines and azepino[4,5‐ b ]indoles in the category of complex 6‐7‐6 and 6‐5‐7 ring heterocycles. In addition, a domino Heck/Heck sequence of reactions that produces the azepinobenzindolizine tetracyclic ring system from N ‐diallylated precursors is described. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Biogenic production of palladium nanocrystals using microalgae and their immobilization on chitosan nanofibers for catalytic applications
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C2RA22402J
Nickel‐Catalyzed C−N Cross‐Coupling of Primary Imines with Subsequent In Situ [2+2] Cycloaddition or Alkylation
Publisher: Wiley
Date: 09-10-2017
Tris(tri-o-tolyl phosphite-κP)nickel: A coordinatively unsaturated nickel(0) complex
Publisher: International Union of Crystallography (IUCr)
Date: 14-02-2015
DOI: 10.1107/S2053229615001680
Abstract: A previously reported complex, [Ni(C 21 H 21 O 3 P) 3 ] or Ni[P(O- o -tolyl 3 ) 3 ] [Gosser & Tolman (1970). Inorg. Chem. 9 , 2350–2353], crystallized in the monoclinic space group C 2/ c , and its solid-state structure was determined. The Ni 0 atom adopts an essentially trigonal-planar geometry as a consequence of the steric congestion of the ligands. Three of the phenoxy rings on two phosphite ligands were modelled as being disordered over two sets of sites, and the occupancy factors were set at 0.5 after trial refinement and intramolecular contact considerations. The exact ligand cone angle has been calculated to be 163.6°.
A one-pot, three-component approach to functionalised tetrahydroisoquinolines using domino Heck-aza-Michael reactions
Publisher: Wiley
Date: 08-02-2011
The synthesis of fluorescent DNA intercalator precursors through efficient multiple heck reactions
Publisher: CSIRO Publishing
Date: 2011
DOI: 10.1071/CH10374
Abstract: A highly efficient synthesis of p-carboethoxy-tristyryl and carboethoxy-terastyrenyl benzene derivatives through a multiple Heck cross coupling reaction is reported. This reaction provides an efficient route to DNA intercalator precursors containing a benzene core.
Recent Advances in Steroid Synthesis: A Tribute to Sir Derek Barton
Publisher: CSIRO Publishing
Date: 2018
DOI: 10.1071/CH18256
Abstract: The synthesis of steroids and gaining an ultimate understanding of their reactivity was one of Sir Derek Barton’s most notable research areas. This highlight will focus on the construction of the steroid ring system from 2016 to 2018, and will include pathways that eventually led to natural product synthesis. For ex le, efficient syntheses of ent-pregnanolone sulfate and oestradiol methyl ether will be explained along with the total synthesis of cannogenol-3-O-α-l-rhamnoside.
Convenient copper-mediated Chan–Lam coupling of 2-aminopyridine: facile synthesis of N-arylpyridin-2-amines
Publisher: Elsevier BV
Date: 08-2015
The Synthesis and Catalytic Activity of New Mixed NHC-Phosphite Nickel(0) Complexes
Publisher: American Chemical Society (ACS)
Date: 27-12-2020
Selective Cleavage of Isopropyl Aryl Ethers by Aluminium Trichloride
Publisher: American Chemical Society (ACS)
Date: 20-07-1999
DOI: 10.1021/JO994003+
The synthesis and fluorescence profile of novel thalidomide analogues
Publisher: Elsevier BV
Date: 10-2015
Dirhodium-Catalyzed Transannulation of N-Sulfonyl-1,2,3-triazoles to 2,3-Dehydropiperazines
Publisher: American Chemical Society (ACS)
Date: 31-07-2023
Efforts toward elucidating Thalidomide's molecular target: An expedient synthesis of the first Thalidomide biotin analogue
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/C0OB00060D
Abstract: Herein we describe the synthesis of the first Thalidomide-biotin analogue in order to initiate investigations into the unknown molecular mode of action of Thalidomide. In this manner we describe the attachment of biotin tether through the Huisgen 1,3-dipolar cycloaddition or "click" synthetic methodology.
Metabolic transformation has a profound effect on anti-inflammatory activity of flavonoids such as quercetin: Lack of association between antioxidant and lipoxygenase inhibitory activity
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.BCP.2007.11.002
Abstract: Dietary flavonoids are thought to have health benefits possibly due to antioxidant and anti-inflammatory properties. Many previous in vitro studies examining the bioactivity of flavonoids have failed to consider the effects of metabolic transformation on flavonoid activity. In this study we examined the effect of quercetin and its major metabolites on the production of pro-inflammatory eicosanoids by human leukocytes. Studies comparing free radical scavenging, antioxidant activity and eicosanoid production demonstrate that there are different structural requirements for antioxidant and anti-inflammatory activity. We also investigated the effect of metabolic transformation on flavonoid bioactivity by comparing the activity of quercetin and its major metabolites to inhibit inflammatory eicosanoid production from human leukocytes. Quercetin was a potent inhibitor of leukotriene B4 formation in leukocytes (IC50 approximately 2 microM), and its activity was dependent on specific structural features, particularly the 2,3-double bond of the C-ring. Functionalisation of the 3'-OH group with either methyl or sulfate reduced inhibitory activity up to 50% while a glucuronide substituent at the 3-OH effectively removed the LTB4 inhibitory activity. The major quercetin metabolite quercetin-3'-O-sulfate retained considerable lipoxygenase inhibitory activity (IC50 approximately 7 microM) while quercetin-3-O-glucuronide maintained antioxidant activity but had no lipoxygenase inhibitory activity at physiological concentrations. In conclusion, we have found that structural modification of quercetin due to metabolic transformation had a profound effect on bioactivity, and that the structural features required for antioxidant activity of quercetin and related flavonoids were unrelated to those required for inhibition of inflammatory eicosanoids.
Combining biomarkers for prognostic modelling of Parkinson’s disease
Publisher: BMJ
Date: 16-05-2022
Abstract: Patients with Parkinson’s disease (PD) have variable rates of progression. More accurate prediction of progression could improve selection for clinical trials. Although some variance in clinical progression can be predicted by age at onset and phenotype, we hypothesise that this can be further improved by blood biomarkers. To determine if blood biomarkers (serum neurofilament light (NfL) and genetic status (glucocerebrosidase, GBA and apolipoprotein E ( APOE ))) are useful in addition to clinical measures for prognostic modelling in PD. We evaluated the relationship between serum NfL and baseline and longitudinal clinical measures as well as patients’ genetic ( GBA and APOE ) status. We classified patients as having a favourable or an unfavourable outcome based on a previously validated model, and explored how blood biomarkers compared with clinical variables in distinguishing prognostic phenotypes . 291 patients were assessed in this study. Baseline serum NfL was associated with baseline cognitive status. Nfl predicted a shorter time to dementia, postural instability and death (dementia—HR 2.64 postural instability—HR 1.32 mortality—HR 1.89) whereas APOEe4 status was associated with progression to dementia (dementia—HR 3.12, 95% CI 1.63 to 6.00). NfL levels and genetic variables predicted unfavourable progression to a similar extent as clinical predictors. The combination of clinical, NfL and genetic data produced a stronger prediction of unfavourable outcomes compared with age and gender (area under the curve: 0.74-age/gender vs 0.84-ALL p=0.0103). Clinical trials of disease-modifying therapies might usefully stratify patients using clinical, genetic and NfL status at the time of recruitment.
Selective Cleavage of Isopropyl Aryl Ethers by Aluminum Trichloride†
Publisher: American Chemical Society (ACS)
Date: 11-1998
DOI: 10.1021/JO9808526
Pd(ii) conjugated chitosan nanofibre mats for application in Heck cross-coupling reactions
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C1CC14717J
Abstract: Pd(II)-chitosan composite nanofibres of 62 ± 9 nm diameter are efficient catalysts for Heck cross-coupling reactions. Using a model reaction of iodo-benzene and n-butyl acrylate, we demonstrate that this material can be used as a recyclable catalytic support with a very low loading of palladium (0.17 mol% Pd).
Fluorescent Triphenyl Substituted Maleimide Derivatives: Synthesis, Spectroscopy and Quantum Chemical Calculations
Publisher: Springer Science and Business Media LLC
Date: 15-04-2010
DOI: 10.1007/S10895-010-0660-Y
Abstract: In this paper we describe a semi-empirical quantum method for predicting the wavelength of maximum fluorescence excitation and emission for several known and new maleimide derivatives. All new maleimides, containing a N-Benzyl attachment, were successfully synthesised via a tandem Suzuki reaction with aryl boronic acids containing either an electron donating, electron withdrawing functional groups. Absorption and emission spectra calculated using the semi-empirical AM1 method with excited state ZINDO calculations proved more reliable than either Hartree-Fock Configuration interaction or time dependent density functional methods. Calculated absorption and emission wavelengths were compared with 26 experimental spectra from known or newly synthesised maleimides and found to have provide reasonable predictions, with an average deviation of less the 6% for absorption maxima and less than 4% for emission peaks. The described method provides a strong benchmark for the accuracy that can be expected from theoretical predictions of fluorescence spectra.
The Development of Domino Reactions Incorporating the Heck Reaction: The Formation of N‐Heterocycles
Publisher: Wiley
Date: 30-11-2011
Spectrum of antibacterial activity and mode of action of a novel tris-stilbene bacteriostatic compound
Publisher: Springer Science and Business Media LLC
Date: 02-05-2018
DOI: 10.1038/S41598-018-25080-W
Abstract: The spectrum of activity and mode of action of a novel antibacterial agent, 135C , was investigated using a range of microbiological and genomic approaches. Compound 135C was active against Gram-positive bacteria with MICs for Staphylococcus aureus ranging from 0.12–0.5 μg/ml. It was largely inactive against Gram-negative bacteria. The compound showed bacteriostatic activity in time-kill studies and did not elicit bacterial cell leakage or cell lysis. Checkerboard assays showed no synergy or antagonism when 135C was combined with a range of other antibacterials. Multi-step serial passage of four S. aureus isolates with increasing concentrations of 135C showed that resistance developed rapidly and was stable after drug-free passages. Minor differences in the fitness of 135C -resistant strains and parent wildtypes were evident by growth curves, but 135C -resistant strains did not show cross-resistance to other antibacterial agents. Genomic comparison of resistant and wildtype parent strains showed changes in genes encoding cell wall teichoic acids. 135C shows promising activity against Gram-positive bacteria but is currently limited by the rapid resistance development. Further studies are required to investigate the effects on cell wall teichoic acids and to determine whether the issue of resistance development can be overcome.
Scalable synthesis of catalysts for the Mizoroki–Heck cross coupling reaction: palladium nanoparticles assembled in a polymeric nanosphere
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0NJ00898B
Association between the LRP1B and APOE loci and the development of Parkinson’s disease dementia
Publisher: Cold Spring Harbor Laboratory
Date: 25-05-2022
DOI: 10.1101/2022.05.23.22275465
Abstract: Parkinson’s disease (PD) is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of PD, particularly in the later stages of the disease. However, the rate of cognitive decline varies widely among PD patients, and the genetic basis for this heterogeneity is incompletely understood. Here, we have analysed 3,964 clinically diagnosed PD cases to explore the genetic factors associated with rate of progression to PD dementia. Genome-wide survival analysis identified the APOE- ε4 allele as a major risk factor for the conversion to PD dementia, as well as three new loci , including the ApoE and APP receptor LRP1B. Biomarker analysis also implicates the amyloid pathway in PD dementia, suggesting that amyloid-targeting therapy may have an important role in preventing PDD.
Chemoenzymatic methods for the enantioselective preparation of sesquiterpenoid natural products from aromatic precursors
Publisher: Walter de Gruyter GmbH
Date: 2003
Abstract: The enantiomerically pure cis -1,2-dihydrocatechols 2 , which are generated by enzymatic dihydroxylation of the corresponding aromatic, engage in regio- and stereo-controlled Diels-Alder cycloaddition reactions to give a range of synthetically useful bicyclo[2.2.2]octenes. Certain ex les of the latter type of compound have been used as starting materials in the synthesis of the sesquiterpenoids (−)-patchoulenone and (−)-hirsutene.
An intramolecular Tsuji-Trost reaction based approach to the synthesis of 6-methylene indolizidines
Publisher: Elsevier BV
Date: 07-2011
Domino reactions for the synthesis of anthrapyran-2-ones and the total synthesis of the natural product (±)-BE-26554A
Publisher: American Chemical Society (ACS)
Date: 05-09-2013
DOI: 10.1021/OL402240V
Abstract: A domino alkyne addition/CO insertion/Nu acylation reaction to a series of novel anthrapyran-2-ones in good to excellent yields is described. In addition, an efficient synthetic sequence involving carbonylation, formation of a β-keto-sulfoxide, and cyclization is presented en route to the antibiotic and antitumor compound (±)-BE-26554A.
Synthesis and TNF expression inhibitory properties of new thalidomide analogues derived via Heck cross coupling
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1016/J.BMCL.2007.08.042
Abstract: A library of new thalidomide analogues containing an olefin functionality were synthesised using a Heck cross coupling reaction from their aryl halogenated precursor. All analogues were tested for their ability to inhibit the synthesis of the proinflammatory cytokine Tumour Necrosis Factor (TNF). Compounds 22, 29, 33 and 37 were the most effective in this assay inhibiting TNF expression 50%, 69%, 52% and 50%, respectively.
Identification of a thalidomide derivative that selectively targets tumorigenic liver progenitor cells and comparing its effects with lenalidomide and sorafenib
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.EJMECH.2016.03.015
Abstract: The availability of non-tumorigenic and tumorigenic liver progenitor cell (LPC) lines affords a method to screen putative anti-liver cancer agents to identify those that are selectively effective. To prove this principle we tested thalidomide and a range of its derivatives and compared them to lenalidomide and sorafenib, to assess their growth-inhibitory effects. Cell growth, the mitotic and apoptotic index of cell cultures were measured using the Cellavista instrument (SynenTec) using commercially available reagents. Neither lenalidomide nor thalidomide (100 μM) affected tumorigenic LPCs but killed their non-tumorigenic counterparts. Sorafenib arrested growth in both cell types. All but two derivatives of thalidomide were ineffective of the two effective derivatives, one (thalidomide C1) specifically affected the tumorigenic cell line (10 μM). Mitotic and apoptotic analyses revealed that thalidomide C1 induced apoptotic cell death and not mitotic arrest. This study shows that screens incorporating non-tumorigenic and tumorigenic liver cell lines are a sound approach to identify agents that are effective and selective. A high throughput instrument such as the Cellavista affords robust and reproducible objective measurements with a large number of replicates that are reliable. These experiments show that neither lenalidomide nor thalidomide are potentially useful for anti-liver cancer therapy as they kill non-tumorigenic liver cells and not their tumorigenic counterparts. Sorafenib in contrast, is highly effective, but not selective. One tested thalidomide derivative has potential as an anti-tumor drug since it induced growth arrest and importantly, it selectively induced apoptotic cell death only in tumorigenic liver progenitor cells.
Norcantharimides, synthesis and anticancer activity: Synthesis of new norcantharidin analogues and their anticancer evaluation.
Publisher: Elsevier BV
Date: 09-2007
DOI: 10.1016/J.BMC.2007.06.034
Abstract: A range of amines was reacted with norcantharidin (2) to provide the corresponding norcantharimides (9-43). Treatment of norcantharidin with allylamine afforded the corresponding allyl-norcantharimide (20) which was amenable to epoxidation (mCPBA, 22) and subsequent ring opening (MeOH/H(+) 23) or alternatively, osmylation (OsO(4)/NMO 24). These simple synthetic modifications of 2 facilitated the development of a novel series of norcantharimides displaying modest to good broad spectrum cytotoxicity against HT29 and SW480 (colorectal carcinoma) MCF-7 (breast adenocarcinoma) A2780 (ovarian carcinoma) H460 (lung carcinoma) A431 (epidermoid carcinoma) DU145 (prostate carcinoma) BE2-C (neuroblastoma) and SJ-G2 (glioblastoma). Analogues possessing a C(10), C(12) or C(14) alkyl chain or a C(12) linked bis-norcantharimide displayed the highest levels of cytotoxicity.
Electrostatic complementarity in pseudoreceptor modeling based on drug molecule crystal structures
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4NJ01503G
Abstract: A combination of pseudoreceptor modeling and electrostatic complementarity maps properties of a native pocket for an enzyme ligand.
An Air-Stable Nickel(0) Phosphite Precatalyst for Primary Alkylamine C-N Cross-Coupling Reactions
Publisher: Wiley
Date: 11-08-2015
Exploring the Catalytic Reactivity of Nickel Phosphine-Phosphite Complexes
Publisher: CSIRO Publishing
Date: 2015
DOI: 10.1071/CH15459
Abstract: In this study, we present an investigation into various nickel phosphite and phosphite–phosphine complexes for use in the Mizoroki–Heck and Suzuki–Miyaura cross-coupling reactions and the ammonia arylation reaction. In these coupling reactions, it was discovered that the Ni[P(OEt)3]4, (dppf)Ni[P(OPh)3]2, and (binap)Ni[P(OPh)3]2 catalysts were the most effective. In addition, an optimisation process for these catalytic systems as well as functional group compatibility are discussed.
The Total Synthesis of Heraclemycin B through β‐Ketosulfoxide and Aldehyde Annulation
Publisher: Wiley
Date: 03-07-2015
Intramolecular Heck Reactions for the Synthesis of the Novel Antibiotic Mensacarcin: Investigation of Catalytic, Electronic and Conjugative Effects in the Preparation of the Hexahydroanthracene Core
Publisher: Wiley
Date: 25-04-2005
Genome‐Wide Association Studies of Cognitive and Motor Progression in Parkinson's Disease
Publisher: Wiley
Date: 28-10-2021
DOI: 10.1002/MDS.28342
Association between the LRP1B and APOE loci and the development of Parkinson’s disease dementia
Publisher: Oxford University Press (OUP)
Date: 09-11-2023
Abstract: Parkinson’s disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson’s disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson’s disease patients, and the genetic basis for this heterogeneity is incompletely understood. To explore the genetic factors associated with rate of progression to Parkinson’s disease dementia, we performed a genome-wide survival meta-analysis of 3923 clinically diagnosed Parkinson’s disease cases of European ancestry from four longitudinal cohorts. In total, 6.7% of in iduals with Parkinson’s disease developed dementia during study follow-up, on average 4.4 ± 2.4 years from disease diagnosis. We have identified the APOE ε4 allele as a major risk factor for the conversion to Parkinson’s disease dementia [hazard ratio = 2.41 (1.94–3.00), P = 2.32 × 10−15], as well as a new locus within the ApoE and APP receptor LRP1B gene [hazard ratio = 3.23 (2.17–4.81), P = 7.07 × 10−09]. In a candidate gene analysis, GBA variants were also identified to be associated with higher risk of progression to dementia [hazard ratio = 2.02 (1.21–3.32), P = 0.007]. CSF biomarker analysis also implicated the amyloid pathway in Parkinson’s disease dementia, with significantly reduced levels of amyloid β42 (P = 0.0012) in Parkinson’s disease dementia compared to Parkinson’s disease without dementia. These results identify a new candidate gene associated with faster conversion to dementia in Parkinson's disease and suggest that amyloid-targeting therapy may have a role in preventing Parkinson’s disease dementia.
Inspiration from Old Dyes: Tris(stilbene) Compounds as Potent Gram‐Positive Antibacterial Agents
Publisher: Wiley
Date: 18-11-2013
Abstract: Herein we describe the preparation and structure-activity relationship studies on range of stilbene based compounds and their antibacterial activity. Two related compounds, each bearing carboxylic acid moieties, exhibit good activity against several bacterial strains, including methicillin-resistant Staphylococcus aureus MRSA (ATCC 33592 and NCTC 10442). Compound 10 was most active against Moraxella catarrhalis with minimum inhibitory concentrations (MICs) of 0.12-0.25 μg mL(-1) and against Staphylococcus spp. with MICs ranging from 2-4 μg mL(-1). The derivative 17 showed increased activity with MICs of 0.06-0.25 μg mL(-1) against M. catarrhalis and 0.12-1 against Staphylococcus spp. This level of activity is similar to that reported for S. aureus for antibiotics, such as vancomycin, with MICs of ≤2.0 μg mL(-1) and clindamycin with MICs of ≤0.5 μg mL(-1). As an indicator of toxicity, 17 was tested for its ability to lyse sheep erythrocytes, and showed low haemolytic activity. Such results highlight the value of tris(stilbene) compounds as antibacterial agents providing suitable properties for further development.
Features ofGBA-associated Parkinson’s disease at presentation in the UKTracking Parkinson’sstudy
Publisher: BMJ
Date: 29-01-2018
Abstract: To examine the influence of the glucocerebrosidase ( GBA ) mutation carrier state on age at onset of Parkinson’s disease (PD), the motor phenotype and cognitive function at baseline assessment in a large cohort of UK patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive function. We prospectively recruited patients with PD in the Tracking Parkinson’s study. We fully sequenced the GBA gene in all recently diagnosed patients (≤3.5 years). We examined cognitive (Montreal Cognitive Assessment) and motor (Movement Disorder Society Unified Parkinson’s Disease Rating Scale part 3) function at a baseline assessment, at an average of 1.3 years after diagnosis. We used logistic regression to determine predictors of PD with mild cognitive impairment and PD with dementia. We studied 1893 patients with PD: 48 (2.5%) were heterozygous carriers for known Gaucher’s disease (GD) causing pathogenic mutations 117 (6.2%) had non-synonymous variants, previously associated with PD, and 28 (1.5%) patients carried variants of unknown significance in the GBA gene. L444P was the most common pathogenic GBA mutation. Patients with pathogenic GBA mutations were on average 5 years younger at disease onset compared with non-carriers (P=0.02). PD patients with GD-causing mutations did not have an increased family risk of PD. Patients with GBA mutations were more likely to present with the postural instability gait difficulty phenotype compared with non-carriers (P=0.02). Patients carrying pathogenic mutations in GBA had more advanced Hoehn and Yahr stage after adjustment for age and disease duration compared with non-carriers (P=0.005). There were no differences in cognitive function between GBA mutation carriers and non-carriers at this early disease stage. Our study confirms the influence of GBA mutations on the age of onset, disease severity and motor phenotype in patients with PD. Cognition did not differ between GBA mutation carriers and non-carriers at baseline, implying that cognitive impairment/dementia, reported in other studies at a later disease stage, is not present in recently diagnosed cases. This offers an important window of opportunity for potential disease-modifying therapy that may protect against the development of dementia in GBA -PD. NCT02881099 Results.
Towards a Total Synthesis of the New Anticancer Agent Mensacarcin: Synthesis of the Carbocyclic Core
Publisher: Wiley
Date: 07-10-2004
Abstract: A synthesis of the carbocyclic core associated with the new anticancer agent mensacarcin (1) is reported. The strategy involves the synthesis of several novel highly substituted aromatic compounds, such as 12 and 23. The lithium derivative of 12 readily engages in a nucleophilic addition to benzaldehyde 4 to provide the diphenylcarbinol rac-15. The analogous benzyl ether rac-16 undergoes an intramolecular Heck reaction to provide the required tetrahydroanthracene rac-17, which can be transformed into the key tricyclic methyl ether rac-20. In a second approach, the lithium derivative of 21 is added to the hexasubstituted benzaldehyde 23 to give the diphenylcarbinol rac-35. Subsequent methylation to rac-36 followed by an intramolecular Heck reaction provides tricycle rac-37. Similarly, the oxidised compound 40 provides an electronically more suitable intramolecular Heck partner to afford compound 41. Further transformations of these substrates leads to rac-43, which incorporates the core structure of mensacarcin (1).
The synthesis and biological activity of novel anthracenone-pyranones and anthracenone-furans.
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.BMC.2015.04.032
Abstract: An efficient and ergent methodology for the synthesis of new anthracenone-pyranones and anthracenone-furans is described. Key reactions discussed in these syntheses include an aldehyde promoted annulation with a β-keto-sulfoxide, a domino alkyne insertion/carbonylation/Nu-acylation and a DMEDA promoted Castro-Stephens reaction. We also report the in vitro growth inhibition of these compounds in a range of human cancer cells. The natural product BE-26554A displayed good cell growth activity on BE2-C neuroblastoma and SMA glioblastoma cell lines at 0.17 and 0.16μM (GI50), respectively. Of note, were a CF3 functionalised anthracenone 4-pyranone (chromone) derivative 22, and an anthracenone-furan derivative 54 which displayed 0.20μM and 0.38μM growth inhibition, respectively, in the BE2-C neuroblastoma cell line.
Heterocyclic substituted cantharidin and norcantharidin analogues--synthesis, protein phosphatase (1 and 2A) inhibition, and anti-cancer activity.
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.BMCL.2007.03.093
Abstract: Norcantharidin (3) is a potent PP1 (IC(50)=9.0+/-1.4 microM) and PP2A (IC(50)=3.0+/-0.4 microM) inhibitor with 3-fold PP2A selectivity and induces growth inhibition (GI(50) approximately 45 microM) across a range of human cancer cell lines including those of colorectal (HT29, SW480), breast (MCF-7), ovarian (A2780), lung (H460), skin (A431), prostate (DU145), neuroblastoma (BE2-C), and glioblastoma (SJ-G2) origin. Until now limited modifications to the parent compound have been tolerated. Surprisingly, simple heterocyclic half-acid norcantharidin analogues are more active than the original lead compound, with the morphilino-substituted (9) being a more potent (IC(50)=2.8+/-0.10 microM) and selective (4.6-fold) PP2A inhibitor with greater in vitro cytotoxicity (GI(50) approximately 9.6 microM) relative to norcantharidin. The analogous thiomorpholine-substituted (10) displays increased PP1 inhibition (IC(50)=3.2+/-0 microM) and reduced PP2A inhibition (IC(50)=5.1+/-0.41 microM), to norcantharidin. Synthesis of the analogous cantharidin analogue (19) with incorporation of the amine nitrogen into the heterocycle further increases PP1 (IC(50)=5.9+/-2.2 microM) and PP2A (IC(50)=0.79+/-0.1 microM) inhibition and cell cytotoxicity (GI(50) approximately 3.3 microM). These analogues represent the most potent cantharidin analogues thus reported.
Synthesis of 2‐Substituted 2‐Amino Ketones by Rhodium‐Catalyzed Reaction of N‐Sulfonyl‐1,2,3‐triazoles with 2‐Alkenols
Publisher: Wiley
Date: 02-2017
Palladium-catalyzed dicarbonylative synthesis of tetracycle quinazolinones
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5OB00368G
Abstract: An interesting palladium-catalyzed carbonylative procedure for the synthesis of isoindolo[1,2- b ]quinazolin-10(12 H )-ones from commercially available 2-bromoanilines and 2-bromobenzyl amines has been developed. The desired products were isolated in good yields.
Stable nickel(0) phosphites as catalysts for C-N cross-coupling reactions
Publisher: Wiley
Date: 28-05-2014
A general approach to N-heterocyclic scaffolds using domino Heck-aza-Michael reactions
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0OB00835D
Abstract: Palladium-catalyzed domino Heck-aza-Michael reactions for the synthesis of a series of C1-substituted tetrahydro-β-carbolines, tetrahydroisoquinolines and isoindolines are described. The domino process involves the initial intermolecular Heck reaction of an aryl bromide with an electron deficient alkene, followed by an intramolecular aza-Michael reaction to form the new N-heterocycle in high yield.
Genome-wide determinants of mortality and motor progression in Parkinson’s disease
Publisher: Cold Spring Harbor Laboratory
Date: 10-07-2022
DOI: 10.1101/2022.07.07.22277297
Abstract: There are 90 genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6,766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out a genome wide survival study for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We identified three novel loci for mortality and motor progression, and nominated genes based on physical proximity and/or expression quantitative trait loci data. One locus within the TBXAS1 gene encoding thromboxane A synthase 1 was associated with mortality in PD (HR = 2.04 [95% CI 1.63 to 2.56], p-value = 7.71 x 10 -10 ). Another locus near the SYT10 gene encoding synaptotagmin 10 was associated with mortality just above genome-wide significance (HR=1.36 [95% CI 1.21 to 1.51], p-value=5.31×10 -8 ). We also report 4 independent loci associated with motor progression: the top locus within MORN1 (HR=2.76 [95% CI 1.97 to 3.87], p-value=3.1×10 -9 ), the second most significant locus near ASNS , the third most significant locus near PDE5A , and a fourth locus within XPO1 . We have nominated causal genes based on physical position, however we also discuss other possible causal genes based on expression quantitative trait loci, colocalization analysis, and tagging of rare variants. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. We report six novel loci associated with PD motor progression or mortality. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, thromboxane synthesis, vesicular peptidergic neurotransmitter release, and phosphodiesterase inhibition may represent new candidates for disease modification in PD. Parkinson’s UK, Aligning Science Across Parkinson’s through the Michael J Fox Foundation for Parkinson’s Research, Southern and Eastern Norway Regional Health Authority
In pursuit of a selective hepatocellular carcinoma therapeutic agent: Novel thalidomide derivatives with antiproliferative, antimigratory and STAT3 inhibitory properties
Publisher: Elsevier BV
Date: 05-2021
Genetic analysis of Mendelian mutations in a large UK population-based Parkinson’s disease study
Publisher: Oxford University Press (OUP)
Date: 19-07-2019
DOI: 10.1093/BRAIN/AWZ191
Abstract: Our objective was to define the prevalence and clinical features of genetic Parkinson’s disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Unified Parkinson’s Disease Rating Scale scores, and Montreal Cognitive Assessment scores. We analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, family history and clinical features. Of the 2262 participants recruited to the Tracking Parkinson’s study, 424 had young-onset Parkinson’s disease (age at onset ≤ 50) and 1799 had late onset Parkinson’s disease. A range of methods were used to genotype 2005 patients: 302 young-onset patients were fully genotyped with multiplex ligation-dependent probe lification and either Sanger and/or exome sequencing and 1701 late-onset patients were genotyped with the LRRK2 ‘Kompetitive’ allele-specific polymerase chain reaction assay and/or exome sequencing (two patients had missing age at onset). We identified 29 (1.4%) patients carrying pathogenic mutations. Eighteen patients carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplication in SNCA. In PRKN, we identified patients carrying deletions of exons 1, 4 and 5, and P113Xfs, R275W, G430D and R33X. In PINK1, two patients carried deletions in exon 1 and 5, and the W90Xfs point mutation. Eighteen per cent of patients with age at onset ≤30 and 7.4% of patients from large dominant families carried pathogenic Mendelian gene mutations. Of all young-onset patients, 10 (3.3%) carried biallelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an SNCA duplication. There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic and familial disease. In young-onset patients, dominant and recessive mutations were equally common. There were no differences in clinical features between LRRK2 carriers and non-carriers. However, we did find that PRKN and PINK1 mutation carriers have distinctive clinical features compared to young-onset non-carriers, with more postural symptoms at diagnosis and less cognitive impairment, after adjusting for age and disease duration. This supports the idea that there is a distinct clinical profile of PRKN and PINK1-related Parkinson’s disease. We estimate that there are approaching 1000 patients with a known genetic aetiology in the UK Parkinson’s disease population. A small but significant number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be targeted by new therapies, such as LRRK2 inhibitors.
Formation and reactions of azepino[4,5-b]indoles: an unprecedented ozone reaction in the formation of novel benzo[c]naphthyridinones
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/C003742G
Abstract: Herein we report the formation and interesting reactivity of several azepino[4,5-b]indole heterocycles. Initially, a key intramolecular Heck reaction is used to efficiently create the azepino[4,5-b]indole seven membered ring containing an exocyclic double bond. Treatment of the olefin with ozone results in an unprecedented secondary reaction of the Criegee intermediate, through intramolecular olefin trapping, to afford a benzo[c]naphthyridione containing a bridging cyclic peroxide.
A One-Pot Reaction of α-Imino Rhodium Carbenoids and Halohydrins
Publisher: American Chemical Society (ACS)
Date: 13-04-2020
Nickel Phosphite-Catalyzed Tetradehydro-Diels-Alder Reactions of (E)-3-ene-1,8-diynes
Publisher: American Chemical Society (ACS)
Date: 10-04-2023
Synthesis and biological evaluation of norcantharidin analogues: towards PP1 selectivity.
Publisher: Elsevier BV
Date: 12-2007
DOI: 10.1016/J.BMC.2007.08.028
Abstract: Simple modifications to the anhydride moiety of norcantharidin have lead to the development of a series of analogues displaying modest PP1 inhibition (low muM IC(50)s) comparable to that of norcantharidin (PP1 IC(50)=10.3+/-1.37 microM). However, unlike norcantharidin, which is a potent inhibitor of PP2A (IC(50)=2.69+/-1.37 microM), these analogues show reduced PP2A inhibitory action resulting in the development of selective PP1 inhibitory compounds. Data indicates that the introduction of two ortho-disposed substituents on an aromatic ring, or para-substituent favours PP1 inhibition over PP2A inhibition. Introduction of a p-morphilinoaniline substituent, 35, affords an inhibitor displaying PP1 IC(50)=6.5+/-2.3 microM and PP2A IC(50)=7.9+/-0.82 microM (PP1/PP2A=0.82) and a 2,4,6-trimethylaniline, 23, displaying PP1 IC(50)=48+/-9 and PP2A IC(5) 85+/-3 microM (PP1/PP2A=0.56). The latter shows a 7-fold improvement in PP1 versus PP2A selectivity when compared with norcantharidin. Subsequent analysis of 23 and 35 as potential PP2B inhibitors revealed modest inhibition with IC(50)s of 89+/-6 and 42+/-3 microM, respectively, and returned with PP1/PP2B selectivities of 0.54 and 0.15. Thus, these analogues are the simplest and most selective PP1 inhibitors retaining potency reported to date.
Sucrose fatty acid esters: synthesis, emulsifying capacities, biological activities and structure-property profiles
Publisher: Informa UK Limited
Date: 04-08-2020
Association of genetic variation at the GJA5/ACP6 locus with motor progression in Parkinson’s
Publisher: Cold Spring Harbor Laboratory
Date: 11-2022
DOI: 10.1101/2022.10.28.22281645
Abstract: There is a pressing need to understand the biology of Parkinson’s disease (PD) progression and to identify biological pathways as possible therapeutic targets. To identify genomic variation associated with PD motor presentation and early stage progression. GWAS meta-analysis of early PD motor progression, from multiple longitudinal cohorts, using MDS-UPDRS III clinical assessments. Multicentre 3572 unrelated European ancestry in iduals diagnosed with PD from 6 studies. Linear mixed effect models under an additive model corrected for age at diagnosis, gender, and the first 5 genetic principal components (PCs), with axial, limb, and total MDS-UPDRS III as outcomes of the model. We identified an association between the PD axial rate of progression and variation at the GJA5 locus at 1q12 (Beta = -0.25, SE = 0.04, P = 3.4e-10). Exploration of the regulation of gene expression in the region (cis-eQTL analysis) showed that the lead variant was associated with expression of ACP6 , a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTLs p-values in blood and brain RNA expression datasets: 10 −8 in eQTLGen and 10 −7 in PsychEncode). In addition, we found a nominal association between axial motor presentation and the MAD1L1 gene at 7q21.11 (Beta = 0.54, SE = 0.11, P = 1.6e-7), a gene previously associated with neuropsychiatric disease, and in the long non-coding RNA LINC00511 at 17q21.31 (Beta = -0.62, SE = 0.11, P = 6.3e-8). Further functional annotation allowed us to nominate the likely causal variants and determine that variants at 7q21.11 may be related to dysregulation of MAD1L1 expression. Variants at LINC00511 may cause a disruption of a distal epigenetic regulation of SOX9 through an anchored chromatin loop. Our large multicentre study sheds new light on the genetic architecture of PD progression, which is distinct from PD susceptibility. Our study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets to tackle disease progression.
Genetic meta-analysis of levodopa induced dyskinesia in Parkinson’s disease
Publisher: Cold Spring Harbor Laboratory
Date: 29-05-2023
DOI: 10.1101/2023.05.24.23290362
Abstract: Forty percent of Parkinson’s disease patients develop levodopa-induced-dyskinesia (LiD) within 4 years of starting levodopa. The genetic basis of LiD remains poorly understood, and there have been few well powered studies. To discover common genetic variants in the PD population that increase the probability of developing LiD. We performed survival analyses to study the development of LiD in 5 separate longitudinal cohorts. We performed a meta-analysis to combine the results of genetic association from each study based on a fixed effects model weighting the effect sizes by the inverse of their standard error. The selection criteria was specific to each cohort. We studied in iduals that were genotyped from each cohort and that passed our analysis specific inclusion criteria. We measured the time for PD patients on levodopa treatment to develop LiD as defined by reaching a score higher or equal than 2 from the MDS-UPDRS part IV, item 1, which is equivalent to a range of 26%-50% of the waking time with dyskinesia. We carried out a genome-wide analysis of the hazard ratio and the association of genome-wide SNPs with the probability of developing LiD using cox proportional hazard models (CPH). This study included 2,784 PD patients of European ancestry, of whom 14.6% developed LiD. Consistent with previous studies, we found female gender (HR = 1.35, SE = 0.11, P = 0.007) and younger age at onset (HR = 1.8, SE = 0.14, P = 2 × 10 −5 ) to increase the probability of developing LiD. We identified three loci significantly associated with time-to-LiD onset. rs72673189 on chromosome 1 (HR = 2.77, SE = 0.18, P = 1.53 × 10 −8 ) located in the LRP8 locus, rs189093213 on chromosome 4 (HR = 3.06,, SE = 0.19, P = 2.81 × 10 −9 ) in the non-coding RNA LINC02353 locus, and rs180924818 on chromosome 16 (HR = 3.13, SE = 0.20, P = 6.27 × 10 −9 ) in the XYLT1 locus. Subsequent colocalization analyses on chromosome 1 identified DNAJB4 as a candidate gene associated with LiD through a change in gene expression. We computed a PRS based on our GWAS meta-analysis and found high accuracy to stratify between PD-LID and PD (AUC 83.9). We also performed a stepwise regression analysis for baseline features selection associated with LiD status. We found baseline anxiety status to be significantly associated with LiD (OR = 1.14, SE = 0.03, P = 7.4 × 10 −5 ). Finally, we performed a candidate variant analysis and found that genetic variability in ANKK1 ( rs1800497 , Beta = 0.24, SE = 0.09, P = 8.89 × 10 −3 ) and BDNF ( rs6265 , Beta = 0.19, SE = 0.10, P = 4.95 × 10 −2 ) loci were significantly associated with time to LiD in our large meta-analysis. In this association study, we have found three novel genetic variants associated with LiD, as well as confirming reports that variability in ANKK1 and BDNF loci were significantly associated with LiD probability. A PRS nominated from our time-to-LiD meta-analysis significantly differentiated between PD-LiD and PD. In addition, we have found female gender, young PD onset and anxiety to be significantly associated with LiD.
Novel thalidomide analogues with potent NFκB and TNF expression inhibition
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C1MD00184A
The antiplasmodial activity of norcantharidin analogs
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.BMCL.2010.09.004
Abstract: The antiplasmodial activities of sixty norcantharidin analogs were tested in vitro against a chloroquine sensitive (D6, Sierra Leone) and chloroquine resistant (W2) strains of Plasmodium falciparum. Forty analogs returned IC(50) values <500 μM against at least one of the P. falciparum strains examined. The ring open compound 24 ((1S,4R)-3-(allylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid) is the most active aliphatic analog (D6 IC(50)=3.0±0.0 and W2 IC(50)=3.0±0.8 μM) with a 20-fold enhancement relative to norcantharidin. Surprisingly, seven norcantharimides also displayed good antiplasmodial activity with the most potent, 5 returning D6=8.9±0.9 and W2 IC(50)=12.5±2.2 μM, representing a fivefold enhancement over norcantharidin.
Enantioselective Synthesis of anti-1,2-Oxaborinan-3-enes from Aldehydes and 1,1-Di(boryl)alk-3-enes Using Ruthenium and Chiral Phosphoric Acid Catalysts
Publisher: American Chemical Society (ACS)
Date: 28-07-2017
DOI: 10.1021/JACS.7B06408
Abstract: A cationic ruthenium(II) complex catalyzes double-bond transposition of 1,1-di(boryl)alk-3-enes to generate in situ 1,1-di(boryl)alk-2-enes, which then undergo chiral phosphoric acid catalyzed allylation of aldehydes producing homoallylic alcohols with a (Z)-vinylboronate moiety. 1,2-Anti stereochemistry is installed in an enantioselective manner. The (Z)-geometry forged in the products allows their isolation in a form of 1,2-oxaborinan-3-enes, upon which further synthetic transformations are operated.
Similarities and Differences between Crystal and Enzyme Environmental Effects on the Electron Density of Drug Molecules
Publisher: Wiley
Date: 14-01-2021
Abstract: The crystal interaction density is generally assumed to be a suitable measure of the polarization of a low‐molecular weight ligand inside an enzyme, but this approximation has seldomly been tested and has never been quantified before. In this study, we compare the crystal interaction density and the interaction electrostatic potential for a model compound of loxistatin acid (E64c) with those inside cathepsin B, in solution, and in vacuum. We apply QM/MM calculations and experimental quantum crystallography to show that the crystal interaction density is indeed very similar to the enzyme interaction density. Less than 0.1 e are shifted between these two environments in total. However, this difference has non‐negligible consequences for derived properties.
High-Pressure-Promoted and Facially Selective Diels–Alder Reactions of Enzymatically Derived cis-1,2-Dihydrocatechols and Their Acetonide Derivatives: Enantiodivergent Routes to Homochiral and
Publisher: American Chemical Society (ACS)
Date: 11-09-2020
Heterologous biosynthesis of elsinochrome A sheds light on the formation of the photosensitive perylenequinone system
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C8SC02870B
Abstract: Formation of the three C–C bridges between the two naphthol monomers for elsinochrome ( 1 ) involves three distinct classes of oxidases.
New thalidomide analogues derived through Sonogashira or Suzuki reactions and their TNF expression inhibition profiles
Publisher: Elsevier BV
Date: 2010
DOI: 10.1016/J.BMC.2009.12.001
Abstract: A library of new thalidomide C4/5 analogues containing either a phenyl or alkyne tether were synthesized using Sonogashira or Suzuki cross coupling reactions from their aryl halogenated precursors. All thalidomide analogues were tested for their ability to inhibit the expression of the proinflammatory cytokine Tumor Necrosis Factor (TNF). More explicitly the use of a novel reporter system utilizing the promoter region of the TNF gene in a human T-cell line provided a rapid and effective measure of NFkappaB transcriptional activity. Several compounds either containing either an aryl-isobutyl or aryl-isopropoxy group were the most effective in inhibiting TNF expression, and were several times more active than thalidomide itself. Five of the more active derivatives indicated an apoptotic response while one of these compounds, containing an aldehyde tether, showed possible influence of cell cycling effects.
Stereoselective Synthesis of 2,3-Dihydropyrroles from Terminal Alkynes, Azides, and α,β-Unsaturated Aldehydes via N-Sulfonyl-1,2,3-triazoles
Publisher: American Chemical Society (ACS)
Date: 04-09-2013
DOI: 10.1021/JA407166R
Abstract: A stereoselective method for synthesis of trans-2,3-disubstituted 2,3-dihydropyrroles is reported. N-Sulfonyl-1,2,3-triazoles prepared from terminal alkynes generate α-imino rhodium carbene complexes, which when combined with α,β-unsaturated aldehydes produce trans-2,3-disubstituted dihydropyrroles. The method can be successfully applied to a one-pot process starting from terminal alkynes.
Domino heck-aza-michael reactions: efficient access to 1-substituted tetrahydro-β-carbolines
Publisher: American Chemical Society (ACS)
Date: 04-02-2010
DOI: 10.1021/JO902652H
Abstract: A simple and efficient palladium-catalyzed domino reaction for the synthesis of a series of C1-substituted tetrahydro-beta-carbolines is described. This domino process involves a Heck reaction at the indole 2-position of a halogenated tryptamine precursor, followed by intramolecular aza-Michael addition.
Asymmetric induction in domino Heck-aza-Michael reactions
Publisher: Elsevier BV
Date: 03-2012
Surface oxygen triggered size change of palladium nano-crystals impedes catalytic efficacy
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0CC03182H
Abstract: Palladium nano-crystals increase in size during the initial recycling in Heck cross coupling reactions. We demonstrate that oxygen adsorbed on the surface of palladium nano-crystals plays a pivotal role in driving the ripening. This in turn is associated with a loss in catalytic activity.
Synthesis of Enantiopure C3‐Symmetric Triangular Molecules
Publisher: Wiley
Date: 14-02-2017
Abstract: An asymmetric synthesis of C
Synthesis of 1,3,4-Oxadiazoles via Annulation of Hydrazides and Benzene-1,3,5-triyl Triformate under Metal-Free Conditions
Publisher: Georg Thieme Verlag KG
Date: 16-04-2018
Abstract: A new and efficient method for the synthesis of 1,3,4-oxadiazoles via the annulation of hydrazides with benzene-1,3,5-triyl triformate (TFBen) under metal-free conditions is reported. A broad range of hydrazides were transformed into the corresponding 1,3,4-oxadiazoles in good yields with excellent functional group tolerance.
Genetics of validated Parkinson’s disease subtypes in the Oxford Discovery and Tracking Parkinson’s cohorts
Publisher: BMJ
Date: 22-06-2022
Abstract: To explore the genetics of four Parkinson’s disease (PD) subtypes that have been previously described in two large cohorts of patients with recently diagnosed PD. These subtypes came from a data-driven cluster analysis of phenotypic variables. We looked at the frequency of genetic mutations in glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 against our subtypes. Then we calculated Genetic Risk Scores (GRS) for PD, multiple system atrophy, progressive supranuclear palsy, Lewy body dementia, and Alzheimer’s disease. These GRSs were regressed against the probability of belonging to a subtype in the two independent cohorts and we calculated q-values as an adjustment for multiple testing across four subtypes. We also carried out a Genome-Wide Association Study (GWAS) of belonging to a subtype. A severe disease subtype had the highest rates of patients carrying GBA mutations while the mild disease subtype had the lowest rates (p=0.009). Using the GRS, we found a severe disease subtype had a reduced genetic risk of PD (p=0.004 and q=0.015). In our GWAS no in idual variants met genome wide significance ( ×10e-8) although four variants require further follow-up, meeting a threshold of ×10e-6. We have found that four previously defined PD subtypes have different genetic determinants which will help to inform future studies looking at underlying disease mechanisms and pathogenesis in these different subtypes of disease.
Rapid Evaluation of Antrodia camphorata Natural Products and Derivatives in Tumourigenic Liver Progenitor Cells with a Novel Cell Proliferation Assay
Publisher: Wiley
Date: 28-09-2009
Abstract: We report the syntheses of five natural product maleimide and maleic anhydrides from the mushroom Antrodia c horata. The ability of these compounds to affect proliferation in non-tumourigenic and tumourigenic liver progenitor cell lines was monitored by the Cellscreen system, a novel and nondestructive rapid-screening instrument. Additionally, a range of new aryl-functionalised differentiated derivatives were prepared through a Suzuki cross-coupling reaction to influence cell-growth effects. Several derivatives radically slowed the proliferation of liver progenitor cells however, of particular interest were two maleic anhydride derivatives containing aryl tethers. These analogues demonstrated selectivity for limiting the proliferation of tumourigenic progenitor cells in comparison with their non-tumourigenic counterparts. Also highlighted is the application of the Cellscreen system in medicinal chemistry to rapidly measure the effect of compound libraries on cell proliferation.
N-Tosyl-1,2,3-triazoles as Scaffolds for Morpholines: The Total Synthesis of (-)-Chelonin A
Publisher: Georg Thieme Verlag KG
Date: 18-11-2022
DOI: 10.1055/A-1982-5433
Abstract: Substituted morpholine derivatives appear frequently in biologically active compounds and thus novel routes towards such structures are of great synthetic interest. Herein, we report the total syntheses of chelonin A, a morpholine-derived marine natural product with reported antibacterial and anti-inflammatory activity. The key step in this process was a rhodium carbenoid 1,3-insertion into a bromohydrin O–H bond, followed by annulation, leading to a 2,6-disubstituted-3,4-dihydro-2H-1,4-oxazine core. This work was then extended to deliver the first asymmetric total synthesis of (–)-chelonin A using an enantioenriched bromohydrin, prepared in turn via asymmetric transfer hydrogenation of an α-bromoketone.
Norcantharidin analogues: synthesis, anticancer activity and protein phosphatase 1 and 2A inhibition.
Publisher: Wiley
Date: 08-12-2008
Abstract: Cantharidin (1) and its derivatives are of significant interest as serine/threonine protein phosphatase 1 and 2A inhibitors. Additionally, compounds of this type have displayed growth inhibition of various tumour cell lines. To further explore both of these inhibition pathways, a number of amide-acid norcantharidin analogues (15-26) were prepared. Compounds 23 and 24, containing two carboxylic acid residues, showed good PP1 and PP2A activity, with IC(50) values of approximately 15 and approximately 3 mum, respectively. Substituted aromatic amide analogues 45, 48, 49, 52, 53, and 54 also displayed good PP1 and PP2A inhibition, with IC(50) values in the range of 15-10 microM (PP1) and 11-5 microM (PP2A). However, bulky ortho substituents on the aromatic ring caused the aromatic ring to be skewed from the NCO planarity, leading to a decrease in PP1 and PP2A inhibition. A number of analogues, 20, 22, 25 and 46, showed excellent tumour growth inhibition, with 46 in particular being more potent than the lead, norcantharidin 2.
Approaching an experimental electron density model of the biologically active trans-epoxysuccinyl amide group-Substituent effects vs. crystal packing
Publisher: Wiley
Date: 24-01-2017
DOI: 10.1002/POC.3683
Asymmetric Synthesis and Stereochemical Assignment of12C/13C Isotopomers
Publisher: American Chemical Society (ACS)
Date: 13-08-2019
DOI: 10.1021/JACS.9B07181
Abstract: A synthesis of chiral hydrocarbons having
Overview of the synthetic approaches to lysergic acid as a precursor to the psychedelic LSD
Publisher: CSIRO Publishing
Date: 07-07-2023
DOI: 10.1071/CH23055
Abstract: In this short primer we will discuss the total synthesis of lysergic acid, an important precursor to both lysergic acid diethylamide (LSD) and its derivatives. Lysergic acid is also noted as a precursor for many drugs targeting the serotonin receptor family of GPCRs, including multiple known hallucinogens. More recently, reinvigorated interest in the therapeutic potential of psychedelics from academic and commercial sectors has placed a renewed importance on practical, scalable means of accessing this complex alkaloid scaffold.
BiCl3-mediated opening of epoxides, a facile route to chlorohydrins or amino alcohols: one reagent, two paths
Publisher: Elsevier BV
Date: 11-2005
A Chemoenzymatic Synthesis of the cis-Decalin Core Associated with the Novel Anti-Mitotic Agent Phomopsidin: Some Observations Concerning a High-Pressure-Promoted Diels–Alder Cycloaddition R
Publisher: CSIRO Publishing
Date: 2004
DOI: 10.1071/CH04036
Abstract: The enantiomerically pure and enzymatically derived cis-1,2-dihydrocatechol 2 engages in a diastereofacially selective Diels–Alder cycloaddition reaction with commercially available lactone 3 at 19 kbar to afford adduct 4, which is readily elaborated to the diene-ol 13. Treatment of this last compound with KH/18[crown]-6 resulted in successive anionic oxy-Cope and 1,2-Wittig rearrangements to afford acyloin 14 embodying the cis-decalin core associated with the natural product phomopsidin (1). Compound 16 also engages in an anionic oxy-Cope rearrangement reaction to give, depending on the molar equivalents of base used, either the cis-decalin 17 or the hexahydroindene 18. The structure of compound 18 has been established by single-crystal X-ray diffraction analysis.
Genetic meta-analysis of levodopa induced dyskinesia in Parkinson’s disease
Publisher: Springer Science and Business Media LLC
Date: 31-08-2023
DOI: 10.1038/S41531-023-00573-2
Abstract: The genetic basis of levodopa-induced-dyskinesia (LiD) is poorly understood, and there have been few well-powered genome-wide studies. We performed a genome-wide survival meta-analyses to study the effect of genetic variation on the development of LiD in five separate longitudinal cohorts, and meta-analysed the results. We included 2784 PD patients, of whom 14.6% developed LiD. We found female sex (HR = 1.35, SE = 0.11, P = 0.007) and younger age at onset (HR = 1.8, SE = 0.14, P = 2 × 10 −5 ) increased the probability of developing LiD. We identified three genetic loci significantly associated with time-to-LiD onset. rs72673189 on chromosome 1 (HR = 2.77, SE = 0.18, P = 1.53 × 10 −8 ) located at the LRP8 locus, rs189093213 on chromosome 4 (HR = 3.06, SE = 0.19, P = 2.81 × 10 −9 ) in the non-coding RNA LINC02353 locus, and rs180924818 on chromosome 16 (HR = 3.13, SE = 0.20, P = 6.27 × 10 −9 ) in the XYLT1 locus. Based on a functional annotation analysis on chromosome 1, we determined that changes in DNAJB4 gene expression, close to LRP8, are an additional potential cause of increased susceptibility to LiD. Baseline anxiety status was significantly associated with LiD (OR = 1.14, SE = 0.03, P = 7.4 × 10 −5 ). Finally, we performed a candidate variant analysis of previously reported loci, and found that genetic variability in ANKK1 ( rs1800497 , HR = 1.27, SE = 0.09, P = 8.89 × 10 −3 ) and BDNF ( rs6265 , HR = 1.21, SE = 0.10, P = 4.95 × 10 −2 ) loci were significantly associated with time to LiD in our large meta-analysis.
tert-Butyldimethylsilyl Amine (TBDMS-NH2): A Mild and Green Reagent for the Protection of Benzyl Alcohols, Phenols, and Carboxylic Acids under Solvent-Free Conditions
Publisher: CSIRO Publishing
Date: 2016
DOI: 10.1071/CH16097
Abstract: Herein, we present the use of the tert-butyldimethylsilyl amine (TBDMS-NH2) as a silylating reagent for phenols, benzyl alcohols, and carboxylic acids. Unlike other silyl protection reactions, this reported process with TBDMS-NH2 does not involve the formation of HCl. Importantly, we report the efficacy of this reagent in operating under solvent-free conditions and enabling short reaction times.
Transition Metal-free Methylation of Amines with Formaldehyde as the Reductant and Methyl Source
Publisher: Swiss Chemical Society
Date: 24-06-2015
Abstract: A simple transition metal-free procedure using formal dehyde for the N,N-dimethylation and N-methylation of primary and secondary anilines is reported. The reaction showed limitations on sterically hindered and electron-withdrawing anilines, but is successful on amines with electron-donating substituents. Formaldehyde acts as both the reducing agent and the carbon source in the reaction.
A concise synthesis of maleic anhydride and maleimide natural products found in Antrodia camphorata
Publisher: Elsevier BV
Date: 03-2007
N6-(5,6-epoxynorbornyl)adenosine analogs as A1 adenosine agonists
Publisher: Elsevier BV
Date: 12-1998
DOI: 10.1016/S0960-894X(98)00668-4
Abstract: A range of related adenosines and 5'-N-ethylcarboxamidoadenosines bearing oxygenated substituents in the N6 position have been synthesised and evaluated as A1-adenosine receptor ligands. Compound 9 emerged with potent affinity (EC50 = 1.1 nM).
Nickel Phosphite/Phosphine-Catalyzed C–S Cross-Coupling of Aryl Chlorides and Thiols
Publisher: American Chemical Society (ACS)
Date: 19-12-2017
DOI: 10.1021/ACS.ORGLETT.7B03560
Abstract: A method for the coupling of aryl chlorides and thiophenols using an air-stable nickel(0) catalyst is described. This thioetherification procedure can be effectively applied to a range of electronically erse aryl/heteroaryl chlorides without more expensive metal catalysts such as palladium, iridium, or ruthenium. This investigation also illustrates both, a variety of thiol coupling partners and, in certain cases, the use of Cs
Related Organisations
University Of Cambridge
Location: United Kingdom of Great Britain and Northern Ireland
University Of Bristol
Location: United Kingdom of Great Britain and Northern Ireland
Keele University
Location: United Kingdom of Great Britain and Northern Ireland
University Of Reading
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
Discovery Projects - Grant ID: DP230101545
Start Date: 2023
End Date: 12-2025
Amount: $507,300.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE0989351
Start Date: 04-2009
End Date: 04-2010
Amount: $425,000.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE0775551
Start Date: 2007
End Date: 12-2008
Amount: $550,000.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP230100051
Start Date: 2023
End Date: 12-2025
Amount: $589,000.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE0882634
Start Date: 2008
End Date: 12-2009
Amount: $220,000.00
Funder: Australian Research Council
View Funded Activity