A5063676198- Synthetic Organic Chemistry Methods
- Chemical Synthesis and Analysis
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Chemical Synthesis and Reactions
- Synthesis and Catalytic Reactions
- Beetle Biology and Toxicology Studies
- Asymmetric Synthesis and Catalysis
- Sulfur-Based Synthesis Techniques
- Receptor Mechanisms and Signaling
- Phytochemical compounds biological activities
- Neuropeptides and Animal Physiology
- Oxidative Organic Chemistry Reactions
- Catalytic C–H Functionalization Methods
- Cyclopropane Reaction Mechanisms
- Microwave-Assisted Synthesis and Applications
- Mass Spectrometry Techniques and Applications
- Crystallography and molecular interactions
- Synthesis of β-Lactam Compounds
- Catalytic Cross-Coupling Reactions
- Computational Drug Discovery Methods
- Biochemical and Molecular Research
- Advanced Synthetic Organic Chemistry
- Catalytic Alkyne Reactions
- Organic Chemistry Cycloaddition Reactions
AstraZeneca (United Kingdom)
2015-2024
AstraZeneca (Brazil)
2012-2021
Loughborough University
2013-2020
University of Warwick
2016
Macclesfield College
2013-2015
University of Sheffield
2003-2015
AstraZeneca (Singapore)
2012
MSD (UK) Limited (United Kingdom)
2005-2006
University of Glasgow
1998-2000
University of Southampton
1997
B-cell lymphoma 6 (BCL6) inhibition is a promising mechanism for treating hematological cancers but high quality chemical probes are necessary to evaluate its therapeutic potential. Here we report potent BCL6 inhibitors that demonstrate cellular target engagement and exhibit exquisite selectivity based on mass spectrometry analyses following proteomic pull down. Importantly, proteolysis-targeting chimera (PROTAC) was also developed shown significantly degrade in number of diffuse large...
KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based design approach led the identification of 21, AZD4625, a clinical development candidate for treatment KRASG12C positive tumors. Highlights include quinazoline tethering strategy lock out bio-relevant binding conformation and optimization focused on reduction...
Inhibition of the protein–protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large (DLBCL) cancers profiling potent selective BCL6 inhibitors are critical to test this hypothesis. We identified pyrazolo[1,5-a]pyrimidine series binders from fragment screen parallel with virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming...
A new class of peptidomimetic is reported in which one the amide C=O bonds peptide backbone replaced by an oxetane ring. They are synthesised conjugate addition various α-amino esters to a 3-(nitromethylene)oxetane, reduction nitro group and further coupling with N-Z protected amino acids grow chain. Structural insights provided X-ray diffraction molecular dynamics simulations.
The mechanism behind the glucose lowering effect occurring after specific activation of GPR120 is not completely understood. In this study, a potent and selective agonist was developed its pharmacological properties were compared with previously described Metabolex-36. Effects both compounds on signaling pathways GLP-1 secretion investigated in vitro. acute studied lean wild-type null mice following oral or intravenous tolerance tests. vitro, overexpressing cells, agonists signaled through...
The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach led the identification 14, AZD4747, a clinical development candidate for treatment KRASG12C-positive tumors, including central nervous system (CNS) metastases. Building on earlier discovery C5-tethered quinazoline AZD4625, excision usually critical pyrimidine ring yielded weak...
The three-dimensional conformations adopted by a free ligand in solution impact bioactivity and physicochemical properties. Solution 1D NMR spectra inherently contain information on conformational flexibility shape, as well the propensity of to fully preorganize into bioactive conformation. Herein we discuss some key learnings, distilled from our experience developing potent selective synthetic macrocyclic inhibitors, including Mcl-1 clinical candidate AZD5991. Case studies have been...
In this paper we describe the stereoselective synthesis of functionalized lactam 7 via two enantiospecific piperidine-forming techniques and its employment in a general synthetic approach to Nuphar alkaloids. Specifically, formation piperidine 18 by formal [3 + 3] cycloaddition stepwise annelation processes is described; latter technique was found be significantly more efficient than Pd-catalyzed TMM addition process. Finally, exploitation exocyclic alkene installed reaction transformation...
Significant rate enhancements in the Diels–Alder reaction of alkynes and 2-pyrones bearing a Lewis basic group are observed when combination alkynyltrifluoroborates BF3·OEt2 is used. This process generates functionalized aromatic compounds with complete regiocontrol. The enhancement was studied by density functional theory methods appears to originate from coordination diene substrate mixture alkynylborane intermediates, followed acid-mediated product equilibration step. Evidence for this...
PRMT5, a type 2 arginine methyltransferase, has critical role in regulating cell growth and survival cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel "MTA-cooperative" compounds identified through high-throughput biochemical screening approach. Optimization hits was achieved structure-based design with focus on improvement oral drug-like properties. Bioisosteric replacement original thiazole...
GPR120 agonists have therapeutic potential for the treatment of diabetes, but few selective been reported. We identified an indazole-6-phenylcyclopropylcarboxylic acid series and conducted SAR studies to optimize potency. Furthermore, we a (S,S)-cyclopropylcarboxylic structural motif which gave selectivity against GPR40. Good oral exposure was obtained with some compounds displaying unexpected high CNS penetration. Increased MDCK efflux utilized identify such as 33 lower penetration,...
[reaction: see text] A stepwise formal [3 + 3] cycloaddition sequence via a Grignard addition-cyclization reaction leads to much improved piperidine synthesis. This methodology provides flexibility in both the aziridine substrate and TMM equivalent.
Two series of inhibitors type III phosphatidylinositol-4-kinase were identified by high throughput screening and optimised to derive probe compounds that independently selectively inhibit the α- β-isoforms with no significant activity towards related kinases in pathway. In a cellular environment, inhibition but not β-subtype led reduction phosphatidylinositol-4-phosphate phosphatidylinositol-4,5-bisphosphate concentration, causing inositol-1-phosphate formation proliferation panel cancer cell lines.
Solid-phase peptide synthesis (SPPS) is used to create peptidomimetics in which one of the backbone amide C═O bonds replaced by a four-membered oxetane ring. The containing dipeptide building blocks are made three steps solution, then integrated into chains conventional Fmoc SPPS. This methodology make range peptides high purity including modified derivatives nonapeptide bradykinin and Met- Leu-enkephalin.
Azetidine and oxetane sulfinate salts are easily prepared from commercially available 3-iodoheterocycle precursors in a three-step sequence.
Tumors have evolved a variety of methods to reprogram conventional metabolic pathways favor their own nutritional needs, including glutaminolysis, the first step which is hydrolysis glutamine glutamate by amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers blocking tumor cell's ability produce glutamine-derived nutrients. Starting from known bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, we describe medicinal chemistry evolution...
A stereocontrolled route to Nuphar alkaloids is described that employs a formal [3 + 3] cycloaddition strategy assemble the piperidine nucleus. The addition of Pd−TMM complexes aziridine 10 was found be sluggish; however, functionalized allyl Grignard reagent followed by Mitsunobu condensation reaction provided 11 in high yield. employment this synthesis (−)-deoxynupharidine 1 described.
A general modular approach to the members of pederin family antitumour agents is exemplified by syntheses mycalamide B and theopederin D as well a formal synthesis pederin. All three compounds are prepared from 6-lithio-2,3-dimethyl-4-phenylselenomethyl-3,4-dihydro-2H-pyran 2-(3-chloropropyl)-3,3-dimethyl-3,4-dihydro-2H-pyran-4-one.
The trimethylsilyl group and other silicon-containing groups are able to migrate anionic centers within the molecule. This phenomenon is used generate tandem processes involving a silyl migration - leaving elimination in systems equipped with silyl-, oxido-, group. Applications of silyloxiranes synthesis described. Other synthetic applications based upon cooperative reactions oxido (hydroxy) discussed. 1. Introduction 2. Reaction (trimethylsilyl)oxiranes α-sulfonyl- related anions 3....
A simple two-step sequence is used to efficiently make novel spirocyclic analogues of the diketopiperazine nucleus. Conjugate addition chiral α-amino esters nitroalkenes, generated from oxetan-3-one or <i>N</i>-Boc-azetidin-3-one, followed by nitro group reduction provides, after spontaneous cyclization, spirocycles in good overall yields. These rigid scaffolds can be functionalized selective N-alkylations as well carbonyl corresponding piperazines.
A new Fmoc-protected dipeptide incorporating an oxetane ring as a surrogate for the amide carbonyl group is effective gelator.
Metallated dihydropyran 9 and the dihydropyranone 10 previously used in a synthesis of insect toxin pederin were adapted to 18-O-methyl mycalamide B, most potent derivative anti-tumour agents isolated from sponge. Key steps include oxidation enol silane 11 more hindered face using dimethyldioxirane introduce hydroxy group at C-12 acylation 6-lithio-3,4-dihydro-2H-pyran with oxalamide 8 forge N-(1-alkoxy-1-alkyl)amide bridge. Biological tests human tumour cell lines confirm anti-proliferative...