A5044667632- Chemical Synthesis and Analysis
- Advanced Synthetic Organic Chemistry
- Asymmetric Synthesis and Catalysis
- Synthetic Organic Chemistry Methods
- Drug Transport and Resistance Mechanisms
- Chemical Synthesis and Reactions
- Organometallic Compounds Synthesis and Characterization
- Computational Drug Discovery Methods
- Fluorine in Organic Chemistry
- Click Chemistry and Applications
- Coordination Chemistry and Organometallics
- Synthesis and Catalytic Reactions
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Blood disorders and treatments
- Antibiotic Resistance in Bacteria
- Synthesis and Reactivity of Sulfur-Containing Compounds
- Protein Kinase Regulation and GTPase Signaling
- Sulfur-Based Synthesis Techniques
- Oxidative Organic Chemistry Reactions
- Synthesis and Reactions of Organic Compounds
- Antibiotics Pharmacokinetics and Efficacy
- Organic Chemistry Cycloaddition Reactions
- Catalytic C–H Functionalization Methods
- Chronic Lymphocytic Leukemia Research
Bicycle Therapeutics (United Kingdom)
2022-2025
Eurofins (United Kingdom)
2019-2021
University of Manchester
1994-2012
GlaxoSmithKline (United Kingdom)
2001-2010
University of California, Los Angeles
2009
Molecular Discovery (United Kingdom)
2009
University of Oxford
2004-2008
The Diels−Alder reactions of a series silyloxydienes and silylated dienes with acyclic α,β-unsaturated ketones N-acyloxazolidinones have been investigated. endo/exo stereochemical outcome is strongly influenced by the substitution pattern reactants. High exo selectivity was observed when termini diene dienophile involved in shorter forming bonds were both substituted, while normal endo preference found otherwise. exo-selective asymmetric using Evans' oxazolidinone chiral auxiliary furnished...
Polymyxins are an important class of antibiotics for the treatment bacterial infections due to multidrug resistant Gram-negative pathogens. However, their clinical utility is limited by nephrotoxicity. Here, we report a series promising next generation polymyxin nonapeptides identified on basis our understanding relationship structure with activity, cytotoxicity, and kidney compartment accumulation. We demonstrate that amine-containing N-terminal moiety specific regio- stereochemistry...
Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but generation potent, drug-like molecules through chemical synthesis challenging. In this study, set macrocyclic cyclophilin inhibitors was synthesized based on core structure natural product sanglifehrin A. Initial compound optimization identified valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in core, stereocenters at C14 C15, hydroxyl group m-tyrosine (m-Tyr) residue as key...
COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines drug-like advantages both. Bicycles are entropically constrained peptides stabilized by central chemical scaffold into bi-cyclic structure. Rapid screening diverse bacteriophage libraries against Spike yielded unique Bicycle binders across entire protein. Exploiting Bicycles' inherent combinability, converted...
Improving the delivery of antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) to skeletal cardiac muscles remains a pivotal task toward broader application oligonucleotide therapeutics. The targeting myofibers cardiomyocytes via conjugation ASOs siRNAs ligands that bind human transferrin receptor 1 (TfR1) has gathered significant interest in recent years. However, selection with low molecular weight optimal biophysical binding properties is crucial maximize potential TfR1...
The scope and limitations of lithium 2,2,6,6-tetramethylpiperidide (LTMP)-modified reductive alkylation epoxides is detailed. A variety organolithiums are added to terminal 2,2-disubstituted in the presence LTMP generate alkenes a completely regio- highly stereoselective manner. Arylated alkenes, dienes, allylsilanes, enynes accessed using this procedure. methodology applied synthesis roller leaf moth pheromone, (3E,5Z)-dodecadienyl acetate. corresponding reaction without has also been...
Novel polymyxin derivatives are often classified either as having direct activity against Gram-negative pathogens or compounds inactive in their own right, which through permeabilization of the outer membrane act potentiators other antibiotics. Here, we report systematic investigation influence lipophilicity on microbiological (including strains with reduced susceptibility to polymyxins), potentiation rifampicin, and vitro toxicity within a series next-generation nonapeptides. We demonstrate...
Bicycles are constrained bicyclic peptides formed through reaction of three cysteine residues within a linear sequence with trivalent, symmetrical small molecule scaffold. high binding affinities to therapeutically important targets can be discovered using screening technologies such as phage display. Increasing the chemical diversity should improve probability finding hits new and achieved by expanding toolbox Bicycle forming chemistries. Gold(III) S-arylation has recently been described...
N-(3-Fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine 12 (GSK962040) is a novel small molecule motilin receptor agonist. It possesses excellent activity at the recombinant human and also native rabbit where its agonist results in potentiation of amplitude neuronal-mediated contractions isolated gastric antrum tissue. Compound highly promising pharmacokinetic profiles both rat dog, these results, combination with further profiling tissue an vivo model...
E-Alkenes (including arylated alkenes, dienes, and allylsilanes) are efficiently prepared by alpha-deprotonation of terminal epoxides using lithium 2,2,6,6-tetramethylpiperidide, followed in situ trapping with organolithiums or Grignard reagents.
[reaction: see text]. Regio- and stereodefined allylic N-sulfonylamines are synthesized in high yields under experimentally straightforward conditions by reaction of N-sulfonylaziridines with excess dimethylsulfonium methylide.
Alk-2-enylstannanes with 4-, 5- and 6-alkoxy- or -hydroxy-substituents are transmetallated stereoselectively tin(IV) halides to generate allyltin trihalides which react aldehydes give (Z)-alk-3-enols useful levels of 1,5-, 1,6- 1,7-stereocontrol. a stereogenic centre bearing hydroxy alkoxy group at the 6-position, overall (Z)-1,5-, 1,7-syn-stereoselectivity respect substituents. The analogous reactions alkoxy- -hydroxyalk-2-enylstannanes methyl 4- 5-position (Z)-1,5- 1,6-anti-stereoselectivity
N-Tosyl-protected 3-hydroxypyrrolidines are prepared by reaction of dimethylsulfoxonium methylide with readily available epoxysulfonamides.
Angiotensin-converting enzyme 2 (ACE2) is a metalloprotease that cleaves angiotensin II, peptide substrate involved in the regulation of hypertension. Here, we identified series constrained bicyclic peptides, Bicycle, inhibitors human ACE2 by panning highly diverse bacteriophage display libraries. These were used to generate X-ray crystal structures which inform design additional Bicycles with increased affinity and inhibition enzymatic activity. This novel structural class among most potent...
Abstract Penicillin binding proteins (PBPs) are well validated antimicrobial targets, but the prevalence of β-lactamase driven resistance and, more rarely, target-based mutations, necessitates new classes PBP-targeting drugs. Here we describe discovery and optimisation novel, bicyclic peptide (Bicycle ® ) inhibitors E. coli PBP3 ( Ec PBP3) using a proprietary phage display platform, their conjugation to linear peptides confer outer membrane permeation. These molecules exhibited high-affinity...
Growing antibiotic resistance is rapidly threatening the efficacy of treatments for Gram-negative infections. Bicycle molecules, constrained bicyclic peptides from diverse libraries generated by bacteriophage display that bind with high affinity to a chosen target are potential new class antibiotics. The generally impermeable bacterial outer membrane currently limits access bacteria. conjugation active offers an avenue penetration. Here, we investigate which physicochemical properties...