A5020262284- Asymmetric Synthesis and Catalysis
- Chemical Synthesis and Analysis
- Asymmetric Hydrogenation and Catalysis
- Catalytic Cross-Coupling Reactions
- Crystallization and Solubility Studies
- Coordination Chemistry and Organometallics
- Synthesis and Catalytic Reactions
- X-ray Diffraction in Crystallography
- Advanced Synthetic Organic Chemistry
- Synthesis and biological activity
- Synthesis and Biological Evaluation
- Melanoma and MAPK Pathways
- Protein Degradation and Inhibitors
- Antifungal resistance and susceptibility
- Sulfur-Based Synthesis Techniques
- Prostate Cancer Treatment and Research
- Phytochemical compounds biological activities
- Cancer-related gene regulation
- Nail Diseases and Treatments
- Ubiquitin and proteasome pathways
- Organic and Inorganic Chemical Reactions
- PI3K/AKT/mTOR signaling in cancer
- Antimicrobial agents and applications
- Chemical Synthesis and Reactions
- Carbohydrate Chemistry and Synthesis
University College London
2014-2017
Transnational Press London
2014-2016
University of Nottingham
2007-2010
Bayer (Germany)
2009
Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of (AR-SV). Inhibitors transcriptional coactivators that regulate activity, the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal cancer. Herein, we validate targeting p300/CBP as a strategy describe CCS1477, novel small-molecule inhibitor conserved bromodomain. We...
The profile of PC945, a novel triazole antifungal designed for administration via inhalation, was assessed in range vitro and vivo studies. PC945 characterized as potent, tightly binding inhibitor Aspergillus fumigatus sterol 14α-demethylase (CYP51A CYP51B) activity (50% inhibitory concentrations [IC50s], 0.23 μM 0.22 μM, respectively) with characteristic type II azole spectra. Against 96 clinically isolated A. strains, the MIC values ranged from 0.032 to >8 μg/ml, while those voriconazole...
Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors BRAF and MEK kinases are approved for treatment mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe fragment-based generation ERK1/2 inhibitors that block catalytic phosphorylation downstream substrates such as RSK also modulate without directly inhibiting MEK. X-ray crystallographic biophysical fragment screening followed...
Addition of AlMe3 to commercial THF solutions RZnX (R = aryl, functionalised vinyl; X Br, I) simultaneously promotes Schlenk equilibria (leading competent nucleophiles) and the formation an Al–Zn-ligand catalyst delivering 80–90% ee for Ar1CH(OH)Ar2 from aldehydes.
ABSTRACT The antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, against Aspergillus fumigatus were tested in a range vitro and vivo studies. PC1244 demonstrated potent activities clinical A. isolates ( n = 96) with MIC 0.016 to 0.25 μg/ml, whereas voriconazole was 0.5 μg/ml. strong tight-binding inhibitor recombinant CYP51A CYP51B (sterol 14α-demethylase) enzymes strongly inhibited ergosterol synthesis 50% inhibitory concentration 8 nM. effective...
The presence of promoted Schlenk equilibria for organozinc halide species has been explicitly demonstrated by 13C NMR studies. Thus, addition methylaluminoxane (MeAlO)n, MAO, to RZnX (R=Et, Bn, ArCH2, (CH2)3CO2Et; X=Cl, Br) leads the formation ZnR2 and ZnX2MAO. For EtZnCl, equilibration ZnEt2 ZnX2MAO is rapid at -35 degrees C; a K value 0.19 M-1 indicates equilibrium favours (0.75-3.0 equiv MAO). Use RZnX/MAO mixtures allows copper-catalysed 1,4-addition 2-cyclohexenone be achieved, but...
Abstract A practical asymmetric 1,2‐addition of functionalised arylzinc halides to aromatic and aliphatic aldehydes is described by the use aminoalcohol catalysis in presence AlMe 3 . The process simple carry out, uses only commercially available reagents/ligands provides moderate good (80–96 % ee ) enantioselectivities for a wide range substrates. Either commercial ArZnX reagents or those prepared situ from low cost aryl bromides can be used. In latter case electrophilic functional groups...
11590 Background: Targeted degradation of androgen receptor (AR) and AR variants (ARV) remains an attractive therapeutic opportunity for patients with castrate resistant prostate cancer (CRPC). E1A binding protein (p300) CREB (CBP) are two closely related transcriptional activators AR. We have developed CCS1477 which is a potent, selective orally active small molecule inhibitor the bromodomain p300/CBP investigated its role in regulating expression function. Methods: Binding to p300, CBP...
Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, number inhibitors have been advanced to investigational clinical trials patients with activating mutations B-Raf proto-oncogene or Ras. Here, we describe discovery candidate ASTX029 (15) through structure-guided optimization our previously published...
Aberrant activation of NLRP3 due to persistent tissue damage, misfolded proteins or crystal deposits has been linked multiple chronic inflammatory disorders such as cryopyrin-associated periodic syndrome (CAPS), neurodegenerative diseases, gouty arthritis, and numerous others. Hence, there an increasing interest in inhibitors therapeutics. A first generation bearing a sulfonylurea core MCC950 (developed by Pfizer) were discovered phenotypic screening, however their mode action was only...
A reductive conjugate addition nitro-Mannich reaction controls diastereoselectivity in a rapid entry to diverse array of 1,2,3,4-tetrahydroquinoxalines high yield.
A conjugate addition nitro-Mannich reaction followed by nitro reduction and intramolecular N-arylation gives diastereomerically pure substituted 1,2-diamine containing indolines. Placing the cyclisation handle on imine precursor derived from an ortho-bromine aromatic aldehyde gave corresponding β-nitroamines in 55-72% yields as single diastereoisomers. Nitro was effected with modified quantities of Zn/HCl a subsequent Pd(0) catalysed Buchwald Hartwig indoline products 40-70%
Conjugate additions of [Zn(bpy*)Cl(Et)] (bpy* = 4,4'-di- tert -butyl-2,2'-bipyridine) to cyclohex-2-en-1-one are promoted by ZnMe 2 in 88% ee but moderate yield under Cu I phosphoramidite catalysis. In the absence is inactive indicating a Schlenk-type equilibrium. Other derivatives [Zn(bpy*)Cl(R)] (R Bu, 4-methylbenzyl), prepared situ from [ZnCl(R)] and bipyridine give low yields due competing chloride abstraction. 13 C NMR studies indicate facile organo-ligand exchange between [Zn(bpy*)(Et)...
Deprotonation of secondary alkane nitriles with nBuLi and addition to aryl imines gives kinetic anti-β-aminonitriles. Use LHMDS allows reversible protonation the reaction intermediate give syn-β-aminonitriles. The pure diastereosiomers can be isolated in good yields, mechanism was elucidated.
The base-promoted 1,2-addition of alkyl phenylsulfones to N-(para-methoxyphenyl) imines was investigated as a direct route stereochemically defined β-aminosulfones. Using nBuLi base, 2-(phenylsulfonyl)ethylbenzene added range give β-aminosulfone products in high yields single anti-diastereoisomers. Other less substituted were not successful.
Abstract Sulfone substituents are found to influence the diastereoselectivity of 1,2‐addition reaction imines (II).
Abstract Electron‐rich aryl bromides are found to be reluctant cyclize.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at glance that was extracted from about 100 leading journals. To access of an article which published elsewhere, please select “Full Text” option. The original trackable via the “References”
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at glance that was extracted from about 200 leading journals. To access of an article which published elsewhere, please select “Full Text” option. The original trackable via the “References”
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at glance that was extracted from about 200 leading journals. To access of an article which published elsewhere, please select “Full Text” option. The original trackable via the “References”