111991-12-9Relevant articles and documents
Reprogramming Epoxide Hydrolase to Improve Enantioconvergence in Hydrolysis of Styrene Oxide Scaffolds
Li, Fu-Long,Qiu, Yan-Yan,Zheng, Yu-Cong,Chen, Fei-Fei,Kong, Xu–Dong,Xu, Jian-He,Yu, Hui-Lei
supporting information, p. 4699 - 4706 (2020/09/21)
Enantioconvergent hydrolysis by epoxide hydrolase is a promising method for the synthesis of important vicinal diols. However, the poor regioselectivity of the naturally occurring enzymes results in low enantioconvergence in the enzymatic hydrolysis of styrene oxides. Herein, modulated residue No. 263 was redesigned based on structural information and a smart variant library was constructed by site-directed modification using an “optimized amino acid alphabet” to improve the regioselectivity of epoxide hydrolase from Vigna radiata (VrEH2). The regioselectivity coefficient (r) of variant M263Q for the R-isomer of meta-substituted styrene oxides was improved 40–63-fold, and variant M263V also exhibited higher regioselectivity towards the R-isomer of para-substituted styrene oxides compared with the wild type, which resulted in improved enantioconvergence in hydrolysis of styrene oxide scaffolds. Structural insight showed the crucial role of residue No. 263 in modulating the substrate binding conformation by altering the binding surroundings. Furthermore, increased differences in the attacking distance between nucleophilic residue Asp101 and the two carbon atoms of the epoxide ring provided evidence for improved regioselectivity. Several high-value vicinal diols were readily synthesized (>88% yield, 90%–98% ee) by enantioconvergent hydrolysis using the reprogrammed variants. These findings provide a successful strategy for enhancing the enantioconvergence of native epoxide hydrolases through key single-site mutation and more powerful enzyme tools for the enantioconvergent hydrolysis of styrene oxide scaffolds into single (R)-enantiomers of chiral vicinal diols. (Figure presented.).
1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
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Page/Page column 45, (2012/05/31)
The present invention relates to novel triazolo[4,3-a]pyridine derivatives of Formula (I) wherein all radicals are as defined in the claims. The compounds according to the invention are positive allosteric modulators of the metabotropic glutamate receptor subtype 2 ("mGluR2"), which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases in which mGluR2 is involved.
DIARYLSULTAM DERIVATIVES
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, (2008/06/13)
Compounds represented by the formula: A-C(X)(Y)-C(R1)(R2)-Z, wherein Z represents, for example, a group of -N(R3)-(CH2)p-B wherein R3is alkyl group or other; p is integer of 3 to 8; B is a group represented by the following formula: wherein R7, R8, R9and R10represent hydrogen atom, halogen atom, alkyl group or other; X' is -S-, S(O)-, -S(O)2-, -O-, or -N(R11)- wherein R11is hydrogen atom, alkyl group or acyl group; W and W' represent benzene ring, or 5- to 7-membered heteroaryl group; X is cycloalkyl group, aryl group or other; Y is hydrogen atom, alkyl group, alkenyl group or other; A is -O-R6wherein R6is hydrogen atom, alkyl group, cycloalkyl group etc.; and R1and R2represent hydrogen atom, alkyl group or other. The compounds have high affinity and selectivity for sigma 2 binding site, and therefore they are useful as selective sigma 2 ligands for therapeutic and/or preventive treatment of various diseases and symptoms caused by sigma 2 ligands.
