176022-47-2Relevant articles and documents
Characterization of Photodegradation Products of Bepotastine Besilate and In Silico Evaluation of Their Physicochemical, Absorption, Distribution, Metabolism, Excretion and Toxicity Properties
Singh, Dilip Kumar,Sahu, Archana,Wani, Aabid Abdullah,Bharatam, Prasad V.,Chakraborti, Asit K.,Giri, Sanjeev,Singh, Saranjit
, p. 1883 - 1895 (2020)
Bepotastine (BPT) is a H1-receptor antagonist. It is used as a besilate salt in ophthalmic solution for allergic conjunctivitis and orally for the treatment of allergic rhinitis and urticaria/pruritus. Its systematic forced degradation study is unreported. The same was carried out in different conditions prescribed by International Conference on Harmonisation. The stressed solutions were subjected to reversed phase liquid chromatographic analysis, and BPT was observed to be labile under photobasic condition only, yielding 5 photodegradation products. The structures of the latter were elucidated from data generated by liquid chromatography–high-resolution mass spectrometry and multistage mass spectrometry. Of the 5, 4 products were further isolated and subjected to nuclear magnetic resonance spectroscopy to justify the proposed structures. Two of them, with similar accurate mass, were additionally and unambiguously characterized from their heteronuclear multiple bond correlation data, hydrogen deuterium exchange mass data, and quantum chemical analysis using density functional theory calculations. One degradation product had a structure that could only be explained by unusual rearrangement involving conversions of N-oxide into hydroxylamine, similar to Meisenheimer rearrangement. The physicochemical, as well as absorption, distribution, metabolism, excretion, and toxicity properties of BPT and its characterized photodegradation products were evaluated in silico by ADMET Predictor software.
Electronic Effect-Guided Rational Design of Candida antarctica Lipase B for Kinetic Resolution Towards Diarylmethanols
Li, Dan-Yang,Lou, Yu-Jiao,Xu, Jian,Chen, Xiao-Yang,Lin, Xian-Fu,Wu, Qi
, p. 1867 - 1872 (2021/02/12)
Herein, we developed an electronic effect-guided rational design strategy to enhance the enantioselectivity of Candida antarctica lipase B (CALB) mutants towards bulky pyridyl(phenyl)methanols. Compared to W104A mutant previously reported with reversed S-stereoselectivity toward sec-alcohols, three mutants (W104C, W104S and W104T) displayed significant improvement of S-enantioselectivity in the kinetic resolution (KR) of various phenyl pyridyl methyl acetates due to the increased electronic effects between pyridyl and polar residues. The electronic effects were also observed when mutating other residues surrounding the stereospecificity pocket of CALB, such as T42A, S47A, A281S or A281C, and can be used to manipulate the stereoselectivity. A series of bulky pyridyl(phenyl) methanols, including S-(4-chlorophenyl)(pyridin-2-yl) methanol (S-CPMA), the intermediate of bepotastine, were obtained in good yields and ee values. (Figure presented.).
Engineering an alcohol dehydrogenase with enhanced activity and stereoselectivity toward diaryl ketones: Reduction of steric hindrance and change of the stereocontrol element
Chen, Rong,Huang, Jiankun,Meng, Xiangguo,Shao, Lei,Wu, Kai,Yang, Zhijun
, p. 1650 - 1660 (2020/04/09)
Steric hindrance in the binding pocket of an alcohol dehydrogenase (ADH) has a great impact on its activity and stereoselectivity simultaneously. Due to the subtle structural difference between two bulky phenyl substituents, the asymmetric synthesis of diaryl alcohols by bioreduction of diaryl ketones is often hindered by the low activity and stereoselectivity of ADHs. To engineer an ADH with practical properties and to investigate the molecular mechanism behind the asymmetric biocatalysis of diaryl ketones, we engineered an ADH from Lactobacillus kefiri (LkADH) to asymmetrically catalyse the reduction of 4-chlorodiphenylketones (CPPK), which are not catalysed by the wild type (WT) enzyme. Mutants seq1-seq5 with gradually increased activity and stereoselectivity were obtained through iterative "shrinking mutagenesis." The final mutant seq5 (Y190P/I144V/L199V/E145C/M206F) demonstrated the highest activity and excellent stereoselectivity of >99% ee. Molecular simulation analyses revealed that mutations may enhance the activity by eliminating steric hindrance, inducing a more open binding loop and constructing more noncovalent interactions. The pro-R pose of CPPK with a halogen bond formed a pre-reaction conformation more easily than the pro-S pose, resulting in the high ee of (R)-CPPO in seq5. Moreover, different halogen bonds formed due to the different positions of chlorine substituents, resulting in opposite substrate binding orientation and stereoselectivity. Therefore, the stereoselectivity of seq5 was inverted toward ortho- rather than para-chlorine substituted ketones. These results indicate that the stereocontrol element of LkADH was changed to recognise diaryl ketones after steric hindrance was eliminated. This study provides novel insights into the role of steric hindrance and noncovalent bonds in the determination of the activity and stereoselectivity of enzymes, and presents an approach producing key intermediates of chiral drugs with practical potential.
