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Design,synthesis and biological evaluation of pyridyl substituted benzoxazepinones as potent and selective inhibitors of aldosterone synthase

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Chinese Chemical Letters 2021年第7期32卷 2327-2332页

作者： Haichao Zhu Meihua Liu Haiyan Li Ting Guan Qi Zhang Yang Chen Yingxiang Liu Rolf RHartmann Lina Yin Qingzhong Hu School of Pharmaceutical Sciences Guangzhou University of Chinese MedicineGuangzhou 51006China Pharmaceutical and Medicinal Chemistry Saarland UniversityCampus C2.3D-66123SaarbruckenGermany

Exorbitant aldosterone is closely associated with various severe diseases,including congestive heart failure and chronic kidney *** aldosterone synthase is the pivotal enzyme in aldosterone biosynthesis,its inhibition constitutes a promising treatment for these *** a structure-based approach,a series of pyridyl substituted 3,4-dihydrobenzo[f][1,4]oxazepin-5(2 H)-ones were designed as inhibitors of aldosterone *** compounds(5 j,5 l,5 m 5 w,5 x and 5 y)distinguished themselves with potent inhibition(IC50<100 nmol/L)and high selectivity over homogenous 11β-*** the most promising compound,5 x exhibited an IC_(50) of 12 nmol/L and an excellent selectivity factor(SF)of157,which are both superior to those of the re ference fadrazole(IC_(50)=21 nmol/L,SF=7).Importantly,5 x showed no inhibition against steroidogenic CYP17,CYP19 and a panel of hepatic CYP enzymes indicating an outstanding sa fety *** it manifested satis factory pharmacokinetic pro perties in rats,compound5 x was considered as a drug candidate for further development.

关键词： Aldosterone synthase selective inhibitors Benzoxazepinones Heart failure Renal diseases

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Synthesis,and anti-inflammatory activities of gentiopicroside derivatives

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Chinese Journal of Natural Medicines 2022年第4期20卷 309-320页

作者： ZHANG Qi-Li XIA Peng-Fei PENG Xue-Jing WU Xiao-Yu JIN Hua ZHANG Jian ZHAO Lei Gansu University of Chinese Medicine Lanzhou 730000China Key Laboratory of Chemistry and Quality of TCM of the College of Gansu Province Lanzhou 730000China Gansu Province Engineering Laboratory for TCM Standardization Technology and Popularization Lanzhou 730000China

A series of 26 novel derivatives have been synthesized through structural modification of gentiopicroside,a lead COX-2 *** their in vivo and in vitro anti-inflammatory activities have been *** in vitro anti-inflammatory activities were evaluated against NO,PGE2,and IL-6 production in the mouse macrophage cell line RAW264.7 stimulated by *** showed that most compounds had good inhibitory *** in vivo inhibitory activities were further tested against xylene-induced mouse ear *** demonstrated that several compounds were more active than the parent compound *** inhibition rate of the most active compound P23(57.26%)was higher than positive control drug celecoxib(46.05%)at dose 0.28 *** docking suggested that these compounds might bind to COX-2 and *** of them,e.g P7,P14,P16,P21,P23,and P24,had high docking scores in accordance with their potency of the anti-inflammatory activitiy,that downregulation of the inflammatory factors,NO,PGE2,and IL-6,was possibly associated with the suppression of iNOS and ***,these gentiopicroside derivatives may represent a novel class of COX-2 and iNOS inhibitors.

关键词： Gentiopicroside derivatives Structural modification Anti-inflammatory activity selective inhibitors

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Purification and studies on characteristics of cholinesterases from Daphnia magna

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2013年第4期14卷 325-335页

作者： Yan-xia YANG Li-zhi NIU Shao-nan LI Institute of Pesticide and Environmental Toxicology College of Agriculture and BiotechnologyZhejiang University

Due to their significant value in both economy and ecology,Daphnia had long been employed to investigate in vivo response of cholinesterase(ChE) in anticholinesterase exposures,whereas the type constitution and property of the enzyme remained unclear.A type of ChE was purified from Daphnia magna using a three-step procedure,i.e.,Triton X-100 extraction,ammonium sulfate precipitation,and diethylaminoethyl(DEAE)-Sepharose Fast-Flow *** to sodium dodecyl sulfate polyacrylamide gel electrophoresis(SDS-PAGE),molecular mass of the purified ChE was estimated to be 84 *** on substrate studies,the purified enzyme preferred butyrylthiocholine iodide(BTCh) [with maximum velocity(Vmax)/Michaelis constant(Km)=8.428 L/(min·mg protein)] to acetylthiocholine iodide(ATCh) [with V max /Km =5.346 L/(min·mg protein)] as its *** of the purified enzyme was suppressed by high concentrations of either ATCh or *** studies showed that the purified enzyme was more sensitive towards inhibition by tetraisopropylpyrophosphoramide(iso-OMPA) than by 1,5-bis(4-allyldimethylammoniumphenyl) pentan-3-one dibromide(BW284C51).Result of the study suggested that the purified ChE was more like a type of pseudocholinesterase,and it also suggested that Daphnia magna contained multiple types of ChE in their bodies.

关键词： Crustacea Pseudocholinesterase Cholinesterase Substrate preference selective inhibitors

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