文献类型：期刊文献

英文题名：Isomerization of bioactive acylhydrazones triggered by light or thiols

作者：Zhang, Zhiwei[1,2];Le, Giang N. T.[1];Ge, Yang[3];Tang, Xiaowen[4];Chen, Xin[4];Ejim, Linda[5];Bordeleau, Emily[5];Wright, Gerard D.[5];Burns, Darcy C.[1];Tran, Susannah[1];Axerio-Cilies, Peter[3];Wang, Yu Tian[3];Dong, Mingxin[4];Woolley, G. Andrew[1]

机构：[1]Univ Toronto, Dept Chem, Toronto, ON, Canada;[2]East China Univ Sci & Technol, Sch Chem & Mol Engn, Key Lab Adv Mat, Shanghai, Peoples R China;[3]Univ British Columbia, Djavad Mowafaghian Ctr Brain Hlth, Dept Med, Vancouver, BC, Canada;[4]Qingdao Univ, Sch Pharm, Dept Med Chem, Qingdao, Peoples R China;[5]McMaster Univ, DeGroote Inst Infect Dis Res, David Braley Ctr Antibiot Discovery MG, Dept Biochem & Biomed Sci, Hamilton, ON, Canada

年份：2023

外文期刊名：NATURE CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001007507200006)】；

基金：The authors gratefully acknowledge the contribution of A. Jaikaran for advice and helpful comments and S. L. Roderick for the crystallization and structure determination of VatD in complex with 3DHO. We also thank referees of the paper for helpful suggestions and, in particular, O. Thorn-Seshold for suggesting important tests. This research was funded by the Natural Science and Engineering Research Council of Canada (NSERC-RGPIN-115110) to G.A.W., a Canadian Institutes of Health Research Foundation Grant (CIHR-FDN-154286) to Y.T.W., the China Scholarship Council (CSC), the China Postdoctoral Science Foundation (2020TQ0095, and 2021M691005) and the National Natural Science Foundation of China (22101084) to Z.Z., an APRENTICE fellowship to G.L. via the Collaborative Research and Training Experience (CREATE) programme (NSERC); a National Key Research and Development Project of China (2018YFA0900804) grant to M.X.D., and a Canadian Institutes of Health Research grant (FRN-148463), and a Canada Research Chair to G.D.W. Y.T.W. is the holder of Heart and Stroke Foundation of British Columbia and Yukon Chair in Stroke Research.

语种：英文

摘要：The acylhydrazone unit is well represented in screening databases used to find ligands for biological targets, and numerous bioactive acylhydrazones have been reported. However, potential E/Zisomerization of the C=N bond in these compounds is rarely examined when bioactivity is assayed. Here we analysed two ortho-hydroxylated acylhydrazones discovered in a virtual drug screen for modulators of N-methyl-D-aspartate receptors and other bioactive hydroxylated acylhydrazones with structurally defined targets reported in the Protein Data Bank. We found that ionized forms of these compounds, which are populated under laboratory conditions, photoisomerize readily and the isomeric forms have markedly different bioactivity. Furthermore, we show that glutathione, a tripeptide involved with cellular redox balance, catalyses dynamic E?Zisomerization of acylhydrazones. The ratio of EtoZisomers in cells is determined by the relative stabilities of the isomers regardless of which isomer was applied. We conclude that E/Zisomerization may be a common feature of the bioactivity observed with acylhydrazones and should be routinely analysed.