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Isomerization of bioactive acylhydrazones triggered by light or thiols

Nature Chemistry volume 15, pages 1285–1295 (2023)Cite this article

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Abstract

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/Z isomerization 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⇄Z isomerization of acylhydrazones. The ratio of E to Z isomers in cells is determined by the relative stabilities of the isomers regardless of which isomer was applied. We conclude that E/Z isomerization may be a common feature of the bioactivity observed with acylhydrazones and should be routinely analysed.

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Fig. 1: Structures and isomers of acylhydrazones.
Fig. 2: Chemistry and bioactivity of 217.
Fig. 3: Isomerization of 3DHO affects bioactivity.
Fig. 4: GSH catalyses dynamic E⇄Z isomerization of acylhydrazones.
Fig. 5: Reversible E/Z switching of 5TUS in vitro and in living cells.
Fig. 6: Reversible photoswitching of HILKOD.

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Data availability

Source data include Excel files containing data for Figs. 2c,d,g,h, 3b,e–g, 4a–d, 5b–g and 6b,c,f–h and Pymol files for models (Figs. 1d,e, 2b,i and 3d). Computed structures included in the tables in Supplementary Information are attached as .xyz files. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC): E-43 (deposition number 2143493) and E-217 (deposition number 2143494). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Source data are provided with this paper.

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Acknowledgements

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.

Author information

Author notes

  1. These authors contributed equally: Zhiwei Zhang, Giang N. T. Le, Yang Ge.

  2. These authors jointly supervised this work: Peter Axerio-Cilies, Yu Tian Wang, Mingxin Dong, G. Andrew Woolley.

Authors and Affiliations

  1. Department of Chemistry, University of Toronto, Toronto, Ontario, Canada

    Zhiwei Zhang, Giang N. T. Le, Darcy C. Burns, Susannah Tran & G. Andrew Woolley

  2. Key Laboratory for Advanced Materials, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, China

    Zhiwei Zhang

  3. Department of Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada

    Yang Ge, Peter Axerio-Cilies & Yu Tian Wang

  4. Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao, China

    Xiaowen Tang, Xin Chen & Mingxin Dong

  5. David Braley Centre for Antibiotics Discovery M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

    Linda Ejim, Emily Bordeleau & Gerard D. Wright

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Contributions

Z.Z., G.N.T.L., M.D. and G.A.W. developed the concepts and designed, carried out and analysed in vitro photoswitching experiments. G.N.T.L. and G.A.W. developed the concepts and designed, carried out and analysed thiol-mediated switching experiments in vitro and in cellulo. Y.G., Y.T.W. and P.A.-C. designed, carried out and analysed all electrophysiology experiments. X.T., X.C. and M.D. designed and synthesized compounds and carried out docking experiments. L.E., E.B. and G.D.W. designed, carried out and analysed enzyme activity assays for compound 3DHO. D.C.B. designed and analysed NMR experiments. S.T. provided additional measurements of ionization and photoswitching of compounds. Y.T.W., M.D. and G.A.W. supervised the project. Z.Z., G.N.T.L., Y.G., Y.T.W., M.D. and G.A.W. wrote the manuscript.

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Correspondence to Peter Axerio-Cilies, Yu Tian Wang, Mingxin Dong or G. Andrew Woolley.

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Competing interests

No financial interest or any direct conflict of interest exists. Y.T.W. and P.A.-C. declare an internationalized patent related to this class of NPAM compounds (N-methyl-d-aspartate receptor (NMDAR) allosteric modulators and methods for their use, WO 2018/107853 A2).

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Nature Chemistry thanks Nadja Simeth, Wiktor Szymanski, Oliver Thorn-Seshold and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Zhang, Z., Le, G.N.T., Ge, Y. et al. Isomerization of bioactive acylhydrazones triggered by light or thiols. Nat. Chem. 15, 1285–1295 (2023). https://doi.org/10.1038/s41557-023-01239-5

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