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Synthesis of C12-Keto Saxitoxin Derivatives with Unusual Inhibitory Activity Against Voltage-Gated Sodium Channels |
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| Authors: | Kanna Adachi Tomoshi Yamada Hayate Ishizuka Mana Oki Shunsuke Tsunogae Noriko Shimada Osamu Chiba Tatsuya Orihara Prof?Dr Masafumi Hidaka Prof?Dr Takatsugu Hirokawa Dr Minami Odagi Prof?Dr Keiichi Konoki Prof?Dr Mari Yotsu-Yamashita Prof?Dr Kazuo Nagasawa |
| Institution: | 1. Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo, 184-8588 Japan
These authors contributed equally to this work.;2. Graduate School of Agriculture Science, Tohoku University, 468-1 Aramaki-Aza-Aoba, Aoba-ku, Sendai, 980-8572 Japan These authors contributed equally to this work.;3. Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo, 184-8588 Japan;4. Graduate School of Agriculture Science, Tohoku University, 468-1 Aramaki-Aza-Aoba, Aoba-ku, Sendai, 980-8572 Japan;5. Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575 Japan Division of Biomedical Science, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575 Japan Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ward, Tokyo, 135-0064 Japan |
| Abstract: | A novel series of C12-keto-type saxitoxin (STX) derivatives bearing an unusual nonhydrated form of the ketone at C12 has been synthesized, and their NaV-inhibitory activity has been evaluated in a cell-based assay as well as whole-cell patch-clamp recording. Among these compounds, 11-benzylidene STX ( 3 a ) showed potent inhibitory activity against neuroblastoma Neuro 2A in both cell-based and electrophysiological analyses, with EC50 and IC50 values of 8.5 and 30.7 nm , respectively. Interestingly, the compound showed potent inhibitory activity against tetrodotoxin-resistant subtype of NaV1.5, with an IC50 value of 94.1 nm . Derivatives 3 a – d and 3 f showed low recovery rates from NaV1.2 subtype (ca 45–79 %) compared to natural dcSTX ( 2 ), strongly suggesting an irreversible mode of interaction. We propose an interaction model for the C12-keto derivatives with NaV in which the enone moiety in the STX derivatives 3 works as Michael acceptor for the carboxylate of Asp1717. |
| Keywords: | drug discovery inhibitors ion channels membrane proteins protein structures |