RRC ID 71777
著者 Adachi K, Yamada T, Ishizuka H, Oki M, Tsunogae S, Shimada N, Chiba O, Orihara T, Hidaka M, Hirokawa T, Odagi M, Konoki K, Yotsu-Yamashita M, Nagasawa K.
タイトル Synthesis of C12-Keto Saxitoxin Derivatives with Unusual Inhibitory Activity Against Voltage-Gated Sodium Channels.
ジャーナル Chemistry
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 NaV 1.5, with an IC50 value of 94.1 nm. Derivatives 3 a-d and 3 f showed low recovery rates from NaV 1.2 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 .
巻・号 26(9)
ページ 2025-2033
公開日 2020-2-11
DOI 10.1002/chem.201904184
PMID 31769085
MeSH Action Potentials / drug effects Amino Acid Sequence Binding Sites Cell Line, Tumor Humans Inhibitory Concentration 50 Molecular Docking Simulation Patch-Clamp Techniques Protein Isoforms / antagonists & inhibitors Protein Isoforms / genetics Protein Isoforms / metabolism Quantum Theory Saxitoxin / chemistry* Saxitoxin / metabolism Saxitoxin / pharmacology Sodium Channel Blockers / chemical synthesis* Sodium Channel Blockers / metabolism Sodium Channel Blockers / pharmacology Tetrodotoxin / chemistry Tetrodotoxin / metabolism Voltage-Gated Sodium Channels / chemistry Voltage-Gated Sodium Channels / genetics Voltage-Gated Sodium Channels / metabolism*
IF 4.857
リソース情報
ヒト・動物細胞 293T(RCB2202)