論文 - 詳細
| 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | 293T(RCB2202) |