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acsmedchemlett.1c00591.pdf | 1.16 MB | Adobe PDF | 見る/開く |
タイトル: | Design of Coibamide A Mimetics with Improved Cellular Bioactivity |
著者: | Kitamura, Takashi Suzuki, Rikito Inuki, Shinsuke https://orcid.org/0000-0002-7525-1280 (unconfirmed) Ohno, Hiroaki https://orcid.org/0000-0002-3246-4809 (unconfirmed) McPhail, Kerry L. Oishi, Shinya |
著者名の別形: | 喜多村, 隆志 鈴木, 力斗 井貫, 晋輔 大野, 浩章 大石, 真也 |
キーワード: | apratoxin A biphenylylalanine coibamide A macrocyclic peptide Sec61 translocon |
発行日: | Jan-2022 |
出版者: | American Chemical Society (ACS) |
誌名: | ACS Medicinal Chemistry Letters |
巻: | 13 |
号: | 1 |
開始ページ: | 105 |
終了ページ: | 110 |
抄録: | Coibamide A, a cyclic depsipeptide isolated from a Panamanian marine cyanobacterium, shows potent cytotoxic activity via the inhibition of the Sec61 translocon. We designed a coibamide A mimetic in which the ester linkage between MeThr and d-MeAla in coibamide A was replaced with an alkyl linker to provide a stable macrocyclic scaffold possessing a MeLys(Me) residue. Taking advantage of a facile solid-phase synthetic approach, an structure–activity relationship (SAR) study of the newly designed macrocyclic structure was performed, with a focus on altering the pattern of N-methyl substitution and amino acid configurations. Overall, the simplified macrocyclic scaffold with an alkyl linker resulted in a significantly reduced cytotoxicity. Instead, more potent coibamide A derivatives with a β-(4-biphenylyl)alanine (Bph) group were identified after the optimization of the Tyr(Me) position in the original macrocyclic scaffold of coibamide A based on the characteristic apratoxin A substructures. The similar SAR between coibamide A and apratoxin A suggests that the binding site of the Tyr(Me) side chain at the luminal end of Sec61α may be shared. |
著作権等: | © 2021 The Authors. Published by American Chemical Society This article is licensed under the Creative Commons Attribution 4.0 International License. |
URI: | http://hdl.handle.net/2433/274023 |
DOI(出版社版): | 10.1021/acsmedchemlett.1c00591 |
PubMed ID: | 35059129 |
出現コレクション: | 学術雑誌掲載論文等 |
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