Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.
Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
J Am Chem Soc. 2022 Jun 22;144(24):11019-11032. doi: 10.1021/jacs.2c04459. Epub 2022 Jun 8.
Sarco/endoplasmic reticulum Ca-ATPase (SERCA) is a membrane protein on the endoplasmic reticulum (ER) that transports Ca from the cytosol into the ER. As its function is associated with various biological phenomena, SERCA has been recognized as a promising druggable target. Here, we report the second-strongest SERCA-inhibitory compound known to date, which we isolated from the marine cyanobacterium and named iezoside (). The structure of iezoside () is fundamentally different from that of any other SERCA inhibitor, and its potency is the strongest among marine natural products ( 7.1 nM). In this article, we report our comprehensive analysis of iezoside (), which covers its isolation, structural characterization supported by density functional theory (DFT) calculations and statistical analysis, total synthesis, and clarification of the mode of action of its potent antiproliferative activity (IC 6.7 ± 0.4 nM against HeLa cells).
肌浆/内质网 Ca2+-ATP 酶（SERCA）是内质网上的一种膜蛋白，它将 Ca2+从细胞质内转运到内质网中。由于其功能与多种生物学现象有关，SERCA 已被认为是一个有前途的可成药靶标。在这里，我们报告了迄今为止已知的第二强的 SERCA 抑制化合物，该化合物是从海洋蓝藻中分离出来的，并将其命名为 iezoside（）。iezoside（）的结构与任何其他 SERCA 抑制剂的结构完全不同，其效力在海洋天然产物中是最强的（7.1 nM）。在本文中，我们报告了对 iezoside（）的全面分析，包括其分离、密度泛函理论（DFT）计算和统计分析支持的结构表征、全合成以及其强效抗增殖活性作用模式的阐明（对 HeLa 细胞的 IC 6.7±0.4 nM）。
