Structural Determination, Total Synthesis, and Biological Activity of Iezoside, a Highly Potent Ca2+-ATPase Inhibitor from the Marine Cyanobacterium Leptochromothrix valpauliae
Structural Determination, Total Synthesis, and Biological Activity of Iezoside, a Highly Potent Ca2+-ATPase Inhibitor from the Marine Cyanobacterium Leptochromothrix valpauliae
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DOI：
10.1021/jacs.2c04459
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发表时间：
2022-06-22
影响因子：
15
通讯作者：
Suenaga, Kiyotake
中科院分区：
文献类型：
--
作者：
Kurisawa, Naoaki;Iwasaki, Arihiro;Suenaga, Kiyotake
Sarco/内质网Ca2+- atp酶（SERCA）是内质网（ER）上的一种膜蛋白，可将Ca2+从细胞质溶胶转运到内质网。由于其功能与多种生物现象相关，SERCA已被认为是一个有前景的药物靶点。在这里，我们报道了迄今为止已知的第二强serca抑制化合物，我们从海洋蓝藻Leptochromothrix valpauliae中分离出来并命名为iezoside(1)。iezoside(1)的结构与其他SERCA抑制剂根本不同，其效力是海洋天然产物中最强的（K-i 7.1 nM）。在这篇文章中，我们报道了我们对iezoside(1)的综合分析，包括它的分离、密度泛函理论（DFT）计算和统计分析支持的结构表征、全合成和阐明其有效的抗增殖活性（对HeLa细胞的IC50为6.7 +/- 0.4 nM）的作用方式。
Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) is a membrane protein on the endoplasmic reticulum (ER) that transports Ca2+ 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 Leptochromothrix valpauliae and named iezoside (1). The structure of iezoside (1) is fundamentally different from that of any other SERCA inhibitor, and its potency is the strongest among marine natural products (K-i 7.1 nM). In this article, we report our comprehensive analysis of iezoside (1), 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 (IC50 6.7 +/- 0.4 nM against HeLa cells).