Biostructural Features of Additional Jasplakinolide (Jaspamide) Analogues

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• 作者：Katharine R. Watts ; Brandon I. Morinaka ; Taro Amagata ; Sarah J. Robinson ; Karen Tenney ; Walter M. Bray ; Nadine C. Gassner ; R. Scott Lokey ; Joseph Media ; Frederick A. Valeriote ; Phillip Crews
• 刊名：Journal of Natural Products
• 出版年：2011
• 出版时间：March 25, 2011
• 年：2011
• 卷：74
• 期：3
• 页码：341-351
• 全文大小：1008K
• 年卷期：v.74,no.3(March 25, 2011)
• ISSN：1520-6025

文摘

The cyclodepsipeptide jasplakinolide (1) (aka jaspamide), isolated previously from the marine sponge Jaspis splendens, is a unique cytotoxin and molecular probe that operates through stabilization of filamentous actin (F-actin). We have recently disclosed that two analogues of 1, jasplakinolides B (3) and E, were referred to the National Cancer Institute鈥檚 (NCI) Biological Evaluation Committee, and the objective of this study was to reinvestigate a Fijian collection of J. splendens in an effort to find jasplakinolide congeners with similar biological properties. The current efforts have afforded six known jasplakinolide analogues (4鈭?b>7, 9, 10), two structures requiring revision (8 and 14), and four new congeners of 1 (11鈭?b>13, 15) including open-chain derivatives and structures with modified 尾-tyrosine residues. Compounds were evaluated for biological activity in the NCI鈥檚 60 cell line screen and in a microfilament disruption assay in both HCT-116 and HeLa cells. These two phenotypic screens provide evidence that each cytotoxic analogue, including jasplakinolide B (3), operates by modification of microfilaments. The new structure jasplakinolide V (13) has also been selected for study by the NCI鈥檚 Biological Evaluation Committee. In addition, the results of a clonogenic dose鈭抮esponse study on jasplakinolide are presented.