Latrunculin A and Its C-17-O-Carbamates Inhibit Prostate Tumor Cell Invasion and HIF-1 Activation in Breast Tumor Cells

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• 作者：Khalid A. El Sayed ; Mohammad A. Khanfar ; Hassan M. Shallal ; A. Muralidharan ; Bhushan Awate ; Diaa T. A. Youssef ; Yang Liu ; Yu-Dong Zhou ; Dale G. Nagle ; Girish Shah
• 刊名：Journal of Natural Products
• 出版年：2008
• 出版时间：March 2008
• 年：2008
• 卷：71
• 期：3
• 页码：396 - 402
• 全文大小：1628K
• 年卷期：v.71,no.3(March 2008)
• ISSN：1520-6025

文摘

The marine-derived macrolides latrunculins A (1) and B, from the Red Sea sponge Negombata magnifica, have been found to reversibly bind actin monomers, forming a 1:1 complex with G-actin and disrupting its polymerization. The microfilament protein actin is responsible for several essential functions within the cell such as cytokinesis and cell migration. One of the main binding pharmacophores of 1 to G-actin was identified as the C-17 lactol hydroxyl moiety that binds arginine 210 NH. Latrunculin A-17-O-carbamates 2−6 were prepared by reaction with the corresponding isocyanates. Latrunculin A (1) and carbamates 4−6 displayed potent anti-invasive activity against the human highly metastatic human prostate cancer PC-3M cells in a Matrigel assay at a concentration range of 50 nM to 1 µM. Latrunculin A (1, 500 nM) decreased the disaggregation and cell migration of PC-3M-CT+ spheroids by 3-fold. Carbamates 4 and 5 were 2.5- and 5-fold more active than 1, respectively, in this assay with less actin binding affinity. Latrunculin A (1, IC₅₀ 6.7 µM) and its 17-O-[N-(benzyl)carbamate (6, IC₅₀ 29 µM) suppress hypoxia-induced HIF-1 activation in T47D breast tumor cells.