Cytotoxic Spliceostatins from Burkholderia sp. and Their Semisynthetic Analogues

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• 作者：Haiyin He ; Anokha S. Ratnayake ; Jeffrey E. Janso ; Min He ; Hui Y. Yang ; Frank Loganzo ; Boris Shor ; Christopher J. O鈥橠onnell ; Frank E. Koehn
• 刊名：Journal of Natural Products
• 出版年：2014
• 出版时间：August 22, 2014
• 年：2014
• 卷：77
• 期：8
• 页码：1864-1870
• 全文大小：385K
• ISSN：1520-6025

文摘

The spliceostatin class of natural products was reported to be potent cytotoxic agents via inhibition of the spliceosome, a key protein complex in the biosynthesis of mature mRNA. As part of an effort to discover novel leads for cancer chemotherapy, we re-examined this class of compounds from several angles, including fermentation of the producing strains, isolation and structure determination of new analogues, and semisynthetic modification. Accordingly, a group of spliceostatins were isolated from a culture broth of Burkholderia sp. FERM BP-3421, and their structures identified by analysis of spectroscopic data. Semisynthesis was performed on the major components 4 and 5 to generate ester and amide derivatives with improved in vitro potency. With their potent activity against tumor cells and unique mode of action, spliceostatins can be considered potential leads for development of cancer drugs.