Synthetic Silvestrol Analogues as Potent and Selective Protein Synthesis Inhibitors

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• 作者：Tao Liu ; Somarajan J. Nair ; Andr茅 Lescarbeau ; Jitendra Belani ; St茅phane Peluso ; James Conley ; Bonnie Tillotson ; Patrick O鈥橦earn ; Sherri Smith ; Kelly Slocum ; Kip West ; Joseph Helble ; Mark Douglas ; Adilah Bahadoor ; Janid Ali ; Karen McGovern ; Christian Fritz ; Vito J. Palombella ; Andrew Wylie ; Alfredo C. Castro ; Martin R. Tremblay
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 25, 2012
• 年：2012
• 卷：55
• 期：20
• 页码：8859-8878
• 全文大小：639K
• 年卷期：v.55,no.20(October 25, 2012)
• ISSN：1520-4804

文摘

Misregulation of protein translation plays a critical role in human cancer pathogenesis at many levels. Silvestrol, a cyclopenta[b]benzofuran natural product, blocks translation at the initiation step by interfering with assembly of the eIF4F translation complex. Silvestrol has a complex chemical structure whose functional group requirements have not been systematically investigated. Moreover, silvestrol has limited development potential due to poor druglike properties. Herein, we sought to develop a practical synthesis of key intermediates of silvestrol and explore structure鈥揳ctivity relationships around the C6 position. The ability of silvestrol and analogues to selectively inhibit the translation of proteins with high requirement on the translation鈥搃nitiation machinery (i.e., complex 5鈥?untranslated region UTR) relative to simple 5鈥睻TR was determined by a cellular reporter assay. Simplified analogues of silvestrol such as compounds 74 and 76 were shown to have similar cytotoxic potency and better ADME characteristics relative to those of silvestrol.