Synthetic Silvestrol Analogues as Potent and Selective Protein Synthesis Inhibitors

被引：64

作者：

Liu, Tao ^{[1
]}

Nair, Somarajan J. ^{[1
]}

Lescarbeau, Andre ^{[1
]}

Belani, Jitendra ^{[1
]}

Peluso, Stephane ^{[1
]}

Conley, James ^{[1
]}

Tillotson, Bonnie ^{[1
]}

O'Hearn, Patrick ^{[1
]}

Smith, Sherri ^{[1
]}

Slocum, Kelly ^{[1
]}

West, Kip ^{[1
]}

Helble, Joseph ^{[1
]}

Douglas, Mark ^{[1
]}

Bahadoor, Adilah ^{[1
]}

Ali, Janid ^{[1
]}

McGovern, Karen ^{[1
]}

Fritz, Christian ^{[1
]}

Palombella, Vito J. ^{[1
]}

Wylie, Andrew ^{[1
]}

Castro, Alfredo C. ^{[1
]}

Tremblay, Martin R. ^{[1
]}

机构：

[1] Infin Pharmaceut Inc, Cambridge, MA 02139 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 20期

关键词：

MESSENGER-RNA TRANSLATION; INITIATION-FACTOR; 4E; EUKARYOTIC TRANSLATION; ROCAGLATE DERIVATIVES; SECONDARY STRUCTURE; AGLAIA-FOVEOLATA; CANCER; LEUKEMIA; TRANSFORMATION; EPISILVESTROL;

D O I：

10.1021/jm3011542

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 activity relationships around the C6 position. The ability of silvestrol and analogues to selectively inhibit the translation of proteins with high requirement on the translation initiation machinery (i.e., complex 5'-untranslated region UTR) relative to simple 5'UTR 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.

引用

页码：8859 / 8878

页数：20

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