2. Academic Validation
  3. Synthetic silvestrol analogues as potent and selective protein synthesis inhibitors

Synthetic silvestrol analogues as potent and selective protein synthesis inhibitors

  • J Med Chem. 2012 Oct 25;55(20):8859-78. doi: 10.1021/jm3011542.
Tao Liu 1,  Somarajan J Nair,  André Lescarbeau,  Jitendra Belani,  Stéphane Peluso,  James Conley,  Bonnie Tillotson,  Patrick O'Hearn,  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
Affiliations

Affiliation

  • 1 Infinity Pharmaceuticals, Inc., 780 Memorial Drive, Cambridge, Massachusetts 02139, USA.
PMID: 23025805 DOI: 10.1021/jm3011542
Abstract

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.

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