Q1 · MEDICINE
Article
Author: Helble, Joseph ; Ali, Janid ; West, Kip ; Bahadoor, Adilah ; Douglas, Mark ; Conley, James ; Tillotson, Bonnie ; Smith, Sherri ; Lescarbeau, André ; Fritz, Christian ; McGovern, Karen ; Belani, Jitendra ; O’Hearn, Patrick ; Nair, Somarajan J. ; Slocum, Kelly ; Wylie, Andrew ; Tremblay, Martin R. ; Liu, Tao ; Castro, Alfredo C. ; Peluso, Stéphane ; Palombella, Vito J.
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.