Synthetic Silvestrol Analogues as Potent and Selective Protein Synthesis Inhibitors
| Autor: | Patrick O'Hearn, Janid A. Ali, Kelly Slocum, Jitendra D. Belani, Sherri Smith, Tao Liu, Adilah Bahadoor, Andre Lescarbeau, Somarajan J. Nair, Christian C. Fritz, Karen McGovern, Kip A. West, Joseph Helble, Bonnie Tillotson, Martin R. Tremblay, Wylie Andrew A, Vito J. Palombella, Alfredo C. Castro, Stéphane Peluso, James M. Conley, Mark Douglas |
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| Rok vydání: | 2012 |
| Předmět: |
Untranslated region
Antineoplastic Agents Stereoisomerism Mice Structure-Activity Relationship chemistry.chemical_compound Genes Reporter Cell Line Tumor Drug Discovery Animals Humans Structure–activity relationship Benzofuran Luciferases ADME Protein Synthesis Inhibitors Reporter gene Natural product Translation (biology) Triterpenes chemistry Biochemistry Microsomes Liver Molecular Medicine Drug Screening Assays Antitumor 5' Untranslated Regions |
| Zdroj: | Journal of Medicinal Chemistry. 55:8859-8878 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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