- AGENTS AND METHODS FOR TREATING DYSPROLIFERATIVE DISEASES
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Compounds are described with the general formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and n are defined as anywhere herein, which are useful for the treatment of cancer and other dysproliferative diseases.
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- Synthetic silvestrol analogues as potent and selective protein synthesis inhibitors
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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.
- Liu, Tao,Nair, Somarajan J.,Lescarbeau, Andre,Belani, Jitendra,Peluso, Stephane,Conley, James,Tillotson, Bonnie,OHearn, Patrick,Smith, Sherri,Slocum, Kelly,West, Kip,Helble, Joseph,Douglas, Mark,Bahadoor, Adilah,Ali, Janid,McGovern, Karen,Fritz, Christian,Palombella, Vito J.,Wylie, Andrew,Castro, Alfredo C.,Tremblay, Martin R.
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p. 8859 - 8878,20
(2020/09/16)
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