title: Synthetic silvestrol analogues as potent and selective protein synthesis inhibitors.
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.
authors.affiliation: Infinity Pharmaceuticals, Inc., 780 Memorial Drive, Cambridge, Massachusetts 02139, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Somarajan J
authors.initials: SJ
authors.lastname: Nair
authors.forename: André
authors.initials: A
authors.lastname: Lescarbeau
authors.forename: Jitendra
authors.initials: J
authors.lastname: Belani
authors.forename: Stéphane
authors.initials: S
authors.lastname: Peluso
authors.forename: James
authors.initials: J
authors.lastname: Conley
authors.forename: Bonnie
authors.initials: B
authors.lastname: Tillotson
authors.forename: Patrick
authors.initials: P
authors.lastname: O'Hearn
authors.forename: Sherri
authors.initials: S
authors.lastname: Smith
authors.forename: Kelly
authors.initials: K
authors.lastname: Slocum
authors.forename: Kip
authors.initials: K
authors.lastname: West
authors.forename: Joseph
authors.initials: J
authors.lastname: Helble
authors.forename: Mark
authors.initials: M
authors.lastname: Douglas
authors.forename: Adilah
authors.initials: A
authors.lastname: Bahadoor
authors.forename: Janid
authors.initials: J
authors.lastname: Ali
authors.forename: Karen
authors.initials: K
authors.lastname: McGovern
authors.forename: Christian
authors.initials: C
authors.lastname: Fritz
authors.forename: Vito J
authors.initials: VJ
authors.lastname: Palombella
authors.forename: Andrew
authors.initials: A
authors.lastname: Wylie
authors.forename: Alfredo C
authors.initials: AC
authors.lastname: Castro
authors.forename: Martin R
authors.initials: MR
authors.lastname: Tremblay
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001572:Benzofurans
chemical_list: D020121:5' Untranslated Regions; D000970:Antineoplastic Agents; D008156:Luciferases; D011500:Protein Synthesis Inhibitors; D014315:Triterpenes; C489897:silvestrol; D001572:Benzofurans