title: Simplified silvestrol analogues with potent cytotoxic activity.
abstract: The complex natural products silvestrol (1) and episilvestrol (2) are inhibitors of translation initiation through binding to the DEAD-box helicase eukaryotic initiation factor 4A (eIF4A). Both compounds are potently cytotoxic to cancer cells in vitro, and 1 has demonstrated efficacy in vivo in several xenograft cancer models. Here we show that 2 has limited plasma membrane permeability and is metabolized in liver microsomes in a manner consistent with that reported for 1. In addition, we have prepared a series of analogues of these compounds where the complex pseudo-sugar at C6 has been replaced with chemically simpler moieties to improve drug-likeness. Selected compounds from this work possess excellent activity in biochemical and cellular translation assays with potent activity against leukemia cell lines.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052 (Australia); Department of Medical Biology, The University of Melbourne, VIC 3010 (Australia).
authors.forename: Bill C
authors.initials: BC
authors.lastname: Hawkins
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Lindqvist
authors.forename: Duong
authors.initials: D
authors.lastname: Nhu
authors.forename: Phillip P
authors.initials: PP
authors.lastname: Sharp
authors.forename: David
authors.initials: D
authors.lastname: Segal
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Powell
authors.forename: Michael
authors.initials: M
authors.lastname: Campbell
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Chambers
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: White
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rizzacasa
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lessene
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Burns
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D039601:Eukaryotic Initiation Factor-4A / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D011485:Protein Binding; D014315:Triterpenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001572:Benzofurans
chemical_list: D000970:Antineoplastic Agents; D039601:Eukaryotic Initiation Factor-4A; D014315:Triterpenes; C489893:episilvestrol; C489897:silvestrol; D001572:Benzofurans
keywords: biological activity; drug discovery; silvestrol; structure-activity relationships; translation inhibitors