Simplified Silvestrol Analogues with Potent Cytotoxic Activity
Details
Publication Year 2014-07, Volume 9, Issue #7, Page 1556-1566
Journal Title
ChemMedChem
Publication Type
Journal Article
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.
Publisher
WILEY
Keywords
biological activity, drug discovery, silvestrol, structure-activity relationships, translation inhibitors
WEHI Research Division(s)
Cell Signalling And Cell Death; Cancer And Haematology; Chemical Biology
PubMed ID
24677741
NHMRC Grants
NHMRC/461221 NHMRC/1016701 NHMRC/361646
Rights Notice
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim


Creation Date: 2014-04-16 08:43:41
Last Modified: 2015-07-16 12:03:54
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