Simplified Silvestrol Analogues with Potent Cytotoxic Activity
- Author(s)
- Hawkins, BC; Lindqvist, LM; Nhu, D; Sharp, PP; Segal, D; Powell, AK; Campbell, M; Ryan, E; Chambers, JM; White, JM; Rizzacasa, MA; Lessene, G; Huang, DC; Burns, CJ;
- 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
- Research Division(s)
- Cell Signalling And Cell Death; Cancer And Haematology; Chemical Biology
- PubMed ID
- 24677741
- Publisher's Version
- https://doi.org/10.1002/cmdc.201400024
- NHMRC Grants
- NHMRC/461221, NHMRC/1016701, NHMRC/361646,
- Terms of Use/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