Simplified silvestrol analogues with potent cytotoxic activity

Bill C Hawkins, Lisa M Lindqvist, Duong Quynh Nhu, Phillip P Sharp, David Segal, Andrew Keith Powell, Michael Campbell, Eileen Ryan, Jennifer M Chambers, Jonathan White, Mark Anthony Rizzacasa, Guillaume Lessene, David CS Huang, Christopher J Burns

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

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. Simplified complexity The natural products silvestrol (1) and episilvestrol (2) are translation initiation inhibitors with potent anticancer activity. We report replacing the complex pseudo-sugar moiety at C6 with readily accessible and drug-like moieties. Selected compounds show potent anti-leukemic activity in vitro.
Original languageEnglish
Pages (from-to)1556 - 1566
Number of pages11
JournalChemMedChem
Volume9
Issue number7
DOIs
Publication statusPublished - 2014

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