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Simplified Silvestrol Analogues with Potent Cytotoxic Activity |
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| Authors: | Dr Bill C Hawkins Dr Lisa M Lindqvist Duong Nhu Dr Phillip P Sharp Dr David Segal Dr Andrew K Powell Dr Michael Campbell Dr Eileen Ryan Dr Jennifer M Chambers Dr Jonathan M White Dr Mark A Rizzacasa Dr Guillaume Lessene Prof David C S Huang Dr Christopher J Burns |
| Affiliation: | 1. Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052 (Australia);2. Department of Medical Biology, The University of Melbourne, VIC 3010 (Australia);3. Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052 (Australia);4. School of Chemistry, The Bio21 Institute, The University of Melbourne, VIC 3010 (Australia) |
| 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. |
| Keywords: | biological activity drug discovery silvestrol structure– activity relationships translation inhibitors |