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Simplified silvestrol analogues with potent cytotoxic activity.

ChemMedChem (2014-03-29)
Bill C Hawkins, Lisa M Lindqvist, Duong Nhu, Phillip P Sharp, David Segal, Andrew K Powell, Michael Campbell, Eileen Ryan, Jennifer M Chambers, Jonathan M White, Mark A Rizzacasa, Guillaume Lessene, David C S Huang, Christopher J Burns
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Cyclohexane, JIS special grade
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Cyclohexane, anhydrous, 99.5%
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Ethyl acetate, ACS reagent, ≥99.5%
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Ethyl acetate, ≥99%, FCC, FG
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Ethyl acetate, suitable for HPLC
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Ethyl acetate, JIS 300, ≥99.5%, for residue analysis
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Ethyl acetate, JIS 1000, ≥99.5%, for residue analysis
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Ethyl acetate, SAJ first grade, ≥99.0%
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Ethyl acetate, natural, ≥99%, FCC, FG
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Ethyl acetate, JIS special grade, ≥99.5%
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Ethyl acetate, suitable for HPLC, ≥99.8%
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Ethyl acetate, suitable for HPLC, ≥99.7%