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Simplified silvestrol analogues with potent cytotoxic activity. 2014
Bill C Hawkins, and
Lisa M Lindqvist, and
Duong Nhu, and
Phillip P Sharp, and
David Segal, and
Andrew K Powell, and
Michael Campbell, and
Eileen Ryan, and
Jennifer M Chambers, and
Jonathan M White, and
Mark A Rizzacasa, and
Guillaume Lessene, and
David C S Huang, and
Christopher J Burns
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052 (Australia); Department of Medical Biology, The University of Melbourne, VIC 3010 (Australia).
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.
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Bill C Hawkins, and
Lisa M Lindqvist, and
Duong Nhu, and
Phillip P Sharp, and
David Segal, and
Andrew K Powell, and
Michael Campbell, and
Eileen Ryan, and
Jennifer M Chambers, and
Jonathan M White, and
Mark A Rizzacasa, and
Guillaume Lessene, and
David C S Huang, and
Christopher J Burns
October 2012,
Journal of medicinal chemistry,
Bill C Hawkins, and
Lisa M Lindqvist, and
Duong Nhu, and
Phillip P Sharp, and
David Segal, and
Andrew K Powell, and
Michael Campbell, and
Eileen Ryan, and
Jennifer M Chambers, and
Jonathan M White, and
Mark A Rizzacasa, and
Guillaume Lessene, and
David C S Huang, and
Christopher J Burns
March 2008,
Journal of medicinal chemistry,
Bill C Hawkins, and
Lisa M Lindqvist, and
Duong Nhu, and
Phillip P Sharp, and
David Segal, and
Andrew K Powell, and
Michael Campbell, and
Eileen Ryan, and
Jennifer M Chambers, and
Jonathan M White, and
Mark A Rizzacasa, and
Guillaume Lessene, and
David C S Huang, and
Christopher J Burns
October 2006,
Journal of medicinal chemistry,
Bill C Hawkins, and
Lisa M Lindqvist, and
Duong Nhu, and
Phillip P Sharp, and
David Segal, and
Andrew K Powell, and
Michael Campbell, and
Eileen Ryan, and
Jennifer M Chambers, and
Jonathan M White, and
Mark A Rizzacasa, and
Guillaume Lessene, and
David C S Huang, and
Christopher J Burns
May 2009,
Journal of medicinal chemistry,
Bill C Hawkins, and
Lisa M Lindqvist, and
Duong Nhu, and
Phillip P Sharp, and
David Segal, and
Andrew K Powell, and
Michael Campbell, and
Eileen Ryan, and
Jennifer M Chambers, and
Jonathan M White, and
Mark A Rizzacasa, and
Guillaume Lessene, and
David C S Huang, and
Christopher J Burns
January 2012,
Bioorganic & medicinal chemistry letters,
Bill C Hawkins, and
Lisa M Lindqvist, and
Duong Nhu, and
Phillip P Sharp, and
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Michael Campbell, and
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Jonathan M White, and
Mark A Rizzacasa, and
Guillaume Lessene, and
David C S Huang, and
Christopher J Burns
November 2004,
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Bill C Hawkins, and
Lisa M Lindqvist, and
Duong Nhu, and
Phillip P Sharp, and
David Segal, and
Andrew K Powell, and
Michael Campbell, and
Eileen Ryan, and
Jennifer M Chambers, and
Jonathan M White, and
Mark A Rizzacasa, and
Guillaume Lessene, and
David C S Huang, and
Christopher J Burns
April 2006,
Journal of medicinal chemistry,
Bill C Hawkins, and
Lisa M Lindqvist, and
Duong Nhu, and
Phillip P Sharp, and
David Segal, and
Andrew K Powell, and
Michael Campbell, and
Eileen Ryan, and
Jennifer M Chambers, and
Jonathan M White, and
Mark A Rizzacasa, and
Guillaume Lessene, and
David C S Huang, and
Christopher J Burns
August 2015,
ChemMedChem,
Bill C Hawkins, and
Lisa M Lindqvist, and
Duong Nhu, and
Phillip P Sharp, and
David Segal, and
Andrew K Powell, and
Michael Campbell, and
Eileen Ryan, and
Jennifer M Chambers, and
Jonathan M White, and
Mark A Rizzacasa, and
Guillaume Lessene, and
David C S Huang, and
Christopher J Burns
September 1998,
Proceedings of the National Academy of Sciences of the United States of America,
Bill C Hawkins, and
Lisa M Lindqvist, and
Duong Nhu, and
Phillip P Sharp, and
David Segal, and
Andrew K Powell, and
Michael Campbell, and
Eileen Ryan, and
Jennifer M Chambers, and
Jonathan M White, and
Mark A Rizzacasa, and
Guillaume Lessene, and
David C S Huang, and
Christopher J Burns
July 2007,
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