Asymmetric Synthesis of Pochonin E and F, Revision of Their Proposed Structure, and Their Conversion to Potent Hsp90 Inhibitors

Authors

  • Dr. Ganesan Karthikeyan,

    1. Institut de Science et Ingénierie Supramoléculaires (ISIS-UMR 7006), Université de Strasbourg CNRS, 8 Allée Gaspard Monge, 67000 Strasbourg (France), Fax: (+33) 368855112
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  • Claudio Zambaldo,

    1. Institut de Science et Ingénierie Supramoléculaires (ISIS-UMR 7006), Université de Strasbourg CNRS, 8 Allée Gaspard Monge, 67000 Strasbourg (France), Fax: (+33) 368855112
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  • Dr. Sofia Barluenga,

    1. Institut de Science et Ingénierie Supramoléculaires (ISIS-UMR 7006), Université de Strasbourg CNRS, 8 Allée Gaspard Monge, 67000 Strasbourg (France), Fax: (+33) 368855112
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  • Dr. Vincent Zoete,

    1. Swiss Institute of Bioinformatics, Quartier Sorge—1015 Lausanne (Switzerland)
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  • Prof. Martin Karplus,

    Corresponding author
    1. Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138 (USA)
    • Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138 (USA)
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  • Prof. Nicolas Winssinger

    Corresponding author
    1. Institut de Science et Ingénierie Supramoléculaires (ISIS-UMR 7006), Université de Strasbourg CNRS, 8 Allée Gaspard Monge, 67000 Strasbourg (France), Fax: (+33) 368855112
    • Institut de Science et Ingénierie Supramoléculaires (ISIS-UMR 7006), Université de Strasbourg CNRS, 8 Allée Gaspard Monge, 67000 Strasbourg (France), Fax: (+33) 368855112
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Abstract

A concise and modular synthesis of pochonin E and F, and their epimers at C-6 established the correct stereochemistry of these two natural products. Several members of the pochonin family have been shown to bind the heat shock protein 90 (Hsp90), which has been the focus of intense drug discovery efforts. Pochonin E and F as well as their epimers were derivatized into the corresponding pochoximes and further modified at the C-6 position. Molecular dynamics simulations, docking studies, and Hsp90 affinity measurements were performed to evaluate the impact of these modifications.

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