Convergent synthesis and discovery of a natural product-inspired paralog-selective Hsp90 inhibitor |
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Authors: | Jeso Valer Cherry Lisa Macklin Todd K Pan Subhas Chandra LoGrasso Philip V Micalizio Glenn C |
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Affiliation: | Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, USA. |
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Abstract: | A convergent synthesis of benzoquinone ansamycin analogs is described that proceeds by a sequence of metallacycle-mediated alkyne-alkyne coupling, followed by site- and stereoselective dihydroxylation and global carbamate formation. These studies have led to (1) validation of alkyne-alkyne coupling to produce geldanamycin analogs that lack the problematic quinone, (2) the discovery that C6-C7 bis-carbamate functionality is compatible with Hsp90 inhibition, and (3) the identification of 1 as a nonquinone geldanamycin-inspired paralog-selective Hsp90 inhibitor. |
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