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J Am Chem Soc. 2004 Jun 30;126(25):7881-9.

New efficient synthesis of resorcinylic macrolides via ynolides: establishment of cycloproparadicicol as synthetically feasible preclinical anticancer agent based on Hsp90 as the target.

Author information

1
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA.

Abstract

A program currently ongoing in our laboratory envisions natural macrolide radicicol-based inhibitors targeting the molecular chaperone Hsp90. Such inhibitors can be potential anticancer agents due to their ability to induce the breakdown of a variety of oncogenic proteins. In this account, we first concern ourselves with a vastly important total synthesis of such an inhibitor. We accomplished this via a new approach, which we term the "ynolide method", directed to the synthesis of resorcinylic macrolides, including cycloproparadicicol and aigialomycin D. The key features of the syntheses involve cobalt-complexation-promoted ring-closing metathesis (RCM) to generate ynolides, followed by Diels-Alder reaction with dimedone-derived bis-siloxy dienes to elaborate the benzo system. A number of interesting analogues were synthesized using this protocol. They were evaluated for their inhibitory activity against the growth of breast cancer cell line, MCF-7. The potency of their cytotoxicity was found to be consistent with their ability to degrade the oncogenic protein, Her2. From these assays, cycloproparadicicol was identified as a most promising candidate for further development.

PMID:
15212536
DOI:
10.1021/ja0484348
[Indexed for MEDLINE]

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