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

Zhi Qiang Yang, Xudong Geng, David Solit, Christine A. Pratilas, Neal Rosen, Samuel J. Danishefsky

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)7881-7889
Number of pages9
JournalJournal of the American Chemical Society
Volume126
Issue number25
DOIs
StatePublished - Jun 30 2004
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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