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

Overview

MeSH Major

  • Antineoplastic Agents
  • Cyclopropanes
  • HSP90 Heat-Shock Proteins
  • Lactones
  • Macrolides
  • Resorcinols

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.

publication date

  • June 30, 2004

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1021/ja0484348

PubMed ID

  • 15212536

Additional Document Info

start page

  • 7881

end page

  • 9

volume

  • 126

number

  • 25