New Efficient Synthesis of Resorcinylic Macrolides via Ynolides: Establishment of Cycloproparadicicol as Synthetically Feasible Preclinical Anticancer Agent Based on Hsp90 as the Target

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• 作者：Zhi-Qiang Yang ; Xudong Geng ; David Solit ; Christine A. Pratilas ; Neal Rosen ; and Samuel J. Danishefsky
• 刊名：Journal of the American Chemical Society
• 出版年：2004
• 出版时间：June 30, 2004
• 年：2004
• 卷：126
• 期：25
• 页码：7881 - 7889
• 全文大小：279K
• 年卷期：v.126,no.25(June 30, 2004)
• ISSN：1520-5126

文摘

A program currently ongoing in our laboratory envisions natural macrolide radicicol-based inhibitorstargeting the molecular chaperone Hsp90. Such inhibitors can be potential anticancer agents due to theirability to induce the breakdown of a variety of oncogenic proteins. In this account, we first concern ourselveswith 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, includingcycloproparadicicol 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 withdimedone-derived bis-siloxy dienes to elaborate the benzo system. A number of interesting analogueswere synthesized using this protocol. They were evaluated for their inhibitory activity against the growth ofbreast cancer cell line, MCF-7. The potency of their cytotoxicity was found to be consistent with their abilityto degrade the oncogenic protein, Her2. From these assays, cycloproparadicicol was identified as a mostpromising candidate for further development.