New efficient synthesis of resorcinylic macrolides via ynolides: establishment of cycloproparadicicol as synthetically feasible preclinical anticancer agent based on Hsp90 as the target.
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.
Yang
Zhi-Qiang
ZQ
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA.
Geng
Xudong
X
Solit
David
D
Pratilas
Christine A
CA
Rosen
Neal
N
Danishefsky
Samuel J
SJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000178:diet therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D003035:Cobalt / Q000737:chemistry; D003521:Cyclopropanes / Q000737:chemistry*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry*; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry; D018832:Molecular Chaperones / Q000502:physiology; D015394:Molecular Structure; D012118:Resorcinols / Q000138:chemical synthesis*
D000970:Antineoplastic Agents; D003521:Cyclopropanes; D018841:HSP90 Heat-Shock Proteins; D007783:Lactones; D018942:Macrolides; D018832:Molecular Chaperones; D012118:Resorcinols; C452445:aigialomycin D; C477936:cycloproparadicicol; D003035:Cobalt