Total Synthesis and Initial Structure-Function Analysis of the Potent V-ATPase Inhibitors Salicylihalamide A and Related Compounds

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• 作者：Yusheng Wu ; Xibin Liao ; Ruifang Wang ; Xiao-Song Xie ; and Jef K. De Brabander
• 刊名：Journal of the American Chemical Society
• 出版年：2002
• 出版时间：April 3, 2002
• 年：2002
• 卷：124
• 期：13
• 页码：3245 - 3253
• 全文大小：152K
• 年卷期：v.124,no.13(April 3, 2002)
• ISSN：1520-5126

文摘

Salicylihalamide A is the first member of a growing class of macrocyclic salicylate natural productsthat induce a variety of interesting phenotypes in cultured mammalian cells. Salicylihalamide A was reportedto be a unique and highly differential cytotoxin and a potent inhibitor of the mammalian vacuolar (H⁺)-ATPase. The total synthesis of both enantiomers of salicylihalamide A, a revision of the absolute configurationassigned to the natural product, and extensive structure-function studies with synthetic salicylihalamidevariants are reported. These studies were possible only due to a highly efficient synthetic strategy thatfeatures (1) a remarkably E-selective ring-closing olefin metathesis to construct the 12-memberedbenzolactone skeleton 29, (2) a mild stereocontrolled elaboration to E-alkenyl isocyanate 41, and (3) additionof carbon, oxygen, and sulfur nucleophiles to isocyanate 41 to obtain salicylihalamide A and congeners.We demonstrate for the first time that salicylihalamide A is a potent inhibitor of fully purified reconstitutedV-ATPase from bovine brain, and have identified several similarly potent side chain modified derivatives,including salicylihalamide dimers 43-45. In combination, these studies have laid the foundation for ongoingstudies aimed at a comprehensive understanding of salicylihalamide's mode-of-action, of potential relevanceto the development of lead compounds for the treatment of osteoporosis and cancer.