Total synthesis and initial structure - Function analysis of the potent V-ATPase inhibitors salicylihalamide A and related compounds

Yusheng Wu, Xibin Liao, Ruifang Wang, Xiao Song Xie, Jef K. De Brabander

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

Salicylihalamide A is the first member of a growing class of macrocyclic salicylate natural products that induce a variety of interesting phenotypes in cultured mammalian cells. Salicylihalamide A was reported to 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 configuration assigned to the natural product, and extensive structure-function studies with synthetic salicylihalamide variants are reported. These studies were possible only due to a highly efficient synthetic strategy that features (1) a remarkably E-selective ring-closing olefin metathesis to construct the 12-membered benzolactone skeleton 29, (2) a mild stereocontrolled elaboration to E-alkenyl isocyanate 41, and (3) addition of 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 reconstituted V-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 ongoing studies aimed at a comprehensive understanding of salicylihalamide's mode-of-action, of potential relevance to the development of lead compounds for the treatment of osteoporosis and cancer.

Original languageEnglish (US)
Pages (from-to)3245-3253
Number of pages9
JournalJournal of the American Chemical Society
Volume124
Issue number13
DOIs
StatePublished - Apr 3 2002

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Adenosine Triphosphatases
Lead compounds
Nucleophiles
Enantiomers
Isocyanates
Dimers
Olefins
Brain
Biological Products
Sulfur
Cells
Derivatives
Carbon
Oxygen
Vacuolar Proton-Translocating ATPases
Salicylates
Cytotoxins
Alkenes
Skeleton
Action Potentials

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Total synthesis and initial structure - Function analysis of the potent V-ATPase inhibitors salicylihalamide A and related compounds. / Wu, Yusheng; Liao, Xibin; Wang, Ruifang; Xie, Xiao Song; De Brabander, Jef K.

In: Journal of the American Chemical Society, Vol. 124, No. 13, 03.04.2002, p. 3245-3253.

Research output: Contribution to journalArticle

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