Boyd, M.R., Farina, C., Belfiore, P., Gagliardi, S., Kim, J.W., Hayakawa, Y., Beutler, J.A., McKee, T.C., Bowman, B.J., Bowman, E.J.: J.Pharmacol.Exp.Ther. 297: 114-120, 2001.
Abstract:
A series of naturally occurring compounds reported recently by multiple laboratories defines a new small-molecule class sharing a distinctive and unique benzolactone enamide core structure and diverse biological actions, including inhibition of growth of tumor cells and oncogene-transformed cell-lines. Here we show that representative members of this class, including salicylihalamide A, lobatamides A-F and oximidines I and II inhibit mammalian vacuolar-type (H+)-ATPases (V-ATPases) with unprecedented selectivity. The compounds potently blocked human osteoclast, kidney and liver V-ATPases, but were essentially inactive against V-ATPases of Neurospora crassa and Saccharomyces cerevisiae as well as other membrane ATPases. Essential regulation of pH in cytoplasmic, intraorganellar and local extracellular spaces is provided by V-ATPases, which are ubiquitously distributed among eukaryotic cells and tissues. The most potent and selective V-ATPases heretofore known were the bafilomycins and concanamycins, which do not discriminate between mammalian and non-mammalian V-ATPases. Numerous physiological processes are mediated by V-ATPases, and aberrant V-ATPase functions are implicated in many different human diseases. Previous efforts to develop therapeutic pharmacological modulators of V-ATPases have been frustrated by a lack of synthetically tractable and biologically selective leads. Therefore, availability of the unique benzolactone enamide inhibitor class may enable further elucidation of functional and architectural features of mammalian versus non-mammalian V-ATPase isoforms, as well as provide new opportunities for targeting V-ATPase-mediated processes implicated in diverse pathophysiological phenomena, including cancer.
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