Novel Marine and Microbial Natural Product Inhibitors of Vacuolar ATPase

Vacuolar-ATPase (V-ATPase) has been proposed as a drug target in osteoporosis due to its involvement in bone resorption, and as a target in cancer due to potential involvement in tumor invasion and metastasis. The classical selective inhibitors of V-ATPase are microbial macrolides of the bafilomycin and concanamycin class. These inhibitors have proven to be too toxic for therapeutic use, however recent structure-activity studies on bafilomycins, and the isolation of novel macrolide structures from marine sources, have provided new avenues for development of potentially less toxic V-ATPase inhibitors. The novel salicylihalamide and lobatamide series of compounds were predicted to share a common mechanism of action based on the patterns of cytotoxicity produced in the NCI 60-cell cancer screen. They have subsequently been shown to selectively interact with mammalian V-ATPases, but not with fungal V-ATPases. With the recent achievement of total syntheses of salicylihalamide, lobatamide, and related compounds, the elaboration of congeners with specificity for particular enzyme isoforms may provide drug candidates which are less toxic. This review summarizes recent advances in V-ATPase inhibition and the prospects for further progress.