[摘要]：Salicylihalamide A I (X = F) (SA), a benzolactone enamide compd., possesses potent cytotoxicity against human tumor cell lines. SA is a selective inhibitor of mammalian vacuolar type H+-ATPase (V-ATPase), and is distinct from previously known V-ATPase inhibitors such as bafilomycins and concanamycins that do not discriminate between mammalian and nonmammalian V-ATPases. Because of its potent antitumor activity and structural simplicity, SA is a promising candidate for an anticancer drug. Although a no. of structure-activity relation studies using synthetic analogs have been reported, no fluorinated deriv. of SA has been evaluated even though selective addn. of a fluorine atom into a therapeutic small mol. candidate often enhances pharmacokinetic and physicochem. properties. We designed and synthesized fluorinated analogs of SA, I (X = F) and its 17-Z-isomer, and evaluated their V-ATPase inhibitory activities. Compared to the natural product, the synthetic analogs were potent V-ATPase inhibitors, suggesting that these analogs are potential drug candidates and potential mol. probes for mode-of-action studies using fluorine-based anal. methods such as 19F-NMR spectroscopy.
