Design, synthesis, and biological evaluation of fluorinated analogues of salicylihalamide

Yoshinori Sugimoto, Keiichi Konoki, Michio Murata, Masafumi Matsushita, Hiroshi Kanazawa, Tohru Oishi

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)


Salicylihalamide A (SA), a benzolactone enamide compound, 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 number of structure-activity relation studies using synthetic analogues have been reported, no fluorinated derivative of SA has been evaluated even though selective addition of a fluorine atom into a therapeutic small molecule candidate often enhances pharmacokinetic and physicochemical properties. We designed and synthesized fluorinated analogues of SA and evaluated their V-ATPase inhibitory activities. Compared to the natural product, the synthetic analogues were potent V-ATPase inhibitors, suggesting that these analogues are potential drug candidates and potential molecular probes for mode-of-action studies using fluorine-based analytical methods such as 19F-NMR spectroscopy.

Original languageEnglish
Pages (from-to)798-806
Number of pages9
JournalJournal of Medicinal Chemistry
Issue number3
Publication statusPublished - Feb 12 2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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