Design, synthesis, and biological evaluation of fluorinated analogues of salicylihalamide.
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 (19)F-NMR spectroscopy.
Sugimoto
Yoshinori
Y
Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
Konoki
Keiichi
K
Murata
Michio
M
Matsushita
Masafumi
M
Kanazawa
Hiroshi
H
Oishi
Tohru
T
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000494:pharmacology*; D019556:COS Cells; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D002837:Chromaffin Granules / Q000187:drug effects; D015195:Drug Design; D013329:Structure-Activity Relationship; D013552:Swine; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C410986:salicylihalamide A; D025262:Vacuolar Proton-Translocating ATPases