Design, synthesis, and biological evaluation of fluorinated analogues of salicylihalamide.
Design, synthesis, and biological evaluation of fluorinated analogues of salicylihalamide.
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DOI：
10.1021/jm801265e
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发表时间：
2009-02
影响因子：
7.3
通讯作者：
Yoshinori Sugimoto;K. Konoki;M. Murata;Masafumi Matsushita;H. Kanazawa;T. Oishi
中科院分区：
文献类型：
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作者：
Yoshinori Sugimoto;K. Konoki;M. Murata;Masafumi Matsushita;H. Kanazawa;T. Oishi
水杨柳酰胺A(SA)是一种苯内酯类烯胺类化合物，对人肿瘤细胞具有较强的细胞毒作用。SA是哺乳动物空泡型H(+)-ATPase(V-ATPase)的选择性抑制剂，不同于已知的不区分哺乳动物和非哺乳动物V-ATPase的V-ATPase抑制剂。由于其强大的抗肿瘤活性和结构简单，SA是一种很有前途的抗癌药物候选药物。虽然已经报道了一些使用合成类似物的构效关系研究，但尚未对SA的氟化衍生物进行评估，尽管在治疗性小分子候选化合物中选择性地添加一个氟原子通常会增强药代动力学和物理化学性质。我们设计合成了含氟的SA类似物，并对它们的V-ATPase抑制活性进行了评价。与天然产物相比，合成的类似物是有效的V-ATPase抑制剂，这表明这些类似物是潜在的候选药物和潜在的分子探针，可用于基于氟的分析方法的研究，如~(19)F-核磁共振波谱。
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.