Synthesis and structure-activity relationships of thioflavone derivatives as specific inhibitors of the ERK-MAP kinase signaling pathway
Synthesis and structure-activity relationships of thioflavone derivatives as specific inhibitors of the ERK-MAP kinase signaling pathway
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DOI：
10.1016/j.bmc.2004.02.002
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发表时间：
2004-05-01
影响因子：
3.5
通讯作者：
Kohno, M
中科院分区：
文献类型：
--
作者：
Kataoka, T;Watanabe, S;Kohno, M
硝基苯甲醛3和α-[o-（p-甲氧基苄硫基）苯甲酰基]亚砜4缩合得到α-亚磺酰基烯酮5。用甲酸处理5引起环化，然后脱苄基，得到3-（甲基亚磺酰基）硫代黄烷酮6。在苯中，用锡还原2-苯基-4H-1-苯并噻喃-4-酮（噻喃酮）7的硝基，使其与甲基亚磺酸发生双键消除反应。评价由此制备的各种2 ′-氨基硫杂蒽酮8对ERK-MAP激酶途径的抑制作用。在基于细胞的测定中，2-（2 '-氨基-3'-甲氧基苯基）-4 H-I-苯并噻喃-4-酮（8b）显示出比相应的氧化合物（PD 98059，1）对Raf-induced ERK-MAP激酶途径活化以及细胞增殖更有效的抑制作用。此外，化合物8b选择性地和有效地抑制其中ERK-MAP激酶途径被组成性激活的肿瘤细胞的增殖。(C)2004 Elsevier Ltd.保留所有权利。
Condensation of nitro benzaldehydes 3 and alpha-[o-(p-methoxybenzylthio)benzoyl] sulfoxide 4 gave alpha-sulfinyl enones 5. Treatment of 5 with formic acid caused cyclization followed by debenzylation to afford 3-(methylsulfinyl)thioflavanones 6. Double-bond formation with elimination of methanesulfenic acid was performed by refluxing 6 in benzene, and, finally, the nitro group of 2phenyl-4H-1-benzothiopyran-4-one (thioflavones) 7 was reduced with tin in tetrafluoroboric acid. Various 2'-aminothioflavones 8 thus prepared were evaluated for their inhibitory effects on the ERK-MAP kinase pathway. In a cell-based assay, 2-(2'-amino-3'methoxyphenyl)-4H-I-benzothiopyran-4-one (8b) showed a more potent inhibitory effect than the corresponding oxygen compound (PD98059, 1) on the Raf-induced activation of the ERK-MAP kinase pathway as well as cell proliferation. Furthermore, compound 8b selectively and potently inhibited the proliferation of tumor cells in which the ERK-MAP kinase pathway is constitutively activated. (C) 2004 Elsevier Ltd. All rights reserved.