Antitumor agents .174. 2',3',4',5,6,7-substituted 2-phenyl-1,8-naphthyridin-4-ones: Their synthesis, cytotoxicity, and inhibition of tubulin polymerization
Antitumor agents .174. 2',3',4',5,6,7-substituted 2-phenyl-1,8-naphthyridin-4-ones: Their synthesis, cytotoxicity, and inhibition of tubulin polymerization
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DOI：
10.1021/jm960858s
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发表时间：
1997-07-04
影响因子：
7.3
通讯作者：
Lee, KH
中科院分区：
文献类型：
--
作者：
Chen, K;Kuo, SC;Lee, KH
合成了2‘，3’，4‘，5，6，7-取代8-苯基-1，8-萘啶-4-酮和2-苯基吡啶-[1，2-a]嘧啶-4-酮两个系列化合物，作为细胞毒性化合物和微管蛋白聚合的抑制剂。大多数2-苯基-1，8-萘啶-4-酮具有较强的细胞毒和抗小管蛋白活性，而2-苯基吡啶并[1，2-a]嘧啶-4-酮在这两种方法中都没有活性。总的来说，在2-苯基-1，8-萘啶-4-酮系列中，细胞毒性和对微管蛋白聚合的抑制之间有很好的相关性。2-苯基-1，8-萘啶-4-酮(44-49)的3‘-甲氧基对大多数肿瘤细胞具有较强的细胞毒作用，其GI(50)值在国家癌症研究所60人肿瘤细胞体外筛选的低微摩尔至纳摩尔浓度范围内。在4‘-位引入取代基(如F、Cl、CH3和OCH3)会导致化合物的活性降低或很少，而在2’-位上的取代会导致化合物失去活性。不同的A环取代对活性的影响取决于C环上的取代。化合物44-50是有效的微管蛋白聚合抑制剂，其活性几乎与有效的抗有丝分裂天然产物秋水仙素、鬼臼毒素和复方苦参素A-4相当。化合物44-49也抑制放射性标记的秋水仙碱与微管蛋白的结合，但抑制作用弱于天然产物。进一步的研究正在进行中，以确定3‘位的取代和C环上的多取代是否会导致化合物的活性增加。
Two series of 2',3',4',5,6,7-substituted 8-phenyl-1,8-naphthyridin-4-ones and 2-phenylpyrido-[1,2-a]pyrimidin-4-ones have been synthesized and evaluated as cytotoxic compounds and as inhibitors of tubulin polymerization. Most 2-phenyl-1,8-naphthyridin-4-ones showed potent cytotoxic and antitubulin activities, whereas 2-phenylpyrido[1,2-a]pyrimidin-4-ones showed no activity in either assay. In general, a good correlation was found between cytotoxicity and inhibition of tubulin polymerization in the 2-phenyl-1,8-naphthyridin-4-one series. The 2-phenyl-1,8-naphthyridin-4-ones (44-49) with a methoxy group at the 3'-position showed potent cytotoxicity against most tumor cell lines with GI(50) values in the low micromolar to nanomolar concentration range in the National Cancer Institute's 60 human tumor cell line in vitro screen. Introduction of substituents (e.g. F, Cl, CH3, and OCH3) at the 4'-position led to compounds with reduced or little activity and substitution at the 2'-position resulted in inactive compounds. The effects of various A-ring substitutions on activity depend on the substitution in ring C. Compounds 44-50 were potent inhibitors of tubulin polymerization, with activity nearly comparable to that of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. Compounds 44-49 also inhibited the binding of radiolabeled colchicine to tubulin, but the inhibition was less potent than that obtained with the natural products. Further investigation is underway to determine if substitution at the 3'-position and multisubstitutions in ring C will result in compounds with increased activity.