SYNTHESIS AND EVALUATION OF ANALOGS OF (Z)-1-(4-METHOXYPHENYL)-2-(3,4,5-TRIMETHOXYPHENYL)ETHENE AS POTENTIAL CYTOTOXIC AND ANTIMITOTIC AGENTS
SYNTHESIS AND EVALUATION OF ANALOGS OF (Z)-1-(4-METHOXYPHENYL)-2-(3,4,5-TRIMETHOXYPHENYL)ETHENE AS POTENTIAL CYTOTOXIC AND ANTIMITOTIC AGENTS
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DOI：
10.1021/jm00090a021
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发表时间：
1992-06-12
影响因子：
7.3
通讯作者：
HAMEL, E
中科院分区：
文献类型：
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作者：
CUSHMAN, M;NAGARATHNAM, D;HAMEL, E
已制备了一系列二苯乙烯，并测试了五种人类癌细胞系 A-549 非小细胞肺癌、MCF-7 乳腺癌、HT-29 结肠、SKMEL-5 黑色素瘤和 MLM 黑色素瘤的细胞毒性。顺式二苯乙烯 6a-f 被证明在所有五种细胞系中均具有细胞毒性，其效力与考布他汀 A-4 相当。这些细胞毒性化合物都是微管蛋白聚合的有效抑制剂。相应的反式芪 7b-f 作为微管蛋白聚合抑制剂没有活性，并且在五种癌细胞系中的细胞毒性显着降低。在二氢系列中，8b、8c和8f作为微管蛋白聚合抑制剂没有活性，而8a、8d和8e的活性低于相应的顺式化合物6a、6d和6e。作为先导化合物 1 的构象刚性类似物合成的菲 23b 缺乏微管蛋白聚合抑制活性和细胞毒性，表明二苯乙烯的活性并非由于完全平面构象。类似地，构象限制类似物26的无活性表明1a的生物活性构象类似于顺式烯烃1。制备的其他无活性化合物包括苄基异喹啉系列28-32以及原小檗碱38和39。将la的双碳桥缩短为二苯甲烷20中的单碳桥导致细胞毒性和微管蛋白聚合抑制性降低。活动。尽管相应的二苯甲酮 18 作为微管蛋白聚合抑制剂的活性与 1a 一样，但其细胞毒性低于 1a，而二苯甲酮 19 基本上无活性。除了显示出低抗微管蛋白活性的酰胺15c之外，所有苯基肉桂酸衍生物14a-c和15a-f在微管蛋白聚合抑制测定中均无活性。尽管酸14b和酯15a作为微管蛋白聚合抑制剂无活性，但它们在一些癌细胞培养物中具有细胞毒性。
A series of stilbenes has been prepared and tested for cytotoxicity in the five human cancer cell lines A-549 non-small cell lung, MCF-7 breast, HT-29 colon, SKMEL-5 melanoma, and MLM melanoma. The cis stilbenes 6a-f proved to be cytotoxic in all five cell lines, with potencies comparable to that of combretastatin A-4. These cytotoxic compounds were all potent inhibitors of tubulin polymerization. The corresponding trans stilbenes 7b-f were inactive as tubulin polymerization inhibitors and were significantly less cytotoxic in the five cancer cell lines. In the dihydro series, 8b, 8c, and 8f were inactive as tubulin polymerization inhibitors, while 8a, 8d, and 8e were less active than the corresponding cis compounds 6a, 6d, and 6e. The lack of tubulin polymerization inhibitory activity and cytotoxicity displayed by the phenanthrene 23b, which was synthesized as a conformationally rigid analogue of the lead compound 1, indicates that the activity of the stilbenes is not due to a totally planar conformation. Similarly, inactivity of the conformationally restricted analogue 26 suggests that the biologically active conformation of 1a resembles that of the cis alkene 1. Additional inactive compounds prepared include the benzylisoquinoline series 28-32 as well as the protoberberines 38 and 39. Shortening the two-carbon bridge of la to a one-carbon bridge in the diphenylmethane 20 resulted in a decrease in cytotoxicity and tubulin polymerization inhibitory activity. Although the corresponding benzophenone 18 was as active as 1a as a tubulin polymerization inhibitor, it was less cytotoxic than 1a, and the benzhydrol 19 was essentially inactive. With the exception of the amide 15c, which displayed low antitubulin activity, all of the phenylcinnamic acid derivatives 14a-c and 15a-f were inactive in the tubulin polymerization inhibition assay. The acid 14b and the ester 15a were cytotoxic in several of the cancer cell cultures in spite of their inactivity as tubulin polymerization inhibitors.