SYNTHESIS AND EVALUATION OF STILBENE AND DIHYDROSTILBENE DERIVATIVES AS POTENTIAL ANTICANCER AGENTS THAT INHIBIT TUBULIN POLYMERIZATION
SYNTHESIS AND EVALUATION OF STILBENE AND DIHYDROSTILBENE DERIVATIVES AS POTENTIAL ANTICANCER AGENTS THAT INHIBIT TUBULIN POLYMERIZATION
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DOI：
10.1021/jm00112a036
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发表时间：
1991-08-01
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
一系列的顺式，反式，和二氢芪和一些N-芳基苄基胺的合成和评价其在五种癌细胞培养物A-549肺癌，MCF-7乳腺癌，HT-29结肠腺癌，SKMEL-5黑色素瘤，和MLM黑色素瘤的细胞毒性。 几种顺式芪类化合物，结构上类似于考布他汀，在所有五种细胞系中具有高度细胞毒性，并且还发现这些化合物作为微管蛋白聚合的抑制剂具有活性。 最具活性的化合物也抑制秋水仙碱与微管蛋白的结合。 作为微管蛋白聚合抑制剂和细胞毒性剂的新化合物中最有效的是（Z）-1-（4-甲氧基苯基）-2-（3，4，5-三甲氧基苯基）乙烯（5a）。 该物质作为微管蛋白聚合抑制剂几乎与最具活性的考布他汀A-4（1a）一样有效。 发现化合物5a对HT-29结肠腺癌细胞的细胞毒性比考布他汀A-4高约140倍，对MCF-7乳腺癌细胞的细胞毒性比考布他汀A-4高约10倍。 然而，发现5a对A-549肺癌细胞的细胞毒性比考布他汀A-4小约20倍，对SKMEL-5黑素瘤细胞的细胞毒性小约30倍，对MLM黑素瘤细胞的细胞毒性小约7倍。 顺式、二氢和反式化合物分别作为微管蛋白聚合抑制剂的相对效力5a > 8a > 6a与先前观察到的考布他汀A-4（1a）、二氢考布他汀A-4（1c）和反式考布他汀A-4（1b）的相对效力一致。 相对效力5a > 8a > 6a也反映在细胞毒性测定的结果中。 并对该类化合物的构效关系进行了讨论。
An array of cis-, trans-, and dihydrostilbenes and some N-arylbenzylamines were synthesized and evaluated for their cytotoxicity in the five cancer cell cultures A-549 lung carcinoma, MCF-7 breast carcinoma, HT-29 colon adenocarcinoma, SKMEL-5 melanoma, and MLM melanoma. Several cis-stilbenes, structurally similar to combretastatins, were highly cytotoxic in all five cell lines and these were also found to be active as inhibitors of tubulin polymerization. The most active compounds also inhibited the binding of colchicine to tubulin. The most potent of the new compounds, both as a tubulin polymerization inhibitor and as a cytotoxic agent, was (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene (5a). This substance was almost as potent as combretastatin A-4 (1a), the most active of the combretastatins, as a tubulin polymerization inhibitor. Compound 5a was found to be approximately 140 times more cytotoxic against HT-29 colon adenocarcinoma cells and about 10 times more cytotoxic against MCF-7 breast carcinoma cells than combretastatin A-4. However, 5a was found to be about 20 times less cytotoxic against A-549 lung carcinoma cells, 30 times less cytotoxic against SKMEL-5 melanoma cells, and 7 times less cytotoxic against MLM melanoma cells than combretastatin A-4. The relative potencies 5a > 8a > 6a for the cis, dihydro, and trans compounds, respectively, as inhibitors of tubulin polymerization are in agreement with the relative potencies previously observed for combretastatin A-4 (1a), dihydrocombretastatin A-4 (1c), and trans-combretastatin A-4 (1b). The relative potencies 5a > 8a > 6a were also reflected in the results of the cytotoxicity assays. Structure-activity relationships of this group of compounds are also discussed.