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首页> 外文期刊>RSC Advances >Synthesis, biological evaluation and molecular modeling of new analogs of the anti-cancer agent 2-methoxyestradiol: potent inhibitors of angiogenesis
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Synthesis, biological evaluation and molecular modeling of new analogs of the anti-cancer agent 2-methoxyestradiol: potent inhibitors of angiogenesis

机译：抗癌药2-甲氧基雌二醇的新类似物的合成，生物学评估和分子建模：血管生成的有效抑制剂

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摘要

The synthesis, cytotoxicity, inhibition of tubulin polymerization and anti-angiogenic effects of 10 analogs of 2-methoxyestradiol are reported. These efforts revealed that the analog with a 4-pyridine ring in the 17-position, in combination with 2-ethyl- and 3-sulfamate substituents on the steroid A-ring, is the most interesting anti-cancer agent. This compound showed potent inhibitory effects against angiogenesis (IC50 = 0.1 +/- 0.02 mu M) and selective cytotoxic effects towards the CEM, H460 and HT-29 cancer cell lines, with no cytotoxicity observed against the healthy VERO cell line. The most interesting analog also displayed inhibition of tubulin polymerization (IC50 = 4.3 mu M) almost as potent as 2-methoxyestradiol (IC50 = 3.5 mu M). Molecular modeling experiments showed that this analog interacts within the colchicine-binding site of beta-tubulin via multiple bonding with several amino acids. These observations provide support that the cytotoxic and anti-angiogenic effects observed for this novel analog are, at least in part, mediated by binding to tubulin.
机译：报道了2-甲氧基雌二醇的10个类似物的合成，细胞毒性，微管蛋白聚合的抑制和抗血管生成作用。这些努力表明，在17位具有4-吡啶环的类似物，与甾族A环上的2-乙基和3-氨基磺酸酯取代基结合在一起，是最令人感兴趣的抗癌药。该化合物显示出对血管生成的有效抑制作用（IC50 = 0.1 +/- 0.02μM），并且对CEM，H460和HT-29癌细胞系具有选择性的细胞毒性作用，而对健康的VERO细胞系则未观察到细胞毒性。最有趣的类似物还显示出对微管蛋白聚合的抑制作用（IC50 = 4.3μM），几乎与2-甲氧基雌二醇（IC50 = 3.5μM）一样强。分子建模实验表明，该类似物通过与多个氨基酸的多次键合在β-微管蛋白的秋水仙碱结合位点内相互作用。这些观察结果提供了支持，即对于这种新型类似物观察到的细胞毒性和抗血管生成作用至少部分是通过与微管蛋白的结合介导的。

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