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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：抗癌剂2-甲氧基雌二醇新类似物的合成，生物学评价和分子建模：血管生成的有效抑制剂

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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 (IC _(50) = 0.1 ± 0.02 μM) 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 (IC _(50) = 4.3 μM) almost as potent as 2-methoxyestradiol (IC _(50) = 3.5 μM). Molecular modeling experiments showed that this analog interacts within the colchicine-binding site of β-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：报道了合成，细胞毒性，对微管蛋白聚合的抑制及10种甲氧基雌二醇的抗血管生成效应。这些努力揭示了在17-位的4-吡啶环中的模拟与类固醇α-环上的2-乙基和3-磺酸盐取代基组合，是最有趣的抗癌剂。该化合物对血管生成（IC _（50）= 0.1±0.1±0.1±0.1±0.1±0.1±0.1±0.1±0.1±0.1±0.1±0.1±0.1±0.1±0.1±0.1±0.1±0.1±0.1±0.1±0.1±29型癌细胞系有效的抑制作用，并且对健康Vero细胞系没有观察到细胞毒性的细胞毒性。最有趣的模拟也显示出对微管蛋白聚合的抑制（IC _（50）=4.3μm）几乎与2-甲氧基雌二醇（IC _（50）=3.5μm）有效。分子建模实验表明该模拟通过与几个氨基酸的多键合的β-微管蛋白的血晶氨酸结合位点相互作用。这些观察结果提供了对这种新型类似物观察到的细胞毒性和抗血管生成效果，至少部分地通过与小管蛋白结合介导。

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