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首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity
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Synthesis and evaluation of diaryl sulfides and diaryl selenide compounds for antitubulin and cytotoxic activity

机译：二芳基硫醚和二芳基硒化物的合成及其抗微管蛋白和细胞毒活性的评估

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摘要

We have devised a procedure for the synthesis of analogs of combretastatin A-4 (CA-4) containing sulfur and selenium atoms as spacer groups between the aromatic rings. CA-4 is well known for its potent activity as an inhibitor of tubulin polymerization, and its prodrugs combretastatin A-4 phosphate (CA-4P) and combretastatin A-1 phosphate (CA-1P) are being investigated as antitumor agents that cause tumor vascular collapse in addition to their activity as cytotoxic compounds. Here we report the preparation of two sulfur analogs and one selenium analog of CA-4. All synthesized compounds, as well as several synthetic intermediates, were evaluated for inhibition of tubulin polymerization and for cytotoxic activity in human cancer cells. Compounds 3 and 4 were active at nM concentration against MCF-7 breast cancer cells. As inhibitors of tubulin polymerization, both 3 and 4 were more active than CA-4 itself. In addition, 4 was the most active of these agents against 786, HT-29 and PC-3 cancer cells. Molecular modeling binding studies are also reported for compounds 1, 3, 4 and CA-4 to tubulin within the colchicine site.
机译：我们设计了一种合成康布雷他汀A-4（CA-4）类似物的方法，该衍生物含有硫和硒原子作为芳环之间的间隔基。 CA-4以其作为微管蛋白聚合抑制剂的有效活性而闻名，其前药康普他汀A-4磷酸酯（CA-4P）和康普他汀A-1磷酸酯（CA-1P）被研究用作引起肿瘤的抗肿瘤药除了作为细胞毒性化合物的活性外，血管塌陷。在这里，我们报告制备CA-4的两种硫类似物和一种硒类似物。评价了所有合成的化合物以及几种合成的中间体对微管蛋白聚合的抑制作用以及对人类癌细胞的细胞毒活性。化合物3和4在nM浓度下对MCF-7乳腺癌细胞具有活性。作为微管蛋白聚合的抑制剂，3和4均比CA-4本身更具活性。此外，在这些药物中，有4种对786，HT-29和PC-3癌细胞的活性最高。还报道了秋水仙碱位点内化合物1、3、4和CA-4与微管蛋白的分子模型结合研究。

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