Two series of structurally related organoselenium compounds designed by fusing the anticancer agent methyl(phenyl)selane into the tubulin polymerization inhibitors isocombretastatins or phenstatins were synthesized and evaluated for antiproliferative activity. Most of these selenium containing hybrids exhibited potent cytotoxicity against a panel of cancel cell lines, with IC₅₀ values in the submicromolar concentration range. Among them, 11a, the 3-methylseleno derivative of isocombretastatin A-4 (isoCA-4) represented the most active compound with IC₅₀ values of 2–34 nM against 12 cancer cell lines, including two drug-resistant cell lines. Importantly, its phosphate salt, 11ab, inhibited tumor growth in xenograft mice models with inhibitory rate of 72.9% without apparent toxicity, which was better than the reference compounds isoCA-4P (inhibitory rate 52.2%) and CA-4P (inhibitory rate 47.6%). Mechanistic studies revealed that 11a is a potent tubulin polymerization inhibitor, which could arrest cell cycle at G₂/M phase and induce apoptosis along with the decrease of mitochondrial membrane potential. In summary, 11a could serve as a promising lead for the development of highly efficient anticancer agents.

中文翻译：

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新型含硒异康他汀和苯他汀类抗肿瘤药的设计，合成及生物学评价

通过将抗癌剂甲基（苯基）硒烷融合到微管蛋白聚合抑制剂异康普他汀或苯他汀中，设计了两个系列的结构相关的有机硒化合物，并评估了其抗增殖活性。这些含硒杂种中的大多数对一组抵消细胞系均表现出强力的细胞毒性，IC ₅₀值在亚微摩尔浓度范围内。其中11a是异康普他汀A-4的3-甲基硒代衍生物（iso CA-4），对12种癌细胞系（包括2种耐药细胞系）的IC ₅₀值为2–34 nM，是活性最高的化合物。重要的是，它的磷酸盐11ab，在异种移植小鼠模型中抑制肿瘤生长，抑制率为72.9％，无明显毒性，优于参考化合物iso CA-4P（抑制率52.2％）和CA-4P（抑制率47.6％）。机理研究表明，11a是一种有效的微管蛋白聚合抑制剂，可以抑制G ₂ / M期的细胞周期并诱导细胞凋亡，并降低线粒体膜电位。总之，11a可以作为开发高效抗癌药的有希望的先导。