Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain; Centro de Investigación de Enfermedades Tropicales de La Universidad de Salamanca (CIETUS). Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007, Salamanca, Spain.
Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), E-28040, Madrid, Spain.
Eur J Med Chem. 2021 Jan 1;209:112933. doi: 10.1016/j.ejmech.2020.112933. Epub 2020 Oct 14.
Isocombretastatins are the not isomerizable 1,1-diarylethene isomers of combretastatins. Both families of antimitotics are poorly soluble and new analogs with improved water solubility are needed. The ubiquitous 3,4,5-trimethoxyphenyl ring and most of its replacements contribute to the solubility problem. 39 new compounds belonging to two series of isocombretastatin analogs with 2-chloro-6-methylsulfanyl-4-pyridinyl or 2,6-bis(methylsulfanyl)-4-pyridinyl moieties replacing the 3,4,5-trimethoxyphenyl have been synthesized and their antimitotic activity and aqueous solubility have been studied. We show here that 2-chloro-6-methylsulfanylpyridines are more successful replacements than 2,6-bis(methylsulfanyl)pyridines, giving highly potent tubulin inhibitors and cytotoxic compounds with improved water solubilities. The optimal combination is with indole rings carrying polar substitutions at the three position. The resulting diheteroaryl isocombretastatin analogs showed potent cytotoxic activity against human cancer cell lines caused by tubulin inhibition, as shown by in vitro tubulin polymerization inhibitory assays, cell cycle analysis, and confocal microscopy studies. Cell cycle analysis also showed apoptotic responses following G/M arrest after treatment. Conformational analysis and docking studies were applied to propose binding modes of the compounds at the colchicine site of tubulin and were in good agreement with the observed SAR. 2-Chloro-6-methylsulfanylpyridines represent a new and successful trimethoxyphenyl ring substitution for the development of improved colchicine site ligands.
异卡梅他汀是卡梅他汀的不可异构 1,1-二芳基乙烯异构体。这两类抗有丝分裂药物的水溶性都很差，需要新的水溶性更好的类似物。无处不在的 3,4,5-三甲氧基苯基环及其大部分替代品都导致了水溶性问题。新合成了 39 种属于两种异卡梅他汀类似物系列的化合物，它们用 2-氯-6-甲硫基-4-吡啶基或 2,6-双(甲硫基)-4-吡啶基取代了 3,4,5-三甲氧基苯基，研究了它们的抗有丝分裂活性和水溶解度。我们在这里表明，2-氯-6-甲硫基吡啶比 2,6-双(甲硫基)吡啶更成功地取代了 3,4,5-三甲氧基苯基，得到了高活性的微管蛋白抑制剂和水溶性改善的细胞毒性化合物。最佳组合是带有三个位置极性取代基的吲哚环。所得的二杂芳基异卡梅他汀类似物表现出很强的抑制微管蛋白聚合的体外细胞毒性活性，通过体外微管蛋白聚合抑制试验、细胞周期分析和共聚焦显微镜研究证实了这一点。细胞周期分析还显示在 G2/M 期阻滞后出现了凋亡反应。构象分析和对接研究用于提出化合物在微管蛋白秋水仙碱结合部位的结合模式，与观察到的 SAR 非常吻合。2-氯-6-甲硫基吡啶是发展改进的秋水仙碱结合配体的一种新的、成功的三甲氧基苯基环取代基。
