School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland.
Eur J Med Chem. 2013 Apr;62:705-21. doi: 10.1016/j.ejmech.2013.01.016. Epub 2013 Jan 18.
The synthesis and biochemical activities of novel water-soluble β-lactam analogues of combretastatin A-4 are described. The first series of compounds investigated, β-lactam phosphate esters 7a, 8a and 9a, exhibited potent antiproliferative activity and caused microtubule disruption in human breast carcinoma-derived MCF-7 cells. They did not inhibit tubulin polymerisation in vitro, indicating that biotransformation was necessary for their antiproliferative and tubulin binding effects in MCF-7 cells. The second series of compounds, β-lactam amino acid amides (including 10k and 11l) displayed potent antiproliferative activity in MCF-7 cells, disrupted microtubules in MCF-7 cells and also inhibited the polymerisation of tubulin in vitro. This indicates that the β-lactam amides did not require metabolic activation to have antiproliferative effects, in contrast to the phosphate series. Both series of compounds caused mitotic catastrophe and apoptosis in MCF-7 cells. Molecular modelling studies indicated potential binding conformations for the β-lactam amino acid amides 10k and 11l in the colchicine-binding site of tubulin. Due to their aqueous solubility and potent biochemical effects, these compounds are promising candidates for further development as microtubule-disrupting agents.
新型水溶性β-内酰胺类考布他汀 A-4 类似物的合成及生化活性研究。所研究的第一系列化合物，β-内酰胺磷酸酯 7a、8a 和 9a，表现出很强的抗增殖活性，并导致人乳腺癌衍生的 MCF-7 细胞中的微管断裂。它们在体外不抑制微管蛋白聚合，表明生物转化是它们在 MCF-7 细胞中发挥抗增殖和微管结合作用所必需的。第二系列化合物，β-内酰胺氨基酸酰胺（包括 10k 和 11l），在 MCF-7 细胞中表现出很强的抗增殖活性，破坏 MCF-7 细胞中的微管，并抑制微管蛋白的聚合。这表明β-内酰胺酰胺不需要代谢激活就具有抗增殖作用，与磷酸酯系列相反。这两个系列的化合物都导致 MCF-7 细胞中的有丝分裂灾难和细胞凋亡。分子建模研究表明，β-内酰胺氨基酸酰胺 10k 和 11l 在微管蛋白的秋水仙碱结合位点具有潜在的结合构象。由于其水溶性和很强的生化作用，这些化合物很有希望进一步开发为微管破坏剂。
