Pettit George R, Minardi Mathew D, Rosenberg Heidi J, Hamel Ernest, Bibby Michael C, Martin Sandie W, Jung M Katherine, Pettit Robin K, Cuthbertson Timothy J, Chapuis Jean-Charles
Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 872404, Tempe, Arizona 85287-2404, USA.
J Nat Prod. 2005 Oct;68(10):1450-8. doi: 10.1021/np058038i.
The present SAR study of combretastatin A-3 (3a) focused on replacement of the 3-hydroxyl group by a series of halogens. That approach with Z-stilbenes resulted in greatly enhanced (>10-100-fold) cancer cell growth inhibition against a panel of human cancer cell lines and the murine P388 lymphocytic leukemia cell line. Synthesis of the 3-fluoro-Z-stilbene designated fluorcombstatin (11a) and its potassium 3'-O-phosphate derivative (16c) by the route 7 --> 8a --> 11a --> 14 --> 16c illustrates the general synthetic pathway. The 3'-O-phosphoric acid ester (15) of 3-bromo-Z-stilbene 13a was also converted to representative cation salts to evaluate the potential for improved aqueous solubility, and the potassium salt (16 mg/mL in water) proved most useful. The fluoro (11a), chloro (12a), and bromo (13a) halocombstatins were nearly equivalent to combretastatin A-4 (1a) as inhibitors of tubulin polymerization and of the binding of colchicine to tubulin. The tubulin binding in cell-free systems was also retained in human umbilical vein endothelial cells. All three halocombstatins retained the powerful human cancer cell line inhibitory activity of combretastatin A-4 (1a) and proved superior to combretastatin A-3 (3a). In addition, the halocombstatins targeted Gram-positive bacteria and Cryptococcus neoformans.
目前对康普他汀A-3（3a）的构效关系研究聚焦于用一系列卤素取代3-羟基。对Z-二苯乙烯采用这种方法后，对一组人类癌细胞系和小鼠P388淋巴细胞白血病细胞系的癌细胞生长抑制作用大大增强（>10 - 100倍）。通过7→8a→11a→14→16c路线合成3-氟-Z-二苯乙烯即氟康普他汀（11a）及其3'-O-磷酸钾衍生物（16c）说明了一般的合成途径。3-溴-Z-二苯乙烯13a的3'-O-磷酸酯（15）也被转化为代表性的阳离子盐以评估改善水溶性的潜力，结果证明钾盐（在水中为16 mg/mL）最为有用。氟代（11a）、氯代（12a）和溴代（13a）卤代康普他汀作为微管蛋白聚合抑制剂以及秋水仙碱与微管蛋白结合的抑制剂，与康普他汀A-4（1a）几乎等效。在无细胞系统中的微管蛋白结合在人脐静脉内皮细胞中也得以保留。所有三种卤代康普他汀都保留了康普他汀A-4（1a）强大的人类癌细胞系抑制活性，并且证明优于康普他汀A-3（3a）。此外，卤代康普他汀还靶向革兰氏阳性菌和新型隐球菌。
