Morgan Rachel E, Ahn Sunnoo, Nzimiro Sandra, Fotie Jean, Phelps Mitch A, Cotrill Jeffrey, Yakovich Adam J, Sackett Dan L, Dalton James T, Werbovetz Karl A
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA.
Chem Biol Drug Des. 2008 Dec;72(6):513-24. doi: 10.1111/j.1747-0285.2008.00729.x.
Tubulin is the proposed target for drugs against cancer and helminths and is also a validated target in kinetoplastid parasites. With the aim of identifying new lead compounds against Leishmania sp., tubulin isolated from L. tarentolae was used to screen a 10 000 compound library. One compound, Chembridge No. 7992831 (5), displayed an IC(50) of 13 microm against Leishmania tubulin in an in vitro assembly assay and showed a greater than threefold selectivity over mammalian tubulin. Another compound, Chembridge No. 9067250 (8), exhibited good activity against mammalian tubulin (IC(50) = 5.0 microm). This compound was also toxic to several cancer cell lines with IC(50) values in the region of 1 microm. Subsequent testing of analogues of 8 contained within the library identified two compounds with greater potency against mammalian tubulin (IC(50) values of 1.1 and 2.8 microm). The more potent antitubulin agent also showed promising activity against cancer cell lines in vitro, with IC(50) values ranging from 0.18 to 0.73 microm.
微管蛋白是抗癌和抗蠕虫药物的潜在靶点，也是动基体寄生虫中已得到验证的靶点。为了鉴定针对利什曼原虫属的新型先导化合物，从塔氏利什曼原虫中分离出的微管蛋白被用于筛选一个包含10000种化合物的文库。一种化合物，Chembridge编号7992831（5），在体外组装试验中对利什曼原虫微管蛋白的IC50为13 μM，并且对哺乳动物微管蛋白的选择性大于三倍。另一种化合物，Chembridge编号9067250（8），对哺乳动物微管蛋白表现出良好的活性（IC50 = 5.0 μM）。该化合物对几种癌细胞系也有毒性，IC50值在1 μM左右。随后对文库中包含的8的类似物进行测试，鉴定出两种对哺乳动物微管蛋白具有更高效力的化合物（IC50值分别为1.1和2.8 μM）。效力更强的抗微管蛋白剂在体外对癌细胞系也显示出有前景的活性，IC50值范围为0.18至0.73 μM。
