Li Yong, Cao Ting-Ting, Guo Shanchun, Zhong Qiu, Li Cai-Hu, Li Ying, Dong Lin, Zheng Shilong, Wang Guangdi, Yin Shu-Fan
College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, China.
RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA.
Molecules. 2016 Jun 20;21(6):771. doi: 10.3390/molecules21060771.
A series of pyrazolo[3,4-d]pyrimidine derivatives related to allopurinol has been synthesized and evaluated for its cytotoxicity against a panel of three cancer cell lines as well as its xanthine oxidase (XOD) inhibitory activities. Among them, compound 4 showed potent cytotoxicity with IC50 values of 25.5 and 35.2 μM against human hepatoma carcinoma cell lines, BEL-7402 and SMMC-7221, respectively. The anticancer activity of 4 was comparable to that of Tanespimycin (17-N-allylamino-17-demethoxy geldanamycin, 17-AAG) that inhibited the growth of BEL-7402 and SMMC-7221 cells at IC50 values of 12.4 and 9.85 μM, respectively. However, unlike allopurinol, which is also a strong inhibitor of XOD, compound 4 is a much weaker XOD inhibitor, suggesting that the anticancer activities of the allopurinol derivatives may not be associated with XOD inhibition. Moreover, the cytotoxicity of 4 toward normal cells is significantly lower than that of 17-AAG, making 4 a promising lead compound for further optimization of structure-activity relationships that may lead to anticancer agents of clinical utility.
已经合成了一系列与别嘌呤醇相关的吡唑并[3,4-d]嘧啶衍生物，并评估了其对一组三种癌细胞系的细胞毒性以及其黄嘌呤氧化酶（XOD）抑制活性。其中，化合物4对人肝癌细胞系BEL-7402和SMMC-7221分别表现出强效细胞毒性，IC50值为25.5和35.2 μM。化合物4的抗癌活性与坦西莫司（17-N-烯丙基氨基-17-去甲氧基格尔德霉素，17-AAG）相当，后者对BEL-7402和SMMC-7221细胞生长的抑制IC50值分别为12.4和9.85 μM。然而，与同样是XOD强抑制剂的别嘌呤醇不同，化合物4是一种弱得多的XOD抑制剂，这表明别嘌呤醇衍生物的抗癌活性可能与XOD抑制无关。此外，化合物4对正常细胞的细胞毒性明显低于17-AAG，这使得化合物4成为进一步优化构效关系以开发具有临床应用价值抗癌药物的有前景的先导化合物。
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