title: Discovery of Novel Allopurinol Derivatives with Anticancer Activity and Attenuated Xanthine Oxidase Inhibition.
abstract: 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.
authors.affiliation: College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, China. liyong562@126.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, China. Caotingting987@163.com.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Cao
authors.affiliation: RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA. sguo@xula.edu.|Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA. sguo@xula.edu.
authors.forename: Shanchun
authors.initials: S
authors.lastname: Guo
authors.affiliation: RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA. qzhong@xula.edu.|Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA. qzhong@xula.edu.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, China. licaihu@yeah.net.
authors.forename: Cai-Hu
authors.initials: CH
authors.lastname: Li
authors.affiliation: College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, China. scdxliying@163.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, China. donglilhy@163.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Dong
authors.affiliation: RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA. szheng@xula.edu.|Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA. szheng@xula.edu.
authors.forename: Shilong
authors.initials: S
authors.lastname: Zheng
authors.affiliation: RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA. gwang@xula.edu.|Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA. gwang@xula.edu.
authors.forename: Guangdi
authors.initials: G
authors.lastname: Wang
authors.affiliation: College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, China. chuandayouji217@163.com.
authors.forename: Shu-Fan
authors.initials: SF
authors.lastname: Yin
mesh_terms: D000493:Allopurinol / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000493:Allopurinol; D014969:Xanthine Oxidase
keywords: XOD inhibition; allopurinol derivatives; cytotoxicity; human hepatoma carcinoma cell