Journal of Medicinal Chemistry p. 3107 - 3121 (2019)
Update date:2022-08-15
Topics:
Chen, Ge
Niu, Chunyi
Yi, Jianhua
Sun, Lin
Cao, Hengyi
Fang, Yanjia
Jin, Taijie
Li, Ying
Lou, Chunli
Kang, Jingwu
Wei, Wanguo
Zhu, Jidong
Triapine, an iron chelator that inhibits ribonucleotide reductase, has been evaluated in clinical trials for cancer treatment. Triapine in combination with other chemotherapeutic agents shows promising efficacy in certain hematologic malignancies; however, it is less effective against many advanced solid tumors, probably due to the unsatisfactory potency and pharmacokinetic properties. In this report, we developed a triapine derivative IC25 (10) with potent antitumor activity. 10 Preferentially inhibited the proliferation of hematopoietic cancers by inducing mitochondria reactive oxygen species production and mitochondrial dysfunction. Unlike triapine, 10 executed cytotoxic action in a copper-dependent manner. 10-Induced up-expression of thioredoxin-interacting protein resulted in decreased thioredoxin activity to permit c-Jun N-terminal kinase and p38 activation and ultimately led to the execution of the cell death program. Remarkedly, 10 showed good bioavailability and inhibited tumor growth in mouse xenograft models. Taken together, our study identifies compound 10 as a copper-dependent antitumor agent, which may be applied to the treatment of hematopoietic cancers.
View MoreContact:0792-8228321
Address:10TH Floor No.121 binjiang Road Xunyang District
Shanghai Mintchem Development ., Ltd
Contact:0086 21 5190 8570
Address:R602,4#,89Nong, Mudan Road Pudong Shanghai China
Basilea Pharmaceutica China Ltd.
Contact:+86-513-82198075
Address:No.638 Xiushan Road(East),Haimen, Jiangsu 226100, P.R.China
chengdu firsterchem Pharmaceutical Co., Ltd.
Contact:028-66825849
Address:chengdu
Contact:86-15588110016
Address:LINYI CITY,SHANDONG PROVINCE,CHINA
Doi:10.1039/c1cc14043d
(2011)Doi:10.1021/ol202420j
(2011)Doi:10.1039/DT9910000299
(1991)Doi:10.1021/jo00015a024
(1991)Doi:10.1016/S0040-4039(00)84193-3
(1986)Doi:10.1039/c5ra02504d
(2015)