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:+86-10-59484199
Address:No.58-A1026 Liangguan Street
Lonzeal Pharmaceuticals Co., Ltd.
website:http://www.lonzeal.com
Contact:+86-13381011962
Address:RM 801, Yue MOMA, No. 26 Anningzhuang Rd. Haidian District, Beijing, China
Hubei Lansun Biochemical Pharmaceutical Co., Ltd
Contact:714-6395977
Address:No. 81 Pengcheng Avenue, economic and technological development zone, Huangshi City, Hubei Province,China
Lianyungang Ningkang Chemical Co., Ltd
Contact:.+86-518-88588008
Address:http://www.chemnk.com
Xiamen XM-Innovation Chemical Co., Ltd
Contact:+86-592-3216205
Address:Unit Q, 11/F, No.1 Office Building, Wuyuan Bay Business Center, Huli District, Xiamen City, Fujian Province, P.R.C
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)