期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 17, 页码 9197-9211出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00257
关键词
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资金
- National Natural Science Foundation of China (NSFC) [81703337]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine)
- Jiangsu Specially-Appointed Professors program
- Six Talent Peaks Project in the Jiangsu Province of China [SWYY-069]
- State Key Laboratory of Coordination Chemistry
- Nanjing University
- Open Project of State Key Laboratory of Natural Medicines, China Pharmaceutical University [SKLNMKF201712, SKLNMKF201808]
A series of halo and pseudohalo gold(I)-NHC complexes (NHC-Au-X) (X = Cl, Br, I, NCO, and OAc) derived from 4,5-diarylimidazoles were synthesized, structurally characterized, and analyzed for their biological activities. The most active complex was iodo(1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene)gold(I) (6), which was at least 2-fold more cytotoxic than cisplatin and auranofin against hepatocellular carcinoma (HCC) cells. In vivo studies indicated that complex 6 exhibited a considerably higher anticancer efficacy (IRT = 75.7%) than cisplatin (IRT = 44.4%) in a HepG2 xenograft mouse model and ameliorated liver injury caused by CCl4 in chronic HCC. Further studies revealed that complex 6 can inhibit the expression of the thioredoxin reductase (TrxR) both in vitro and in vivo, block the HepG2 cells in the G2/M phase, induce reactive oxygen species (ROS) production, damage mitochondrial membrane potential (MMP), and promote HepG2 cell apoptosis.
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