Halo and Pseudohalo Gold(I)-NHC Complexes Derived from 4,5-Diarylimidazoles with Excellent In Vitro and In Vivo Anticancer Activities Against HCC.,Journal of Medicinal Chemistry

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Halo and Pseudohalo Gold(I)-NHC Complexes Derived from 4,5-Diarylimidazoles with Excellent In Vitro and In Vivo Anticancer Activities Against HCC.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-08-03 , DOI: 10.1021/acs.jmedchem.0c00257
Mianli Bian ₁ , Rong Fan ₁ , Guizhi Jiang ₁ , Yingxiang Wang ₁ , Yunlong Lu ₁ , Wukun Liu _{1,

2,

3}

Affiliation

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.

中文翻译：

衍生自4,5-二芳基咪唑的Halo和Pseudohalo Gold（I）-NHC复合物具有出色的HCC体外和体内抗癌活性。

合成了一系列衍生自4,5-二芳基咪唑的卤代和假卤代金（I）–NHC络合物（NHC–Au–X）（X = Cl，Br，I，NCO和OAc），对其结构进行了表征并分析了他们的生物活动。活性最高的复合物是碘（1,3-二乙基-4,5-双（4-甲氧基苯基）咪唑-2-亚甲基）金（I）（6），其细胞毒性比顺铂和金诺芬至少高2倍。针对肝细胞癌（HCC）细胞。体内研究表明，在HepG2异种移植小鼠模型中，复合物6表现出比顺铂（IRT = 44.4％）高得多的抗癌功效（IRT = 75.7％），并且减轻了慢性HCC中由CCl ₄引起的肝损伤。进一步的研究表明复合物6可以抑制硫氧还蛋白还原酶（的TrxR）两者的表达在体外和在体内，框在G2 / M期的HepG2细胞，诱导反应性氧物质（ROS）的产生，破坏线粒体膜电位（MMP），和促进的HepG2细胞细胞凋亡。

更新日期：2020-09-10

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