基于羰基钴一氧化碳释放分子的毒性及生物活性研究  

Toxicology and bioactivities of CO-releasing molecules based on cobalt complexes

作　　者：弓亚国 张涛锋[1] 李勐[1] 赵全义[1] 贺殿[1] 席娜[1] 程杰[2] 陈永林[3] 刘斌[4] 

机构地区：[1]兰州大学药学院药物化学研究所,甘肃兰州730000 [2]兰州大学基础医学院GLP实验中心,甘肃兰州730000 [3]兰州大学第一医院,甘肃兰州730000 [4]兰州大学口腔医学院,甘肃兰州730000

出　　处：《药学学报》2016年第3期425-433,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(21171079);兰州市科技发展项目(2014-2-34)

摘　　要：含金属钴和一氧化碳配体的羰基钴配合物（CORMs）具有抗肿瘤和抗炎的潜力。本文在合成3个杂化型钴一氧化碳释放分子（分别含乙酰水杨酸、对氨基苯甲酸、7-羟基香豆素结构片段）的基础上,从动物毒性、抗肿瘤及抗炎活性等方面对其生物活性进行了初步评价。结果表明：配合物CO释放半衰期在43-53 min之间;小鼠经口LD50介于1 500-5 000 mg·kg-1;大鼠连续等剂量给药后,配合物1对大鼠肝细胞的生理形态和功能都有影响,对肾脏的功能和生理形态的影响都较为严重;配合物1对He La细胞和Hep G2细胞均表现出较强的生长抑制作用（IC50分别为36.20和39.25μmol·L-1）,配合物2对He La细胞的增殖抑制作用低于对照组5-FU（IC50114.19μmol·L-1）,但它们三者对Hep G2细胞的生长抑制作用都强于对照组5-FU（IC50 171.34μmol·L-1）。抗炎实验表明：它们均能降低细胞内亚硝酸盐水平,配合物1和2比3表现出更强的活性,通过与相应配体对照实验证实,它们的抗炎活性主要来自于CORMs释放的CO分子。Complexes containing cobalt and carbon monoxide ligands, CO releasing molecules（CORMs）, have the potential of anti-tumor and anti-inflammatory. In this paper, three hybrid CORMs 1-3 were synthesized and tested for their toxicology in vivo and bioactivities. The results suggest that the complexes have a long half-life in the range of 43-53 min; their oral LD50 to mouse are between 1 500 mg·kg-1 and 5 000 mg·kg-1. After the successive administration, complex 1 exhibited a toxic activity in rats＇ liver, and induced an injury to liver cells. Complex 1 had a strong growth inhibition activity（IC50 36.20 μmol·L-1 and 39.25 μmol·L-1） in both He La cells and Hep G2 cells, complex 2 displayed a lower activity in the inhibition of He La cells proliferation than the control 5-FU（IC50 114.19 μmol·L-1）, but had a higher activity in the inhibition of Hep G2 cells than the control 5-FU（IC50 171.34 μmol·L-1）. The anti-inflammatory study suggests that all of them reduce intracellular nitrite level, complexes 1 and 2 have a stronger activity than complex 3. Their anti-inflammatory activity attributes to the CO molecules of the CORMs, which was confirmed by comparison with the corresponding ligand.

关 键 词：钴 一氧化碳释放分子 抗肿瘤 抗炎活性 

分 类 号：R916[医药卫生—药学]