Conway Institute of Biomolecular and Biomedical Research, Centre for Synthesis and Chemical Biology (CSCB), UCD School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.
Metallomics. 2011 Jan;3(1):74-88. doi: 10.1039/c0mt00034e. Epub 2010 Dec 6.
From the reaction of 1-methylimidazole (1a), 4,5-dichloro-1H-imidazole (1b(I)) and 1-methylbenzimidazole (1c) with p-cyanobenzyl bromide (2a), non-symmetrically substituted N-heterocyclic carbene (NHC) [(3a-c)] precursors, 5,6-dimethyl-1H-benzimidazole (1d) and 4,5-diphenyl-1H-imidazole (1e) with p-cyanobenzyl bromide (2a) and benzyl bromide (2b), symmetrically substituted N-heterocyclic carbene (NHC) [(3d-f)] precursors were synthesised. These NHC-precursors were then reacted with silver(i) acetate to yield the NHC-silver complexes (1-methyl-3-(4-cyanobenzyl)imidazole-2-ylidene)silver(i)acetate (4a), (4,5-dichloro-1-(4-cyanobenzyl)-3-methyl)imidazole-2-ylidene)silver(i)acetate (4b), (1-methyl-3-(4-cyanobenzyl)benzimidazole-2-ylidene)silver(i)acetate (4c), (1,3-bis(4-cyanobenzyl)5,6-dimethylbenzimidazole-2-ylidene) silver(i) acetate (4d), (1,3-dibenzyl-5,6-dimethylbenzimidazole-2-ylidene) silver(i) acetate (4e) and (1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene) silver(i) acetate (4f) respectively. Three NHC-precursors 3c-e and four NHC-silver complexes 4b and 4d-f were characterised by single crystal X-ray diffraction. Preliminary in vitro antibacterial activity of the NHC-precursors and NHC-silver complexes was investigated against Gram-positive bacteria Staphylococcus aureus, and Gram-negative bacteria Escherichia coli using the qualitative Kirby-Bauer disk-diffusion method. NHC-silver complexes have shown very high antibacterial activity compared to the NHC-precursors. All six NHC-silver complexes were tested for their cytotoxicity through MTT based in vitro tests on the human renal-cancer cell line Caki-1 in order to determine their IC₅₀ values. NHC-silver complexes 4a-f were found to have IC₅₀ values of 6.2 (±1.0), 7.7 (±1.6), 1.2 (±0.6), 10.8 (±1.9), 24.2 (±1.8) and 13.6 (±1.0) μM, respectively. These values represent improved cytotoxicity against Caki-1, most notably for 4c, which is a three times more cytotoxic than cisplatin (IC₅₀ value = 3.3 μM) itself.
从 1-甲基咪唑（1a）、4,5-二氯-1H-咪唑（1b（I））和 1-甲基苯并咪唑（1c）与对氰基苄基溴（2a）的反应，非对称取代的 N-杂环卡宾（NHC）[（3a-c）]前体，5,6-二甲基-1H-苯并咪唑（1d）和 4,5-二苯基-1H-咪唑（1e）与对氰基苄基溴（2a）和苄基溴（2b），对称取代的 N-杂环卡宾（NHC）[（3d-f）]前体被合成。然后，这些 NHC 前体与银（I）乙酸反应，生成 NHC-银配合物（1-甲基-3-（4-氰基苄基）咪唑-2-亚基）银（I）乙酸盐（4a）、（4,5-二氯-1-（4-氰基苄基）-3-甲基）咪唑-2-亚基）银（I）乙酸盐（4b）、（1-甲基-3-（4-氰基苄基）苯并咪唑-2-亚基）银（I）乙酸盐（4c）、（1,3-双（4-氰基苄基）5,6-二甲基苯并咪唑-2-亚基）银（I）乙酸盐（4d）、（1,3-二苄基-5,6-二甲基苯并咪唑-2-亚基）银（I）乙酸盐（4e）和（1,3-二苄基-4,5-二苯基咪唑-2-亚基）银（I）乙酸盐（4f）。通过单晶 X 射线衍射对三种 NHC 前体 3c-e 和四种 NHC-银配合物 4b 和 4d-f 进行了表征。通过定性 Kirby-Bauer 圆盘扩散法，对革兰氏阳性菌金黄色葡萄球菌和革兰氏阴性菌大肠杆菌进行了 NHC 前体和 NHC-银配合物的体外初步抗菌活性研究。与 NHC 前体相比，NHC-银配合物具有非常高的抗菌活性。为了确定它们的 IC₅₀ 值，通过基于 MTT 的体外试验对人肾癌细胞系 Caki-1 进行了六种 NHC-银配合物的细胞毒性测试。结果表明，NHC-银配合物 4a-f 的 IC₅₀ 值分别为 6.2（±1.0）、7.7（±1.6）、1.2（±0.6）、10.8（±1.9）、24.2（±1.8）和 13.6（±1.0）μM。这些值代表对 Caki-1 的细胞毒性有了显著提高，尤其是 4c，其细胞毒性是顺铂（IC₅₀ 值=3.3μM）本身的三倍。
