Lv Gaochao, Guo Liubin, Qiu Ling, Yang Hui, Wang Tengfei, Liu Hong, Lin Jianguo
Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China.
Dalton Trans. 2015 Apr 28;44(16):7324-31. doi: 10.1039/c5dt00169b.
Five Ru(II)-N-heterocyclic carbenes (NHC) (1-5) were synthesized by reacting the appropriately substituted imidazolium chlorides with Ag2O, forming the NHC-silver chloride in situ followed by transmetalation with dimeric p-cymene ruthenium(II) dichloride. All the complexes were characterized by NMR and ESI-MS, and complex 1 was also characterized by single-crystal X-ray diffraction. The IC50 values of these five complexes were determined by the MTT-based assay on four human cancer cell lines, SKOV-3 (ovarian), PC-3 (prostate), MDA-MB-231 (breast) and EC109 (esophagus). The cytotoxicities of these complexes changed from a moderate effect to a fine one, corresponding to the increasing lipophilicity order of the complex of 2 < 1 < 3 < 4 < 5 (0.91, 0.88, 1.36, 1.85 and 2.62 for 1–5 respectively). Complex 5 showed the most cytotoxicity with the IC50 values 10.3 ± 0.3 μM for SKOV-3, 2.9 ± 0.1 μM for PC-3, 8.2 ± 0.6 μM for MDA-MB-231, 6.4 ± 0.2 μM for EC109 cell lines. Due to the superior cytotoxicity of complex 5 against the PC-3 cell lines, further biological evaluations were carried out to elucidate its action mechanism. The morphologic changes and cell cycle analysis showed that complex 5 can inhibit PC-3 cell lines by inducing cell cycle arrest at the G2/M phase. The DNA binding experiments further demonstrate that complex 5 has a better binding ability for DNA (Kb = 2.2 × 10(6) M(-1)) than complexes 1-4 (3.8 × 10(5), 7.0 × 10(5), 5.7 × 10(5), and 1.9 × 10(5) respectively).
通过使适当取代的咪唑鎓氯化物与氧化银反应，原位形成N-杂环卡宾-氯化银，随后与二聚对异丙基苯钌（II）二氯化物进行金属转移反应，合成了五种钌（II）-N-杂环卡宾（NHC）（1-5）。所有配合物均通过核磁共振（NMR）和电喷雾电离质谱（ESI-MS）进行表征，配合物1还通过单晶X射线衍射进行了表征。通过基于MTT的方法在四种人类癌细胞系SKOV-3（卵巢癌）、PC-3（前列腺癌）、MDA-MB-231（乳腺癌）和EC109（食管癌）上测定了这五种配合物的半数抑制浓度（IC50）值。这些配合物的细胞毒性从中等效应变为良好效应，这与配合物的亲脂性增加顺序2 < 1 < 3 < 4 < 5相对应（1-5的亲脂性分别为0.91、0.88、1.36、1.85和2.62）。配合物5表现出最强的细胞毒性，对SKOV-3细胞系的IC50值为10.3±0.3 μM，对PC-3细胞系为2.9±0.1 μM，对MDA-MB-231细胞系为8.2±0.6 μM，对EC109细胞系为6.4±0.2 μM。由于配合物5对PC-3细胞系具有优异的细胞毒性，因此进行了进一步的生物学评估以阐明其作用机制。形态学变化和细胞周期分析表明，配合物5可通过诱导细胞周期停滞在G2/M期来抑制PC-3细胞系。DNA结合实验进一步证明，配合物5对DNA的结合能力（结合常数Kb = 2.2×10(6) M(-1)）优于配合物1-4（分别为3.8×10(5)、7.0×10(5)、5.7×10(5)和1.9×10(5)）。
