title: Lipophilicity-dependent ruthenium N-heterocyclic carbene complexes as potential anticancer agents.
abstract: 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).
authors: Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China. linjianguo@jsinm.org qiuling@jsinm.org.
authors: Gaochao
authors: G
authors: Lv
authors: Liubin
authors: L
authors: Guo
authors: Ling
authors: L
authors: Qiu
authors: Hui
authors: H
authors: Yang
authors: Tengfei
authors: T
authors: Wang
authors: Hong
authors: H
authors: Liu
authors: Jianguo
authors: J
authors: Lin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D002417:Cattle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D008968:Molecular Conformation; D012428:Ruthenium / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D006571:Heterocyclic Compounds; C030011:carbene; D012428:Ruthenium; D004247:DNA; C427203:calf thymus DNA; D008697:Methane