Microwave-assisted synthesis of arene ruthenium(II) complexes that induce S-phase arrest in cancer cells by DNA damage-mediated p53 phosphorylation.

Abstract: A series of arene ruthenium(II) complexes coordinated by phenanthroimidazole derivates, [(C6H6)Ru(L)Cl]Cl·2H2O (1b L = IP, 2b L = p-NMe2PIP, 3b L = p-MeOPIP, 4b L = p-HOPIP, 5b L = p-COOHPIP, 6b L = p-CF3PIP, 7b L = p-BrPIP) have been synthesized in yields of 89–92% under microwave irradiation in 30 min, and the crystal structure of 1b by XRD gives a typical “piano stool” conformation. The antitumor activity of these complexes against various tumor cells have been evaluated by MTT assay, and the results show that this type of arene Ru(II) complexes exhibit acceptable inhibitory effect against all of these tumor cells, especially osteosarcoma MG-63 cells, but with low toxicity toward HK-2 human normal cells. Studies on the mechanism revealed that cell cycle arrest at S-phase in MG-63 cells induced by the arene Ru(II) complex 2b, which was confirmed by the increase in the percentage of cells at S-phase and down-regulator of cyclin A. The further studies by Comet assay at single cell level indicated that DNA damage in MG-63 cells was triggered by 2b, following with the up-regulation of phosphorylated p53 and histone. The studies by spectroscopy in vitro also indicate that 2b bind to DNA molecule by intercalative mode to disturb the bio-function of tumor cells. In conclusion, the synthetic arene Ru(II) complexes could serve as novel p53 activator with potential application in cancer chemotherapy. [Copyright &y& Elsevier]