Syntheses, Toxicity, Bio-distribution And Metabolism Of CO Donors Based On Group Ⅵ Metal Carbonyl Complexes

Like NO, carbon monoxide (CO) is produced in animals as biologically active factors. It may elicit a range of beneficial effects. For example, it can exert anti-inflammatory effects, regulate blood pressure under stress conditions, and suppress organ graft rejection and so on. Transition metal-carbonyl complexes as CO donors are more attractive. Therefore, we synthesized and characterized 27 CO-donors based on the M(CO)5L unit. Furthermore, we also explored their CO-release behavior, toxicity, bio-distribution and metabolism. The results are following:1) The release of CO has been monitored spectrophotometrically with half-lives varying from 6.5 to 73.8 min. The stability of complexes 25 and 26 was evaluated by means of UV-Vis spectroscopy and 1H-NMR spectra at different pH solutions. They were stable in acid media and unstable in base media.2) The cytotoxic effects of the complexes on the proliferation of Hela and L929 cell line were assayed by MTT. The IC50 of those complexes were 50～600μmol/L,6～165μmol/L on L929 and Hela cell lines, respectively; Effects of complexes 25、26 and 20 containing aspirin and nicotinamide fragments on cell cycle and apoptosis in Hela cells were investigated. Complex 25 induced cell cycle arrest at S phase. Complex 26 and 20 blocked the cell cycle at G2/M phase. Cell apoptosis of the three compounds occurred in "Late apoptosis".3) There were some extent toxicities to mice after oral drugs. Oral LD50 values were 75-500 mg/kg. Through blood, urine analysis, TEM, they have little effect on the function of liver, but they damage liver cells physiologically. By contrast, they severely affect kidney in both functional and physiological aspects.4) Distribution studies were measured using ICP-AES and the results showed that these complexes mainly distributed into blood, kidney and liver, the proportion of brain less than 0.5%.5) The metabolisms of the complexes were investigated by FT-IR. and XPS. The results showed the metal carbonyl during the metabolism were gradually lost. There was no CO signal in urines in the IR spectra. The Mo and W atoms of Mo(CO)5L and W(CO)5L were existed with the form of MoⅣ and WⅣ through metabolism.