Study On The Controllable Release Of Carbon Monoxide And Anticancer Activity Of Carboxylic Acid Bridge Across The Bisruthenium Tetracarbonyl Complex

Tuning biological activity of ruthenium carbonyl complexes have become one of the hot issues in bioorganometallic chemistry.In this thesis,a ligand strategy of regulating bioactivity of ruthenium carbonyl complexes was developed,the CO release,anti cancer activity and water solubility of carboxylate bridged diruthenium tetracarbonyl structure were precisely tunned by introducing axial heterocyclic ligands and bridging ligands.The experiments clearly demonstrated that the ruthenium carbonyl complexes containing heterocyclic ligands were toxic to cancer cells,whilst hydrophilic salicylic acid and polyethylene glycol monomethyl ether succinate as bridged ligands greatly improved the water solubility of sawhorse structure,thereby accelerating the release rate of carbon monoxide.In this thesis,twenty-four new sawhorse ruthenium carbonyl CORMs were synthesized and characterized,and a single crystal structure of 2a was analyzed.The myoglobin assay revealed that all complexes released CO under UV irradiation(365 nm)in vitro physiological environment.The MTT experiments indicated that the ruthenium carbonyl complexes were cytotoxicity,and 2a showed significant anticancer activity against HCT116 cell line with the IC50 value of less than 100 μM.The specific work of this thesis was summarized as following five parts:1.The pyrolysis reaction of ruthenium carbonyl with carboxylic acid,the three types of carboxylate bridging sawhorse ruthenium carbonyl complexes were successfully prepared,1a-6a containing a variety of N heterocyclic axial ligands and acetic acid bridging ligands;1d-6d with salicylic acid bridging ligands;and 1b-6c with mPEG-OOCCH2CH2COOH bridging ligands.All of CORMs were fully characterized by NMR,IR,MS,etc.,all results consistent with the expectations.Moreover,the single crystal X-ray diffrraction of 2a was analyzed.2.The CO release properties of carboxylate bridged sawhorse complexes were measured by the myoglobin assay.Experimental results showed that these complexes were stable in vitro physiological environment,and UV irradiation(365 nm)can effectively trigger the released CO.The CO released kinetic data indicated that CO released properties of these complexes were relevant to both bridging ligands and the axial ligands.The hydrophilic ligands can improve the carbon monoxide release capability of these complexes.3.The oil-water partition coefficient(logP)of the ruthenium carbonyl complexes containing the hydrophilic bridged ligands was determined by shake flask method,and evaluated water solubility of CORMs.The experimental results revealed that the logP range of 1b-6b fluctuating between 0.01 and 1.37,and the logP of 1c-6c spanning the range of-0.29 to 0.32,indicated that there was a positive correlation between water solubility and polymerization degree of polyethylene glycol.The logP of 1d-6d was range from 0.09 to 2.30.The study indicated that the polyethylene glycol groups play an important role in controlling the water solubility of these complexes.4.The cytotoxic activity of the ruthenium carbonyl complexes was evaluated against RAW264.7 cell lines and HCT116 cell lines.According to the MTT experimental results,1a-6a exhibited markedly improved cytotoxic activity under light irradiation against HCT116 cells.The in vitro results indicated that these CORMs have significant anticancer potency and were able to kill cancer cells in the absence of UV light.5.To understand the structure-activity relationship of the ruthenium carbonyl complexes,the degradation pathway was studied by IR and 1H NMR spectroscopic.The results revealed that in the case of 2a formed several ruthenium carbonyl intermediates under UV illumination.IH NMR experimental found that the axial ligands of these complexes were easily replaced by DMSO.Interestingly,the cytotoxicity of the DMSO-substituted products(2a’)was much less than 2a,indicated that the anticancer activity may be derived from sawhorse ruthenium carbonyl complexes containing heterocyclic axial ligands.