Synthesis,characterization And In Vitro Cytotoxicity Study Of Palladium(?) Complex Of Functionalized ?-diketonate

Antitumoral metal complexes have played importment role in the field of bioinorganic chemistry and medicinal chemistry since the discovery of cisplatin.However,due to its serious side effects such as nephrotoxicity,ototoxicity,neurotoxicity and resistance,the application of cisplatin is greatly limited.Therefore,the design,synthesis and antitumor activity study of non-platinum-based anti-tumor complexes has become an important task for bio-inorganic chemical workers.The structural and thermodynamic analogy between platinum(?)and palladium(?)complexes,make palladium complexes become a new class of potential anticancer drugs.Some of ?-diketone compunds exexhibit extent of pharmacological activities,such as antioxidant,antiviral,antibacterial,insecticidal,and potential antitumor activities.As an excellent O,O'-bidentate chelating ligands,?-diketone can form a stable hexagonal chelate ring with the metal ions,which not only can effectively inhibit the hydrolysis of palladium(?)complex,but also can improve the utilization rate of drug.The main works are shown as follows:1.Hispolon is an active ingredient extracted from Phellinus.Numerous studies have explored the medicinal propertie of hispolon,such as antioxidant,anti-inflammatory,anti-cancer and anti-estrogenic activity.Hispolon is non-toxic to most normanl cells and its incorporation into metal complex may effectively reduce the toxic and side effects of metal complex.Based on the synthesis of hispolon and its derivatives from aromatic aldehydes,a series of palladium(?)complexes with hispolon(or its derivatives)and 2,2'-bipyridine have been synthesized through a directed self-assembly approach that involves spontaneous deprotonation of the ?-diketone ligands in H2O/acetone solution.These complexes have been characterized by 1H(13C)NMR,MS and elemental analysis.The cytotoxicity were tested by MTT.The preliminary results showed that complex 2e exhibit significant cytotoxic activity toward Hela,which were significantly better than cisplatin.Further mechanistic studies indicated that complex 2e could increase the level of reactive oxygen species(ROS)in HeLa cells.Complex 2e may disrupted mitochondrial membrane potential and induced apoptosis of tumor cells.The cell cycle indicated that complex 2e could arrest cell cycle progression through the G2/M phase.The complex could interact with ct-DNA through intercalation mode,and quench the fluorescence of BSA by a static quenching mechanism.2.Coumarin,a natural product widely found in nature,has good anti-oxidation,anti-inflammatory,anti-bacterial,anti-tumor and other biological activity.The complex modified by coumarin have a good inhibitory effect on the proliferation of tumor cells.Based on the synthesis of coumarin derivatives from aromatic aldehydes,a series of new palladium(?)complexes(4a-4n)have been synthesized with these ligands and 2,2'-bipyridine.These complexes have been characterized by 1H(13C)NMR,MS and elemental analysis.The tumor growth inhibition test in vitro was done to test the abilities of complexes to inhibit cell growth.The results showed that complex exhibit significant cytotoxic activities toward tumor cell lines.The preliminary results showed that complex 4m have significant inhibition on proliferation of three carcinoma cells.The antitumor activities and mechanisms for complex 4m was also investigated through ROS level,Cell cycle arrest,Annexin V/PI analysis by flow cytometry and mitochondrial membrane potential was measured under the fluorescence microscopy.The results showed that 4m could increase the level of ROS in HeLa cells.Complex 4m may disrupted mitochondrial membrane potential and induced apoptosis of tumor cells.The cell cycle indicated that complex 4m could arrest cell cycle progression through the G2/M phase.The complex could interact with ct-DNA through intercalation mode,and quench the fluorescence of BSA by a static quenching mechanism.