Synthesis, Characterization And In Vitro Photocytotoxicity Study Of Platinum(?)of Curcuminoids

Cancer?malignancy?poses a serious threat to people's quality of life.Metal platinum complexes are one of the typical chemotherapeutic agents widely used in the treatment of cancer.However,platinum compounds have a number of deficiencies?such as serious toxic side effects,low bioavailability,and drug resistance.?originating from the rapidity of pharmacokinetics,the lack of tumor selectivity,and poor water solubility of platinum drugs.In recent years,platinum prodrugs have been widely concerned.Excited by endogenous substances?such as GSH overexpressed in cancer cells?,platinum prodrugs can exhibit better antitumor selectivity.Photoactive drugs also have better antitumor selectivity,due to spatial and temporal control of light?exogenous substances?.However,there are still some shortcomings through GSH activation or light activation,individually,such as the toxic side effects produced by the GSH reduction of platinum?IV?prodrugs in normal tissues,the low efficiency of light conversion of prodrugs,and the toxic side effects of the active intermediates or active drugs produced by the prodrugs on the normal cells in the radiation area.Therefore,the combined activation mode of GSH and light may play an important role in improving the precise release of photoactive drugs,achieving synergistic attenuation,and overcoming the resistance of platinum drugs.Oxidative stress is different in normal cells and cancer cells.Increasing intracellular ROS level and changing redox state has become a new targeting strategy to improve the anticancer activity and selectivity of anticancer drugs.Curcumin is an important natural plant polyphenol,which has the functions of anti-tumor,anti-metastasis,anti-angiogenesis,antibacterial,and anti-inflammatory.The structure of phenolic hydroxyl group and?,?-unsaturated ketone in curcumin molecule is not only the structural basis of its important physiological activity,but also part of the reason for its poor stability and low water solubility.The coordination of?-diketones with metal ions and the protection?or removal?of free phenolic hydroxyl groups on the benzene ring can,to a certain extent,improve the water solubility,stability,and pro-oxidant activity of curcumin.Based on the above viewpoints,a series of new platinum?II?complex prodrugs with curcuminoids were designed and synthesized,which have the activation mode of combined GSH and light.Their kinetics and release mechanism were preliminarily explored.The photocytotoxicity of the complexs,the mechanism of the photocytotoxicity of the complexs and the interaction with the biomolecules?CT-DNA,BSA?were also studied.The works are shown as follows:1.Based on the synthesis of curcuminoids from aldehydes with different substituents,a novel series of platinum?II?complexes of curcuminoids were synthesized.These complexes have been characterized by ¹H NMR,¹³C NMR,elemental analysis and HRMS.ESI-MS,¹H NMR and fluorescence were used to investigate the active drug release mechanism.The results indicate that the complexes7j and 7n can release free ligands curcuminoids and platinum?II?intermediates under GSH.The stability of the complexes 7j,7n and the corresponding ligands 5j and 5n were studied by UV-vis.The results indicate that the stability of complexes 7j,7n is greater than that of respective ligands 5j and 5n.Meanwhile,The lipid-water partition coefficients?logP?of the complexes 7e,7j,7n were studied by UV-Vis.The results indicate that logP lies in the following order as 7e>7j>7n.2.The in vitro photocytotoxicity of the platinum?II?complexes against a panel of human carcinoma cell lines including Hela,A549,MCF-7 and MGC-803 were tested by MTT assay.The results indicate that complexe 7j showed the best photocytotoxicity in MCF-7 cells.DCFDA assay was used to investigate intracellular ROS level.The results show that 7j displays higher pro-oxidant properties than 7n.Meanwhile,the mechanism of the photocytotoxicity of the complexs was further studied.The results indicate that under the blue light irradiation,complex 7j could decreased the cell mitochondrial membrane potential???m?and arrested S phase cell cycle,finally induced apoptosis of tumor cells.3.The interaction of complexes 7j and 7n with CT-DNA and BSA were studied by UV-vis,fluorescence,and circular dichroism.The results indicate that both 7j and7n can intercalate with CT-DNA and the interaction between 7j and CT-DNA is stronger than 7n.Meanwhile,complexes 7j and 7n interacted with BSA in 1:1 mode.At the same time,the interaction between 7j and BSA is stronger than 7n.