Synthesis,Characterization And In Vitro Cytotoxicity Study Of Naphthalimide ?-diketone Ruthenium (?) Arene Complex

Cancer is a major disease that seriously endangers human health in recent years,and the incidence rate is also increasing year by year.Due to its excellent antitumor efficacy,aryl ruthenium?II?complex has received extensive attention.The ligand,leaving group and aromatic ring type in the aryl ruthenium?II?complex can affect its antitumor activity.Naphthalimide is a kind of nitrogen-containing aromatic heterocyclic compound,which has anti-metastatic and anti-tumor activity.?-diketone is a bidentate ligand,which keto-enol tautomers in the structure enables it to form a stable six-membered chelate ring with metal ruthenium through O,O coordination.Based on this,a series of naphthalimide?-diketone aryl ruthenium?II?complexes were designed and synthesized,and their structures were characterized.On the basis of the stability study of the complexes,the vitro cytotoxicity was determined by MTT assay,and studied the vitro anti-tumor mechanism.The interaction of the complex with CT-DNA and BSA was investigated by UV-vis and fluorescence spectroscopy.The main contents are as follows:1.Two naphthalimide?-diketone derivatives 6a and 6b were synthesized by amidation,formylation and condensation reaction using 3-hydroxy-1,8-naphthalimide as raw material.Next,by coordination reaction with[RuCl₂?cym?]₂ obtained an aryl ruthenium?II?complex with Cl as a leaving group 7a and 7b.Further,a series of functionalized complexes 8a,8b,9a,9b,10a,10b,11a,11b were obtained by the action of PTA and imidazole-modified perfluorooctane,dichloroacetic acid,and ethenic acid.The structures of the complexes were characterized by ¹H-NMR,¹³C-NMR and ESI-HRMS.2.UV-vis studies show that the naphthalimide?-diketone aryl ruthenium?II?complex has good stability.The antitumor activity and structure-activity relationship in vitro studies showed that the types of aryl side chains and leaving groups have a significant effect on the antitumor activity of the complexes.Furthermore,The complex activity of the leaving group with perfluorooctyl imidazole and ethacrynic acid imidazole is superior to the corresponding complex with PTA and dichloroacetic acid imidazole as a leaving group.In them,8b and 11b showed significant cytotoxicity against MCF-7.In addition,complexes 8b and 11b were selected for further mechanism studies.Studies have shown that complexes 8b and 11b can increase the level of reactive oxygen species in MCF-7 cells,arrest cell cycle in G2/M phase.And leads to the decrease of mitochondrial membrane potential that induces the late apoptosis of MCF-7 cells.Studies have also found that complexes 8b and 11b inhibit the migration of triple negative breast cancer MDA-MB-231 cells by inducing the production of reactive oxygen species.3.The binding methods of complexes 7b,8b and 11b with ct-DNA and BSA were studied by UV-vis and fluorescence spectrometry.The results showed that 7b,8b and 11b can interacted with DNA in a nested manner,and 11b had the strongest binding ability with DNA.The fluorescence quenching of BSA with 7b,8b and 11b is static quenching,and 8b has the strongest ability to interact with BSA.