Synthesis And In Vitro Cytotoxicity Studies Of Palladium(?) Complexes With Curcuminoid And Metformin

Cancer is a serious threat to human health.The discovery of cisplatin has opened a new era of cancer treatment,which has greatly stimulated the interest of scientists in the development of metal anticancer drugs.However,the disadvantages of platinum drugs,such as high side effects,low bioavailability and the emergence of drug resistance,limit the further application in the field of cancer treatment.Palladium and platinum belong to homologous elements,and the complexes of palladium?II?and platinum?II?have similar spatial structure and physical and chemical properties.Therefore,palladium?II?complexes have become more and more popular as potential antitumor drugs.Curcumin�a polyphenolic compound extracted from rhizome of turmeric,is an important natural product with michael acceptor structural unit.It has many physiological activities such as antiinflammatory,antioxidation,antiinfection,antitumor.However,the drawbacks of curcumin,such as poor aqueous solubility and stability,low bioavailability,and high dosage,limit its promotion and application.The?-diketone structural unit in the curcumin can coordinate with various metal ions to form a metal complex,which can effectively improve the stability of curcumin and expand the scope of application.Metformin id currently the first-line drug for the treatment of type 2 diabetes?T2D?.Recent studies have shown that metformin also has the function of reducing the incidence and mortality of cancer.As a small molecule drug,metformin has the special advantages of low cost,small toxic side effects,safety and good tolerance.The presence of two cis-imino groups in the biguanide can coordinate with various metal ions as a bidentate chelate ligand,and hydrogen bond donors and acceptor groups in the molecule also contribute to their binding to related biological targets.Therefore,the synthesis of some biguanide metal complexes and their antitumor activity research have attracted the attention of scientists.Based on the above viewpoints,10 palladium?II?complexes with curcuminoid and metformin were designed and synthesized.Based on structural characterization and stability studies,the in vitro cytotoxicity,cytotoxicity mechanism and interaction with biomacromolecules?CT-DNA,BSA?were studied.The works are shown as fllows:1?10 palladium?II?complexes with curcuminoids and metformin were synthesized by the coordination reaction of curcuminoids and metformin palladium nitrate,which was obtained by the reacting of metformin,potassium tetrachloropalladate and silver nitrate.The complexes wre characterized by ¹H NMR,¹³C NMR,HRMS.The stability of the complexes 4a,4e and the corresponding ligands 3a,3e were investigated by UV-vis spectroscopy,and the results indicate that the stability of the complexes 4a,4e is greater than that of the respective ligands 3a,3e.2?The in vitro cytotoxicity of the complexes was tested by MTT assay towards HeLa,A549,MCF-7,MDA-MB-231 and MGC-803 cancer cell lines.The results indicate that the complexes 4a-4j have good cytotoxicity(IC₅₀=1.55³3.78?M),and complex 4a has the greatest cytotoxicity against MDA-MB-231(IC₅₀=1.55?M),which is 16 flod that of the cisplatin.Preliminary mechanism studies have shown that the complex 4e could arrest the cell growth cycle in the S phase and induce a large amount of ROS in a short period of time,which causes damage to the mitochondria and causes a decrease in mitochondrial membrane potential,finally induced apoptosis of tumour cells.3?The interaction of complexes 4a,4e with CT-DNA and BSA was studied by UV-vis spectroscopy and fluorescent spectrum.The experimental results indicate that both complexes4a and 4e can intercalate with CT-DNA and The binding ability of complex 4a to DNA is stronger than that of 4e.The complexes 4a and 4e interacted with BSA in 1?1 mode,and the binding ability of complex 4e to BSA is stronger than that of 4a.