Synthesis And Anticancer Activity Of Novel Polypyridine Binuclear Monofunctional Platinum Complexe

Objective:To synthesize a novel polypyridine binuclear monofunctional platinum complex Pt₂-BPA-TPA,and to investigate the characterization,crystal structure,DNA cleavage,toxicity and mechanism of Pt₂-BPA-TPA against human basal epithelial adenocarcinoma cells A549.Methods:Based on the Pt-NNN coordination mode,a novel dual-nuclear single-function Pt（Ⅱ）complex Pt₂-BPA-TPA was prepared with polypyridinyl as the non-leaving group.The characterization of Pt₂-BPA-TPA was determined by nuclear magnetic resonance spectroscopy and resolved mass spectrometry.The crystal structure of Pt₂-BPA-TPA was analyzed by single crystal X-ray diffraction.The cleavage activity of Pt₂-BPA-TPA on plasmid DNA of superhelical p BR322 was studied by agarose gel electrophoresis,and the effect of Pt₂-BPA-TPA on proliferation of A549 cells was analyzed by CCK-8.Protein expression of p21 and cleaved caspase-3 in A549,Hep G2,and H9C2cells was detected by western blotting.Results:A new type of Pt（Ⅱ）binuclear mono-functional complex,Pt₂-BPA-TPA,was prepared using Pt-NNN coordination mode and using polypyridine group as non-leaving group.X-ray diffraction analysis of single crystal shows that Pt₂-BPA-TPA belongs to the P₂₁/c space group of monoclinic system.By agarose gel electrophoresis,it was found that Pt₂-BPA-TPA could effectively cut p BR322 DNA at a low concentration of 10μM.,CCK-8 assay showed that Pt₂-BPA-TPA inhibited the growth of A549 cells,showing higher cytotoxicity than cisplatin 48 h after incubation.Western blot analysis also confirmed that the anticancer mechanism of Pt₂-BPA-TPA involves cisplatin and modulates the protein levels of downstream apoptosis-related proteins,including p21 and cleaved caspase-3 proteins.Conclusions:Based on the Pt-NNN coordination mode,we have successfully prepared a novel dual-nuclear single-function Pt（Ⅱ）complex Pt₂-BPA-TPA using polypyridinyl as the non-leaving group.X-ray diffraction analysis of single crystal shows that Pt₂-BPA-TPA belongs to the monoclinic system with space group P₂₁/c.The cleavage activity of Pt2-BPA-TPA on superhelical plasmid p BR322 DNA was also studied by agar-agar gel electrophoresis,which proved that Pt2-BPA-TPA could effectively cut p BR322 DNA at a low concentration of 10μM.CCK-8 analysis showed that Pt₂-BPA-TPA inhibited the growth of A549 cells,and that Pt₂-BPA-TPA exhibited higher cytotoxicity than cisplatin after 48 h incubation.In addition,western blot analysis provided evidence that the anticancer mechanism of Pt₂-BPA-TPA was involved in up-regulation of important downstream apoptosis-related proteins,including p21 and cleaved caspase-3.In conclusion,Pt₂-BPA-TPA is a novel dual-nuclear single-function Pt（Ⅱ）complex,which is expected to be a new anticancer therapy.