Synthesis And Antitumor Activity Of Biological Functional Complexes Containing Platinum And Palladium

Cancer is a disease with high mortality rate in the world nowadays, and is treatedby surgical removal, chemotherapy and immunotherapy adopted recently. Cisplatin，achemotherapy drug that was discovered by chance, made tremendous success inclinical, which greatly promote the design and application of metal anticancer drug.However, the efficacy of cisplatin is largely limited by drug resistance and side effects.To overcome these defects and broaden the spectrum of anti-cancer activity,polynuclear platinum complexes have received considerable interests because theyform different DNA adducts compared to cisplatin. On the other hand, given that theshortcomings of platinum-based drugs, many new non-platinum complexes withdifferent pharmacology have been synthesized in order to improve and supplementcurrent platinum drugs. Among them, Pd (II) complexes which possesses the samesquare planar configuration with Pt (II) complexes, is one of compounds moreresearched in recent years.First of all, since most polyamine-bridged polynuclear platinum complexes witheach coordinating nitrogen acting as a monodentate ligand are susceptible to sulfurbiomolecule, leading to chemical degradation and inactivation and producing hightoxicity. While bulkier non-leaving groups or chelating ligands could reduce thedeactivation of platinum compounds caused by sulfur-containing molecules, whichcould ameliorate the biostability and bioavailabilty of the complexes. Yet, currently,there is little research on polynuclear chelating platinum anticancer complexes, whilethe structure-activity relationship of such complexes is not yet explored. In view ofthis, in this thesis, we respectively selected flexible triethylamine and rigid2,4,6-tris(4-methylphenyl)-1,3,5-triazine to link three Pt (BPA)(BPA=bis (2-pyridylmethyl)amine) coordination groups to form two3N-chelate trinuclear platinum complexes,and compared their DNA binding ability and anti-tumor activity. UV-visible,fluorescence and circular dichroism spectroscopy all showed that enhancing therigidity of the complex may increase DNA binding ability of such trinuclear platinum complexes. Moreover, the result of ESI-MS following reaction between complexes andGSH shows that flexible complex was decomposed by GSH, but rigid complex formmonoGS adduct with GSH and keeps the trinuclear skeleton stable for24h. Theseresults provided a basis for further understanding of anticancer mechanism of thepolynuclear chelating platinum complexes, and performed as guidance for the futuredesign of new polynuclear chelating platinum complexes with highly anti-tumoractivity.Additionally，owing to remarkable antitumor activity of polynuclear complexes andmode of action different from cisplatin as well as few trinuclear Pd(II) complexeshave been reported on antitumor activities, we designed three different rigid andflexible trinuclear Pd(II) complexes and investigate the stiffness&flexibility ofcomplexes how to influence their anticancer activity. The results demonstrate thatalthough rigidity of complex may improve the DNA binding ability, the trinuclearPd(II) complexes which combine the flexibility and rigidity in one complex exhibitedthe highest DNA unwinding affinity and the most potent cytotoxicity. These resultsenlarge the field of palladium-based antitumor agents and offer some new clues todesigning Pd(II) based drugs of higher activity and low side effects.