Design, Synthesis, And Biological Activity Of Novel Monofunctional Platinum(Ⅱ) Complexes

Platinum-based drugs play an important role in cancer chemotherapy, but the side effects, toxicity, and drug resistance have limited their clinical applications. The structural features and DNA binding modes of monofunctional platinum complexes are different from those of cisplatin but still display an impressive antitumor activity. They have the potential to overcome the drawbacks of traditional platinum-based drugs and become a new class of antitumor drugs.This thesis is divided into four chapters:Chapter 1, the research background and development status of platinum-based antitumor drugs were briefly reviewed. The meanings and methods about the interaction between metal complexes and protein were also introduced.Chapter 2, a new fluorescent monofunctional platinum(II) complex, [PtLCl]Cl(1, L = 4’-bis(pyridine-2-ylmethyl)amino-2-phenylbenzothiazole), was obtained by covalently tethering a fluorophore thioflavin-T(ThT) derivative to a tridentate chelating PtII center. The fluorescence properties, DNA binding ability, cytotoxic activity, and cellular distribution in human cervical cancer(HeLa) cells were studied. The results show the complex exhibits considerable and stable fluorescence, and shows lower cytotoxicity towards the human cervical carcinoma(HeLa), human pulmonary carcinoma(A-549), and human breast carcinoma(MCF-7) compared to cisplatin. The complex could interact with DNA and induce a conformational change in DNA. The study of interaction between complex 1 and 5’-GMP shows the complex has the potential to form monofunctional Pt-DNA adducts in vivo. Confocal fluorescence imaging of complex 1 in HeLa discloses that the complex are permeable through the cell membrane and could enter into cells and could be visualized in living cells. The absence of fluorescence because of the platinum(II) complex in the nucleus does not preclude the possibility that complex 1 could reach the nucleus. The localization studies of the complex in HeLa show complex 1 is preferentially accumulated in mitochondira and partially accumulated in the lysosome apparatus.Chapter 3, the interaction of a mononuclear monofunctional anticancer Pt(II) complex, [PtLCl]Cl(1, L = 4’-bis(pyridine-2-ylmethyl)amino-2-phenylbenzothiazole), which was synthesized in the second chapter, and human serum albumin(HSA) was investigated under physiological conditions using UV-vis absorption, circular dichroism, fluorescence, and synchronous fluorescence. The experimental results suggested that the Pt(II) complex could bind to HSA, induce conformation and microenvironmental changes of HSA with a moderate binding affinity, and quench the intrinsic fluorescence of HSA through a static quenching mechanism. The thermodynamic parameters, ΔGο, ΔHο, ΔSο, calculated at different temperatures, indicated that the binding reaction was spontaneous and hydrophobic forces and π-π stacking played major roles in the association. Based on the number of binding sites, it was considered that one molecule of complex 1 could bind to a single site of HSA. In view of the results of site marker competition experiments, the reactive site of HSA to complex 1 mainly located in subdomain IIA(site I). Moreover, the binding distance, r, between donor(HSA) and acceptor(complex 1) was 4.69 nm according to F?rster nonradiation energy transfer theory.Chapter 4, a new monofunctional platinum(II) complex, [PtLCl]Cl(2, L = N,N-bis(benzothiazol-2-ylmethyl)-5-(dimethylamino)naphthalene-1-sulfonamide), was obtained by covalently tethering a dansyl chloride derivative to a tridentate chelating PtII center. The interaction of complex 2 and human serum albumin(HSA) was investigated under physiological conditions using UV-vis absorption, circular dichroism and fluorescence. The experimental results suggested that the Pt(II) complex could bind to HSA, induce conformation and microenvironmental changes of HSA with a moderate binding affinity, and quench the intrinsic fluorescence of HSA through a dynamic quenching mechanism. The thermodynamic parameters, ΔGο, ΔHο, ΔSο, calculated at different temperatures, indicated that the binding reaction was spontaneous and hydrophobic forces played major roles in the association. Based on the number of binding sites, it was considered that one molecule of complex 2 could bind to a single site of HSA. In view of the results of site marker competition experiments, the reactive site of HSA to complex 2 mainly located in subdomain IIA(site I) or subdomain IIIA(site II). Moreover, the binding distance, r, between donor(HSA) and acceptor(complex 2) was 5.39 nm according to F?rster nonradiation energy transfer theory.