Studies On Synthesis, Structural Characterization And Antitumor Activity Of Modification Of Containing N Natural Activie Compounds And Their Metal Complexes

Based on some clinical faults of cisplatin and improved strategies for metal-antitumor drugs, in this dissertation, we have synthesized a series of derivatives that some functional groups enhanced anticancer activity are induced from natural and bioactive compounds containing N atom, and some platinum or non-platinum metal compounds are abtained with these derivatives, in which their structures are characterized and their antitumor activities, action mechanism are also studied by a variety of methods. The mainly contents include the following chapters in this dissertation:Chapter one:The prominent clinical faults, active mechanism and improved strategies are summarized for cisplatin anticancer drugs, and the recent progresses in non-platinum metal complexes anticancer agents are also reviewed briefly.Chapter two:We have synthesized thirty derivatives that some amides known to induce apoptosis are applied, and other functional groups of halogens, naphthalene ring enhanced bioactivity are also induced from natural and bioactive aminophosphonate. Corresponding thirty new mononuclear platinum complexes with mono-aminophosphonate esters as the non-leaving group were synthesized and characterized by elemental analysis,1HNMR,13CNMR, ESI-MS spectroscopy, and single crystal X-ray diffraction analysis. Their antitumour activities against a series of cancer cell lines were evaluated. And the primary action mechanisms of anticancer activity were performed for those complexes with better anticancer activity. In addition, we tried to compare their interactions with ct-DNA to cisplatin through circular dichroism spectral analysis, competitive binding studies by fluorescence spectra, agarose gel electrophoresis assay, the results suggest that compared to cisplatin, the synthesized platinum complexes have different action mechanisms with DNA monotonously.Chapter three:We have synthesized two derivatives that the methylenedioxy group known to enhance DNA interaction and pyridine ring were induced from natural and bioactive isoquinolines at C3, C4and C1sites. Two isoquinolines were reacted with different metal salts to give fourteen metal complexes having different coordination modes, including six Cu(Ⅱ), six Zn(Ⅱ) complexes and two Mn(Ⅱ), Ni(Ⅱ) complexes with MPDQ ligand, respectivelly. These complexes were characterized and their crystal structures were determined by single-crystal X-ray diffraction analysis. The in vitro cytotoxicity of compounds1-14against six selected human tumor cell lines is different, in most cases, Cu(Ⅱ) and Zn(Ⅱ) complexes exhibited higher antitumor activity compared with that of Mn(Ⅱ), Ni(Ⅱ) complexes. With complexes1and9as representatives, by means of a series of experiments on cell apoptosis, antitumour activity are achieved through the induction of cell apoptosis correlated the intrinsic pathways of caspase-mitochondria. DNA binding studies indicated that the binding modes of complexes to DNA existed a certain action of intercalation.Chapter four:Three halogenated-oxoglaucine were synthesized by multi-steps reaction firstly. Their structures have been determined by1HNMR,13C NMR, ESI-MS, single-crystal X-ray diffraction analysis. Thirty eight metal complexes using three halogenated-oxoglaucine as ligands were obtained in order to develop bi-functional metal-based antitumor active agents with synergistic effects. Their crystal structures were determined by single-crystal X-ray diffraction analysis. The antitumor activity of three halogenated-oxoglaucine and their metal-based compounds was assayed in cellular levels. The cytotoxicities of these compounds against five tumor cell lines were all tested using MTT colorimetric method. The results indicate that most of these metal-based compounds exhibit enhanced.cytotoxicity against the five selected tumor cell lines compared to the halogenated-oxoglaucine, which display the prominent potent synergistic effects. These compounds present the different inhibition rates on the five tumor cell lines. All compounds exhibited higher antitumor activity against HepG2and HeLa229cell lines. Besides, the fourteen transition metal compounds have the obviously higher antitumor activity than rare-earth compounds.In molecular level, interactions between DNA and these compounds were investigated schematically using various spectroscopic methods, agarose gel electrophoresis experiments. The results show that three halogenated-oxoglaucine interacted with ct-DNA in an intercalation binding mode due to its good planarity and extended cyclic conjugated system; most of these metal-based complexes exhibit some certain extent intercalation with ct-DNA. Also, most of metal-based complexes have distinctly higher intercalation than their ligands; the complexes exhibit different DNA-binding affinity, which may relate to the different metallic ions in nature and different structures of the complexes. Therefore, these results suggest that the possible antitumor action mechanism of these complexes might depend on the blocking DNA replication via the intercalation binding mode. It was assumed that these metal ions might have their functions which facilitate the intercalation style of oxoglaucine into base pairs of DNA via some undetermined mechanisms such as electrostatic interactions or hydrogen bonding.