Design, Synthesis And Biological Activities Of Small Organic Molecules And Metal Complexes With DNA- And BSA-binding Ability

Nucleic acids and proteins are not only the primary substances constituting the life entity, but also the main targets for many drugs to work. Hence, the research of the interaction of small organic molecules and metal complexes with nucleic acids and proteins can provide important biological chemistry basis for rational design, synthesis and antineoplastic activity research of the novel high-efficient, high selective, harmfulless antitumor drugs. In this paper, a series of dinuclear metal complexes with N,N’-bis(substituent)oxamides as bridging ligands were designed, synthesized and characterized via single-crystal X-ray diffraction. Their DNA- and BSA-binding activities well as in vitro antitumor activities were studied systematically and comprehensively. The detailed contents are as follows:1. Interaction between small organic molecules and DNA as well as BSA:In this section, the previously obtained oxadiazole derivatives a-c, triazole derivatives d-g and oxamide derivatives h and i were chosen as research objects, and were structurally characterized by elemental analysis, IR, mass spectra and so on. The single-crystal structures of compounds h and i were obtained and analyzed. The interaction between these compounds and herring sperm DNA (HS-DNA) as well as bovine serum albumin (BSA) were studied by electronic and fluorescence spectra and viscosity measurements. The interaction mode and the binding ability of these compounds with DNA, as well as the BSA quenching mechanism and binding site were further discussed. The results indicate that the binding ability of the compounds interacting with DNA by intercalation is stronger than that of compounds interacting with DNA by groove mode. The compounds containing electron-withdrawing substituent groups can enhance their DNA-binding ability for whether intercalation or groove mode. All of the studied compounds can interact with BSA, and the binding site of these organic small molecule compounds with BSA may be the Trp-212 residue in the hydrophobic pocket inside BSA.2. Design, synthesis and structures of oxamide ligands and their dinuclear complexes:With consideration of the excellent bridged ability and favorable biological activity of the oxamide derivatives, N-(5-chloro-2-hydroxyphenyl)-N’-(3-aminopropyl)oxamide (H3chapoxd) and N-(5-chloro-2-hydroxyphenyl)-N’-[3-(diethylamino)propyl]oxamide (H3chdepoxd) were synthesized. With these two compounds as bridging ligands and changing the terminal ligands, reaction condition and metal ions, we synthesized nine dinuclear copper(II) complexes, [Cu2(chapoxd)Cl(H2O)(bpy)]Cl·3H2O (1). [Cu2(chapoxd)(H2O)(bpy)](ClO4)CH3CN (2)、[Cu2(chapoxd)(CH3CH2OH)(Me2bpy)] (ClO4) (3)、[Cu2(chapoxd)(H2O)(phen)] (NO3)·H2O (4)、[Cu2(chapoxd)(H2O)(phen)](NO3)-CH3OH (5)、[Cu2(chapoxd)(H2O)-(dabt)](ClO4)·2H2O (6)、[Cu2(chdepoxd)(H2O)(Me2bpy)](ClO4)·DMF (7) [Cu2(chdepoxd)(H2O)(dabt)](ClO4)·H2O (8)、[Cu2(chdepoxd)(CH3OH)(phen)](ClO4) (9), and a dinuclear nickel(Ⅱ) complex [Ni2(chdepoxd)(bpy)2](ClO4) (10). They were structurally characterized by elemental analysis, IR, NMR, mass spectra and X-ray single crystal diffraction technology.3. Interaction of oxamide ligands and their dinuclear complexes with DNA: The DNA-binding activities of the oxamide ligands H3chapoxd and H3chdepoxd as well as their dinuclear complexes (1)～(10) were studied by electronic and fluorescence spectra, electrochemial titration and viscosity measurements. The influence of the bridging ligands, terminal ligands, reaction solvent and metal ion on the DNA-binding abilities was discussed. The results indicate that the ligands and the complexes all interact with HS-DNA by intercalation. The better planarity of the terminal ligands in the complexes is in favor of the interaction between the complexes and DNA, while the enlarged steric hindrance of the terminal ligands goes against such interaction. The increase of hydrophobic forces of the bridging ligands can enhance the interaction between the complexes and DNA. The DNA-binding activity of dinickel(Ⅱ) complex is weaker than those of dicopper(Ⅱ) complexes.4. Interaction of oxamide ligands and their dinuclear complexes with BSA: The BSA-binding activities of the oxamide ligands H3chapoxd and H3chdepoxd as well as their dinuclear complexes (1)～(10) were studied by electronic spectra and tryptophan fluorescence quenching experiment. The results indicate that the ligands and the complexes can all interact with BSA and their quenching mechanism for extincting BSA endogenous fluorescence is static quenching. There is only one binding site between the studied compounds and BSA, hydrophobic Trp-212 residue inside BSA for oxamide ligands, while hydrophilic Trp-134 residue on the surface of BSA for the complexes.5. In vitro antitumor activity of small organic molecules and metal complexes:The in vitro antitumor activities of small organic molecules a-i, oxamide ligands H3chapoxd and H3chdepoxd, and dinuclear metal complexes (1)～(10) against human hepatocellular carcinoma cell line SMMC-7721 and human lung adenocarcinoma cell line A549 were studied through Sulforhodamine B (SRB). The results indicate that, all the studied compounds exhibit certain inhibition against the two selected cell lines, and their IC50 values is within the scope of 16.9-95.1 μg/mL. The DNA-binding activities of the studied compounds have obvious correlation with their in vitro antitumor activities, implying that the studied compounds might target DNA to show their in vitro antitumor activities.