Metal-organic Cages: Synthesis And Nucleic Acid Binding Studies

Nucleic acid is one of the important targets of anticancer drugs.Particularly,human telomere G-quadruplex DNA secondary structure have attracted much attention since it can effectively inhibit the activity of telomerase and the growth of tumor cells.New metal organic complexes are promising in anticancer drug research due to their flexible structure,their highly positive charge contributing to the interaction with DNA phosphoric acid skeleton.In this paper,we aimed to find new type of metal-organic cages with high stabilization of G-quadruplex DNA,and further explore their structural factors influencing G-quadruplex DNA binding abilities.The binding mechanism of G-quadruplex DNA interaction was also investigated.And the research work is mainly done from the following three aspects:1.G-quadruplex DNA binding properties and anticancer properties of flexible tetrahedral metal-organic cages were firstly studied.A series of chiral tetrahedral metal-organic cages(R-1/S-1,R-2/S-2,R-3/S-3,R-4/S-4)with flexible ligands have been synthesized.X-ray single crystal diffraction confirmed the successful synthesis of the tetrahedral cage structure with a high degree of stereochemical purity(???? or ????).The binding interaction and mode of action between metal-organic cages and G4-DNA were studied by UV-vis,circular dichroism(CD),fluorescence resonance energy transfer(FRET)experiments.And the anticancer properties of metal-organic cages were further investigated by cytotoxicity assay.The results showed that the tetrahedral metal-organic cages had a strong binding ability to G4-DNA(Kb=1.13×105-5.66×105 M-1),and had strong stabilization effect on anti-parallel G4-DNA(?Tm=19.2-25.1 °C).Their enantiomers ???? and ???? showed enantioselective selectivity towards G-quadruplex DNA.The end-stacking binding mode can be inferred,and R-3/S-3 showed the strongest stabilization effect on the G4-DNA.The cytotoxicity test indicated that the metal-organic cages had different inhibitory effect on different cancer cells,among which R-3/S-3 and R-4/S-4 were the most promising anti-cancer drugs.2.The interaction between rigid tetrahedral metal-organic cages and G-quadruplex DNA was investigated and the structure–activity relationship of cages for G4 interactions was further explored.A series of rigid tetrahedral metal-organic cages 1-7 with different ligands,metal ion and overall charge were synthesized and characterized by IR,~1H NMR,mass spectrometry and elemental analysis.The structure of the tetrahedral metal-organic cages 1 and 4 were confirmed by X-ray single crystal diffraction.Their binding properties with G-quadruplex DNA were investigated by a series of experiments.Compared with the chiral tetrahedral metal organic cages,the rigid nickel(II)tetrahedral cages 1-2 and 7 with eight positive charges showed much better binding abilities to G-quadruplex DNA(Kb=2.29×106-4.35×106 M-1)and enhanced stabilization of anti-parallel G4-DNA(?Tm=39.1-41.7 °C).The iron cages 3 and 4 showed lower binding abilities with G-quadruplex than nickel cages(?Tm=18.33-24.80 °C).What's more,the tetrahedral cages 5 and 6 with four negative charges were shown to be inefficient for stabilizing G4-DNA(?Tm <1 °C).These results indicated that central metal ion,overall charge and structural rigidity of metal-organic cages played important roles in G4 DNA stabilization.3.The interaction between two rigid cubic porphyrin metal-organic cages and G-quadruplex DNA was investigated.Cubic porphyrin metal-organic cages 8 and 9 with a unique large ? conjugated system and 16 positive charges were synthesized and characterized by a series of spectroscopic characterization.The binding results between two metal-organic cages and G-quadruplex DNA indicated that cages 8 and 9 stacked on the terminal G-quartets with high electrostatic interaction.The metal-organic cages showed strong affinities toward G-quadruplex DNA(Kb=3.89×106-5.02×106 M-1),and exhibited highly effective stabilization of antiparallel G-quadruplex DNA(?Tm=32.46-41.68 °C,0.50 ?M).Among them,cubic cage 8 based on the porphyrin amine(TAPP)and pyridine ligand showed stronger binding abilities toward G-quadruplex DNA than cage 9 which is based on metalloporphyrin amine(Zn-TAPP)and pyridine ligand.