Studies On A Series Of Porphyrin Complexes Targeting G-Quadruplex DNA

The formation of telomeric G-quadruplexes(G4-DNA) has been shown to inhibit the activity oftelomerase,art enzyme that is over expressed in 85%～90%of human cancer cells in comparison to normal somatic cells.Therefore,small molecules that can stabilize or promote G4-DNA structures in telomere would have the potential to be developed into anticancer drugs. In recent years,a considerable number of organic molecules have been synthesized and evaluated for their ability to stabilize G-quadruplex structures and inhibit telomerase.Porphyrins is one of the most valuable compounds in G4-DNA stabilization because of their special structures and spectroscopic properties.Eight compounds were synthesized and confirmed,including four nonionic porphyrins,two cationic porphyrins and two Zn derivatives..Human telomeric oligonucleotide AG22(AGGG(TTAGGG)3) can form anti-parallel G4-DNA structure in the presence of Na~+,this formation is characterized by its particular CD feature.We examined the binding behavior ofporphyrins to G4-DNA formed by AG22 using CD,UV-vis and fluorescence titration in 100 mM NaC1 or KCl at neutral pH.We have found that the 5,10,15,20-tetrakis[3,5-bis(2'-piperidylethoxyl)phenyl]porphyrin can interact with G4-DNA but cannot stabilize the structure.While the other three nonionic porphyrins have no obvious interaction with G4-DNA.All the four cationic porpyrins were found to be capable of binding to G4-DNA,and this resulted in obvious induced CD(ICD) signals at around 440nm,and small bathochromic shift and hypochromicity of the Soret band absorption.Further analysis suggests that the electrostatic attractions between G4-DNA and cationic porphyrins are the most important force.The melting temperature(Tm) measurements indicate that the stabliazation effect of the porphyrins is weak.In a novel triad system,we found that synergetic binding of two ligands,NMM and PIPER, induces the human telomeric G-quadruplex structure transition from antiparallel to parallel in Na~+ solution and significantly enhances its thermostability.An increase of 27.2℃in Tm is observed at molar ratio of 1:1:1.Neither NMM nor PIPER alone has this ability.This is the first finding that synergetic action exists in G-quadruplex ligands,and it provides a novel concept for the future development of telomerase inhibitors.