Interaction of cationic porphyrin-imidazophenazine conjugates with DNA quadruplex: FID assay and quantum-chemical modeling

Abstract

To study the efficiency of tricationic porphyrin-imidazo[4,5-b]phenazine conjugate and its Zn(II) and Mn(III) complexes as G-quadruplex (G4) DNA ligands. Methods. FID (Fluorescent Intercalator Displacement) assay was used to evaluate the affinity of compounds for a model duplex and Tel22 quadruplex DNA at various ionic strengths. Molecular modeling of the conjugate interaction with G4 DNA was performed using the Density Functional Theory (DFT) calculations with M06-2X functional and 6-31G(d) basis set. Guanine octet stabilized with K + ion was used as a G4 model. Results. DC 50 values and dissociation constants were determined for the complexes of three conjugates with duplex and quadruplex DNA. The structures and energetic parameters of G-octet complexes with Zn-metalated conjugate were obtained. Conclusions. All complexes have a strong affinity to the Tel22 quadruplex. The increase of ionic strength results in an increase in selectivity for quadruplex over duplex DNA and the decrease of binding affinity of the ligands. The structure of ligand-G4 complexes is determined by stacking interaction of porphyrin fragment with G-quartet, rather than an intercalative binging of the ligand.