Targeting Human Telomeric G-Quadruplex DNA by Berberine Analogs: A Comparative Biophysical Investigation

Abstract

Nucleic acids are potential target molecules in various anticancer therapies. Understanding how drug molecules interact with nucleic acid has become an active research area at the interface between chemistry, molecular biology and medicine. Berberine is the most widely known alkaloid belonging to the protoberberine group, exhibiting myriad therapeutic applications. The anticancer potency of berberine is thought to emanate from its strong interaction with nucleic acids, and inhibition of the enzymes topoisomerases, telomerases. Berberine also binds strongly to the G-quadruplex structure, an alternative DNA structural motif. The capability of berberine analogs bearing substitution at 9 and 13-position to strongly bind G-quadruplex structure is studied for developing effective anti cancer therapeutics. Compared with berberine, these derivatives exhibit stronger binding affinity with G-quadruplex and the non cooperative binding affinity of berberine was propagated in the analogs also. The circular dichroism studies indicated that the alkaloid bound quadruplex DNA has a fold similar to the unbound form. In all cases, the stoichiometry was found to be one mole of ligand binding per mole of quadruplex. Calorimetric results indicated that the interaction of these analogs with the quadruplex was entropy driven phenomenon. The negative heat capacity changes in all systems along with significant enthalpy-entropy compensation may be correlated to the involvement of multiple weak non-covalent forces in the complexation process. The amino alkyl substitution at 9-position were found to be more effective in stabilizing G-quadruplex structure compared to the phenyl alkyl substitution at 13-position. Detailed studies on these analogs stabilizing telomeric G-quadruplex-DNA through entropy driven process with high binding affinity shall be presented that enable consideration as a leads compounds for telomerase inhibition and anticancer therapy.