Conformational Stabilization Of G-quadruplex DNA By Metalloporphyrins

Abstract

Formation and stabilization of the human telomeric G-quadruplexed DNA in vitro has been found to inhibit the enzyme telomerase, which is overactivated in tumor cells. Quadruplex interacting agents (QIAs), ligands that bind and stabilize the human telomeric G-quadruplex DNA, have been recognized as potential chemotherapeutic agents. Porphyrins are promising QIAs with the additional versatility of central metal-ion chelation. In the present study we have investigated the effects of various metal ions (Co (III), Cr (III), and Mn (II)) bound to the base porphyrin mesoporphyrin IX (MPIX) on the overall binding selectivity and specificity with the G-quadruplex conformation, using fluorescence, absorbance and circular dichoism spectroscopies. Our data suggests that all three metal-porphyrin derivatives exhibit high binding selectivity for G-quadruplex over double-stranded DNA, and appear to promote a conformational switch from antiparallel to parallel quadruplex conformation. Changes in the metalloporphyrin absorption spectra on binding with the G-quadruplex DNA suggests intercalating, groove binding or external stacking interactions. In addition, melting curve data reveal that all three metalloporphyin derivatives can stabilize the G-quadruplexed DNA over N-methyl mesoporphyrin IX (NMM), with a central methyl group instead of a metal ion, in the order: NMM < Co(III) MPIX < Mn(II) MPIX < Cr(III) MPIX. Consequences of our studies for design of potential new QIAs will be discussed.