DIFFERENT EFFECTS OF NONINTERCALATIVE ANTITUMOR DRUGS ON DNA TRIPLE-HELIX STABILITY - SN-18071 PROMOTES TRIPLE-HELIX FORMATION

The interaction of the nonintercalating bisquaternary ammonium heteroc yclic drugs SN-18071 and SN-6999 with a DNA triple helix has been stud ied using thermal denaturation and CD spectroscopy. Our data show, tha t both minor groove binders can bind to the triple helix of poly(dA). 2poly(dT) under comparable ionic conditions, but they influence the st ability of the tripler relative to the duplex structure of poly(dA)pol y(dT) in a different manner. SN-18071, a ligand devoid of forming hydr ogen bonds, can promote tripler formation and thermally stabilizes it up to 500 mM Na+ concentration. SN-6999 destabilizes the tripler to du plex equibilirium whereas it stabilizes the duplex. The binding consta nt of SN-18071 is found to be greater than that to the duplex. The sta bilizing effect of SN-18071 is explained by electrostatic inetractions of three ligand molecules with the three grooves of the triple strand ed structure. From the experiments it is concluded that SN-6999 binds to the triplex minor groove thereby destabilizing the tripler similar as previously reported for netropsin.