Interactions of chromomycin A(3) and mithramycin with the sequence d(TAGCTAGCTA)(2)

Anti-cancer antibiotics, chromomycin A(3) (CHR) and mithramycin (MTR) inhib it DNA directed RNA synthesis in vivo by binding reversibly to template DNA in the minor groove with GC base specificity, in the presence of divalent cations like Mg2+. Under physiological conditions, (drug)(2)Mg2+ complexes formed by the antibiotics are the potential DNA binding ligands, Structures of CHR and MTR differ in their saccharide residues. Scrutiny of the DNA bi nding properties reveal significant differences in their sequence selectivi ty, orientation and stoichiometry of binding. Here, we have analyzed bindin g and thermodynamic parameters for the interaction of the antibiotics with a model oligonucleotide sequence, d(TAGCTAGCTA)(2) to understand the role o f sugars. The oligomer contains two potential binding sites (GpC) for the l igands. The study illustrates that the drugs bind differently to the sequen ce. (MTR)(2)Mg2+ binds to both sites whereas (CHR)(2)Mg2+ binds to a single site. UV melting profiles for the decanucleotide saturated with the ligand s show that MTR bound oligomer is highly stabilized and melts symmetrically . In contrast, with CHR, loss of symmetry in the oligomer following its ass ociation with a single (CHR)(2)Mg2+ complex molecule Leads to a biphasic me lting curve. Results have been interpreted in the light of saccharide depen dent differences in ligand flexibility between the two antibiotics.