Differential interactions of antitumor antibiotics chromomycin A(3) and mithramycin with d(TATGCATA)(2) in presence of Mg2+

The antitumor antibiotics chromomycin A(3) (CHR) and mithramycin (MTR) are known to inhibit macromolecular biosynthesis by reversibly binding to doubl e stranded DNA with a GC base specificity via the minor groove in the prese nce of a divalent cation such as Mg2+. Earlier reports from our laboratory showed that the antibiotics form two types of complexes with Mg2+: complex I with 1:1 stoichiometry and complex II with 2:1 stoichiometry in terms of the antibiotic and Mg2+. The binding potential of an octanucleotide, d(TATG CATA)(2), which contains one potential site of association with the above c omplexes of the two antibiotics, was examined using spectroscopic technique s such as absorption, fluorescence, and circular dichroism. We also evaluat ed thermodynamic parameters for the interaction. In spite of the presence o f two structural moieties of the antibiotic in complex II, a major characte ristic feature was the association of a single ligand molecule per molecule of octameric duplex in all cases. This indicated that the modes of associa tion for the two types of complexes with the oligomeric DNA were different. The association was dependent on the nature of the antibiotics. Spectrosco pic characterization along with analysis of binding and thermodynamic param eters showed that differences in the mode of recognition by complexes I and II of the antibiotics with polymeric DNA existed at the oligomeric level. Analysis of the thermodynamic parameters led us to propose a partial accomm odation of the ligand in the groove without the displacement of bound water molecules and supported earlier results on the DNA structural transition f rom B --> A type geometry as an obligatory requirement for the accommodatio n of the bulkier complex II of the two drugs. The role of the carbohydrate moieties of the antibiotics in the DNA recognition process was indicated wh en we compared the DNA binding properties with the same type of Mg2+ comple x for the two antibiotics. (C) 2001 John Wiley & Sons, Inc.