Structure of TANDEM and its implication for bifunctional intercalation into DNA

Quinoxaline antibiotics (Fig. 1 a, b ) form a useful group of compounds for the study of drug–nucleic acid interactions 1,2 . They consist of a cross-bridged cyclic octadepsipeptide, variously modified, bearing two quinoxaline chromophores. These antibiotics intercalate bifunctionally into DNA 2,3 probably via the narrow groove, forming a complex in which, most probably, two base pairs are sandwiched between the chromophores 4,5 . Depending on the nature of their sulphur-containing cross-bridge and modifications to their amino acid side chains, they display characteristic patterns of nucleotide sequence selectivity when binding to DNAs of different base composition and to synthetic polydeoxynucleotides 4,6,7 . This specificity has been tentatively ascribed to specific hydrogen-bonding interactions between functional groups in the DNA and complementary moieties on the peptide ring 2,4,5 . Variations in selectivity have been attributed both to changes in the conformation of the peptide backbone 6 and no modifications of the cross-bridge 7 . These suggestions were made, however, in the absence of firm knowledge about the three-dimensional structure and conformation of the antibiotic molecules. We now report the X-ray structure analysis of the synthetic analogue of the antibiotic triostin A, TANDEM (des- N -tetramethyl triostin A) (Fig. 1 c ), which binds preferentially to alternating adenine-thymine sequences 7 . The X-ray structure provides a starting point for exploring the origin of this specificity and suggests possible models for the binding of other members of the quinoxaline series.