Structure of TANDEM and its implication for bifunctional intercalation into DNA

Abstract

Quinoxaline antibiotics (Fig. 1a, 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 backbone⁶ and no modifications of the cross-bridge⁷. 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. 1c), which binds preferentially to alternating adenine-thymine sequences⁷. 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.