Cooperative Hydrogen Bonding in Glyco-Oligoamides: DNA Minor Groove Binders in Aqueous Media

A strategy to create cooperative hydrogen-bonding centers by using strong and directional intramolecular hydrogen-bonding motifs that can survive in aqueous media is presented. In particular, glyco-oligoamides, a family of DNA minor groove binders, with cooperative and non-cooperative hydrogen-bonding donor centers in the carbohydrate residues have been designed, synthesized, and studied by means of NMR spectroscopy and molecular modeling methods. Indeed, two different sugar moieties, namely, beta-D-Man-Py-gamma-Py-Ind (1; Ind = indole, Man = mannose, Py = pyrrole) and beta-D-Tal-Py-gamma-Py-Ind (2; Tal = talose), were chosen according to our design. These sugar molecules should present one-or two-directional intramolecular hydrogen bonds. The challenge has been to study the conformation of the glyco-oligoamides at low temperature in physiological media by detecting the exchangeable protons (amide NH and OH resonances) by means of NMR spectroscopic analysis. In addition, two more glyco-oligoamides with non-coop-erative hydrogen-bonding centers, that is, beta-D-Glc-Py-gamma-PyInd (3; Glc = glucose), beta-D-Gal-Py-gamma-Py-Ind (4; Gal = galactose), and the model compounds beta-D-Man-Py-NHAc (5) and beta-D-Tal-Py-NHAc (6) were synthesized and studied for comparison. We have demonstrated the existence of directional intramolecular hydrogen bonds in 1 and 2 in aqueous media. The unexpected differences in terms of stabilization of the intramolecular hydrogen bonds in 1 and 2 relative to 5 and 6 promoted us to evaluate the influence of CH-pi interactions on the establishment of intramolecular hydrogen bonds by using computational methods. Initial binding studies of 1 and 2 with calf-thymus DNA and poly(dA-dT)(2) by NMR spectroscopic analysis and molecular dynamics simulations were also carried out. Both new sugar-oligoamides are bound in the minor groove of DNA, thus keeping a stable hairpin structure, as in the free state, in which both intramolecular hydrogen-bonding and CH-pi interactions are present.