title: Cooperative hydrogen bonding in glyco-oligoamides: DNA minor groove binders in aqueous media.
abstract: 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, β-D-Man-Py-γ-Py-Ind (1; Ind=indole, Man=mannose, Py=pyrrole) and β-D-Tal-Py-γ-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-cooperative hydrogen-bonding centers, that is, β-D-Glc-Py-γ-Py-Ind (3; Glc=glucose), β-D-Gal-Py-γ-Py-Ind (4; Gal=galactose), and the model compounds β-D-Man-Py-NHAc (5) and β-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-π 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-π interactions are present.
authors.affiliation: Instituto de Química Orgánica General, IQOG-CSIC, Juan de la Cierva 3, 28006 Madrid (Spain).
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Blázquez-Sánchez
authors.forename: Filipa
authors.initials: F
authors.lastname: Marcelo
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Fernández-Alonso
authors.forename: Ana
authors.initials: A
authors.lastname: Poveda
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.forename: Cristina
authors.initials: C
authors.lastname: Vicent
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D002241:Carbohydrates / Q000737:chemistry*; D002417:Cattle; D004247:DNA / Q000737:chemistry*; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D013696:Temperature; D014867:Water
chemical_list: D000577:Amides; D002241:Carbohydrates; D014867:Water; D004247:DNA; C427203:calf thymus DNA
keywords: DNA; carbohydrates; cooperativity; hydrogen bonds; pi interactions