title: 5'-Modified G-quadruplex forming oligonucleotides endowed with anti-HIV activity: synthesis and biophysical properties.
abstract: Oligodeoxyribonucleotides of sequence d(5'TGGGAG3') carrying bulky aromatic groups at the 5' end were found to exhibit potent anti-HIV activity [Hotoda, H., et al. (1998) J. Med. Chem. 41, 3655-3663 and references therein]. Structure-activity relationship investigations indicated that G-quadruplex formation, as well as the presence of large aromatic substituents at the 5'-end, were both essential for their antiviral activity. In this work, we synthesized some representative examples of the anti-HIV active Hotoda's 6-mers and analyzed the resulting G-quadruplexes by CD, DSC, and molecular modeling studies, in comparison with the unmodified oligonucleotide. In the case of the sequence carrying the 3,4-dibenzyloxybenzyl (DBB) group, identified as the best candidate for further drug optimization, we developed an alternative protocol to synthesize the 5'-DBB-thymidine phosphoramidite building block in higher yields. The thermodynamic and kinetic parameters for the association/dissociation processes of the 5'-conjugated quadruplexes, determined with respect to the unmodified one, were discussed in light of the molecular modeling studies. The aromatic groups at the 5' position of d(5'TGGGAG3') dramatically enhance both the equilibrium and the rate of formation of the quadruplex complexes. The overall stability of the investigated quadruplexes was found to correlate with the reported IC50 values, thus furnishing quantitative evidence for the hypothesis that the G-quadruplex structures are the ultimate active species, effectively responsible for the biological activity.
authors.affiliation: Dipartimento di Chimica Organica e Biochimica, Università degli Studi di Napoli Federico II, Complesso Universitario di Monte S. Angelo, via Cintia, 4, I-80126 Napoli, Italy.
authors.forename: Jennifer
authors.initials: J
authors.lastname: D'Onofrio
authors.forename: Luigi
authors.initials: L
authors.lastname: Petraccone
authors.forename: Eva
authors.initials: E
authors.lastname: Erra
authors.forename: Luigi
authors.initials: L
authors.lastname: Martino
authors.forename: Giovanni Di
authors.initials: GD
authors.lastname: Fabio
authors.forename: Lorenzo De
authors.initials: LD
authors.lastname: Napoli
authors.forename: Concetta
authors.initials: C
authors.lastname: Giancola
authors.forename: Daniela
authors.initials: D
authors.lastname: Montesarchio
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D002942:Circular Dichroism; D007700:Kinetics; D008958:Models, Molecular; D009841:Oligonucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D019380:Anti-HIV Agents; D009841:Oligonucleotides