5'-Modified G-Quadruplex Forming Oligonucleotides Endowed with Anti-HIV Activity: Synthesis and Biophysical Properties
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- 作者：Jennifer D'Onofrio ; Luigi Petraccone ; Eva Erra ; Luigi Martino ; Giovanni Di Fabio ; Lorenzo De Napoli ; Concetta Giancola ; Daniela Montesarchio
- 刊名：Bioconjugate Chemistry
- 出版年：2007
- 出版时间：July 2007
- 年：2007
- 卷：18
- 期：4
- 页码：1194 - 1204
- 全文大小：502K
- 年卷期：v.18,no.4(July 2007)
- ISSN：1520-4812
文摘
Oligodeoxyribonucleotides of sequence d(5'TGGGAG3') carrying bulky aromatic groups at the 5' end were foundto 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 oflarge aromatic substituents at the 5'-end, were both essential for their antiviral activity. In this work, we synthesizedsome representative examples of the anti-HIV active Hotoda's 6-mers and analyzed the resulting G-quadruplexesby CD, DSC, and molecular modeling studies, in comparison with the unmodified oligonucleotide. In the case ofthe sequence carrying the 3,4-dibenzyloxybenzyl (DBB) group, identified as the best candidate for further drugoptimization, we developed an alternative protocol to synthesize the 5'-DBB-thymidine phosphoramidite buildingblock in higher yields. The thermodynamic and kinetic parameters for the association/dissociation processes ofthe 5'-conjugated quadruplexes, determined with respect to the unmodified one, were discussed in light of themolecular modeling studies. The aromatic groups at the 5' position of d(5'TGGGAG3') dramatically enhance boththe equilibrium and the rate of formation of the quadruplex complexes. The overall stability of the investigatedquadruplexes was found to correlate with the reported IC50 values, thus furnishing quantitative evidence for thehypothesis that the G-quadruplex structures are the ultimate active species, effectively responsible for the biologicalactivity.