Biologically active oligodeoxyribonucleotides. Part 11: The least phosphate-modification of quadruplex-forming hexadeoxyribonucleotide TGGGAG, bearing 3-and 5-end-modification, with anti-HIV-1 activity.

Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.

Bioorg Med Chem. 1998 Dec;6(12):2469-75. Unique Identifier : AIDSLINE MED/99122712
Koizumi M; Koga R; Hotoda H; Ohmine T; Furukawa H; Agatsuma T; Nishigaki T; Abe K; Kosaka T; Tsutsumi S; Sone J; Kaneko M; Kimura S; Shimada K; Exploratory Chemistry Research Lab., Sankyo Co., Ltd, Tokyo,; Japan. koizum@shina.sankyo.co.jp

Abstract: We have found that a hexadeoxyribonucleotide (5'TGGGAG3', R-95288), Koizumi, M. et al. Bioorganic & Medicinal Chemistry, 1997, 5, 2235, bearing a 3,4-dibenzyloxybenzyl (3,4-DBB) group at the 5'-end and a 2-hydroxyethylphosphate at the 3'-end, has high anti-HIV-1 activity and the least cytotoxicity in vitro and in vivo. In order to synthesize more potent hexadeoxyribonucleotides, we substituted phosphodiester (P-O) bonds in the 6-mer with the least phosphorothioate (P-S), phosphoramidate (P-N), or methylphosphonate (P-Me) bonds. When more than two P-N or P-Me bonds were introduced into a 6-mer, the phosphate-modified 6-mers had weak or no anti-HIV- activity, in spite of quadruplex structure formation. However, when P-S bonds were substituted for P-O bonds, anti-HIV-1 activity of their 6-mers did not dramatically decrease, compared with compounds substituted with P-N or P-Me bonds. The results suggest that the formation of a quadruplex structure is not always sufficient for anti-HIV-1 activity of the 6-mer, and that net negative charges derived from P-O or P-S bonds in the quadruplex are important for anti-HIV-1 activity. Moreover, among various phosphate-modified ODNs, we found that the anti-HIV-1 activity of ODN PS7 with only one P-S bond was the same as that of R-95288, both having a high stability in human plasma.

Keywords: JOURNAL ARTICLE Anti-HIV Agents/BLOOD/CHEMISTRY/*CHEMICAL SYNTHESIS/PHARMACOLOGY Base Sequence Benzyl Compounds Cell Survival/DRUG EFFECTS Circular Dichroism Drug Design Drug Stability Human HIV-1/*DRUG EFFECTS Models, Molecular Molecular Structure *Nucleic Acid Conformation Oligodeoxyribonucleotides/BLOOD/CHEMISTRY/*CHEMICAL SYNTHESIS/ PHARMACOLOGY Structure-Activity Relationship
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