| Autor: |
Koizumi, Makoto, Koga, Rika, Hotoda, Hitoshi, Ohmine, Toshinori, Furukawa, Hidehiko, Agatsuma, Toshinori, Nishigaki, Takashi, Abe, Koji, Kosaka, Toshiyuki, Tsutsumi, Shinya, Sone, Junko, Kaneko, Masakatsu, Kimura, Satoshi, Shimada, Kaoru |
| Zdroj: |
Bioorganic & Medicinal Chemistry; 1998, Vol. 6 Issue: 12 p2469-2475, 7p |
| Abstrakt: |
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&z.sbnd;O) bonds in the 6-mer with the least phosphorothioate (P&z.sbnd;S), phosphoramidate (P&z.sbnd;N), or methylphosphonate (P&z.sbnd;Me) bonds. When more than two P&z.sbnd;N or P&z.sbnd;Me bonds were introduced into a 6-mer, the phosphate-modified 6-mers had weak or no anti-HIV-1 activity, in spite of quadruplex structure formation. However, when P&z.sbnd;S bonds were substituted for P&z.sbnd;O bonds, anti-HIV-1 activity of their 6-mers did not dramatically decrease, compared with compounds substituted with P&z.sbnd;N or P&z.sbnd;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&z.sbnd;O or P&z.sbnd;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&z.sbnd;S bond was the same as that of R-95288, both having a high stability in human plasma. |
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