Structure-activity relationships of 2'-fluoro-2',3'-unsaturated D-nucleosides as anti-HIV-1 agents.
We studied the structure-activity relationships of a series of 2'-fluoro-2',3'-unsaturated D-nucleosides against HIV-1 in human peripheral blood mononuclear (PBM) cells. The target compounds 10-21 and 28-33 were prepared by N-glycosylation of the acetate 4, which was readily prepared from 2,3-O-isopropylidene-D-glyceraldehyde in five steps. Among the newly synthesized nucleosides, 2-amino-6-chloropurine (11), adenine (14), inosine (16), guanine (18), 2,6-diaminopurine (20), and 5-fluorocytosine (30) derivatives were found to exhibit interesting anti-HIV activities with EC(50) values of 4.3, 0.44, 1.0, 2.6, 3.0, and 0.82 microM, respectively. The implications for drug resistance of the titled nucleosides with respect to lamivudine-resistant variants (M184V) were also examined, and no significant cross-resistance with the variants was observed with the D-series.
Lee
Kyeong
K
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, rdag, Athens, Georgia 30602, USA. dchu@rx.uga.edu
Choi
Yongseok
Y
Gumina
Giuseppe
G
Zhou
Wen
W
Schinazi
Raymond F
RF
Chu
Chung K
CK
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D006845:Hydrocarbons, Fluorinated; D009705:Nucleosides