Synthesis, antiviral activity, and mechanism of drug resistance of D- and L-2',3'-didehydro-2',3'-dideoxy-2'-fluorocarbocyclic nucleosides.
Carbocyclic nucleosides have received much attention due to their interesting biological activity and metabolic stability. Among nucleoside analogues, a fluorine substitution on the carbohydrate moiety or introduction of a 2',3'-unsaturated structure motif has been proven to be successful in producing effective antiviral agents. By combining these structural features, both D- and L-2',3'-dideoxy-2',3'-didehydro-2'-fluoro-carbocyclic nucleosides (D- and L-2'F-C-d4Ns) were synthesized as potential anti-HIV agents. The target D- and L-carbocyclic nucleosides were both stereospecifically synthesized from D-ribose. The structure-activity relationships of synthesized compounds against HIV-1 in activated human peripheral blood mononuclear (PBM) cells were studied, from which we found that the L-2',3'-dideoxy-2'3'-didehydro-2'-fluoroadenosine analogue (L-2'F-C-d4A) 46 showed potent anti-HIV activity (EC50 = 0.77 microM), although it is cross-resistant to the lamivudine-resistant variant (HIV-1M184V). Modeling studies demonstrated a good correlation between calculated relative binding energies and activity/resistance data. The modeling study also indicated that an additional hydrogen bond and a favorable van der Waals interaction contribute to the higher antiviral activity of L-2'F-C-d4A in comparison to its D-counterpart. Also, like other L-nucleosides, the unfavorable steric hindrance of the sugar moiety of L-2'F-C-d4A and the side chain of Val184 could explain the cross-resistance of L-2'F-C-d4A with the M184V mutant. The significant difference of antiviral activity between carbovir and its analogue L-2'F-C-d4G 25 may be due to distortion of the phenyl ring of Tyr115 in the L-2'F-C-d4G-TP/HIV-RT complex, which resulted in a poor pi-pi interaction.
Wang
Jianing
J
College of Pharmacy, The University of Georgia, Athens, Georgia 30602, USA.
Jin
Yunho
Y
Rapp
Kimberly L
KL
Bennett
Matthew
M
Schinazi
Raymond F
RF
Chu
Chung K
CK
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D019259:Lamivudine / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C501696:9-(2',3'-dideoxy-2',3'-didehydro-2'-fluoro-6'-hydroxymethylcyclopent-2-enyl)adenine; D019380:Anti-HIV Agents; D003517:Cyclopentanes; D015224:Dideoxynucleosides; D019259:Lamivudine; D054303:HIV Reverse Transcriptase; D000225:Adenine