Synthesis, structure-activity relationships, and mechanism of drug resistance of D- and L-beta-3'-fluoro-2',3'-unsaturated-4'-thionucleosides as anti-HIV agents.
Various D- and L-2',3'-unsaturated 3'-fluoro-4'-thionucleosides (D- and L-3'F-4'Sd4Ns) were synthesized for the studies of structure-activity relationships. The synthesized D-2',3'-unsaturated 3'-fluoro-4'-thionucleosides did not show any significant antiviral activity against HIV-1, while unnatural L-nucleosides such as cytosine 34 (EC(50) = 0.13 microM; EC(90) = 1.7 microM) and 5-fluorocytosine 35 (EC(50) = 0.031 microM; EC(90) = 0.35 microM) derivatives exhibited potent anti-HIV activity without significant toxicity. Molecular modeling study shows that the 3'-fluorine atom of the d-2',3'-unsaturated cytidine triphosphate (D-3'F-4'Sd4CTP) experiences unfavorable electrostatic interaction with its own triphosphate moiety, resulting in the decreased binding affinity to wild-type HIV-1 reverse transcriptase (RT), which may be one of the reasons for the insensitivity of HIV-1 RT to these compounds. On the other hand, L-3'F-4'Sd4CTP binds to the active site of wild-type HIV-1 RT without steric hindrance and there is a possible hydrogen bonding between the 3'-fluorine atom and Asp185, which correlates with its potent anti-HIV activity. However, L-3'F-4'Sd4C 34 and L-3'F-4'Sd4FC 35 showed high cross-resistance to 3TC-resistant mutant (M184V) RT. Like other unnatural L-nucleosides, the unfavorable steric hindrance of the sugar moiety of L-3'F-4'Sd4CTP with the side chain of Val184 explains its significant cross-resistance to the M184V mutant.
Zhu
Wei
W
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia 30602, USA.
Chong
Youhoon
Y
Choo
Hyunah
H
Mathews
Judy
J
Schinazi
Raymond F
RF
Chu
Chung K
CK
D019380:Anti-HIV Agents / 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; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013872:Thionucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D019380:Anti-HIV Agents; D013872:Thionucleosides; D054303:HIV Reverse Transcriptase