title: Synthesis and evaluation of "AZT-HEPT", "AZT-pyridinone", and "ddC-HEPT" conjugates as inhibitors of HIV reverse transcriptase.
abstract: To test the concept that HIV reverse transcriptase could be effectively inhibited by "mixed site inhibitors", a series of seven conjugates containing both a nucleoside analogue component (AZT 1, ddC 2) and a nonnucleoside type inhibitor (HEPT analogue 12, pyridinone 27) were synthesized and evaluated for their ability to block HIV replication. The (N-3 and C-5)AZT-HEPT conjugates 15, 22, and 23 displayed 2-5 microM anti-HIV activity, but they had no effect on the replication of HIV-2 or the HIV-1 strain with the Y181C mutation. The (C-5)AZT-pyridinone conjugates 34-37 were found to be inactive. In marked contrast, the ddC-HEPT molecule 26 displayed the same potency (EC(50) = 0.45 microM) against HIV-1 (wild type and the Y181C nevirapine-resistant strain) and HIV-2 in cell culture. No synergistic effect was observed for these bis-substrate inhibitors, suggesting that the two individual inhibitor components in these molecules do not bind simultaneously in their respective sites. Interestingly, however, the results indicate that the AZT-HEPT conjugates and the ddC-HEPT derivative 26 inhibit reverse transcriptase (RT) in an opposite manner. One explanation for this difference is that the former compounds interact preferentially with the hydrophobic pocket in RT, whereas 26 (after supposed triphosphorylation) inhibits RT through binding in the catalytic site.
authors.affiliation: UMR 176 CNRS/Institut Curie, Section de Recherche, 26 rue d'Ulm, F-75248 Paris Cedex 05, France.
authors.forename: R
authors.initials: R
authors.lastname: Pontikis
authors.forename: V
authors.initials: V
authors.lastname: Dollé
authors.forename: J
authors.initials: J
authors.lastname: Guillaumel
authors.forename: E
authors.initials: E
authors.lastname: Dechaux
authors.forename: R
authors.initials: R
authors.lastname: Note
authors.forename: C H
authors.initials: CH
authors.lastname: Nguyen
authors.forename: M
authors.initials: M
authors.lastname: Legraverend
authors.forename: E
authors.initials: E
authors.lastname: Bisagni
authors.forename: A M
authors.initials: AM
authors.lastname: Aubertin
authors.forename: D S
authors.initials: DS
authors.lastname: Grierson
authors.forename: C
authors.initials: C
authors.lastname: Monneret
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003562:Cytidine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D015394:Molecular Structure; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D016047:Zalcitabine / Q000737:chemistry*; D015215:Zidovudine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C409866:2',3'-dideoxy-4-N-(N-13-(6-(3,5-dimethylphenylthio)-5-ethyl-1-(5-oxopentyl)uracil)-13-azadodecyl)cytidine; C409865:3'-azido-2',3'-dideoxy-5-(N-15-(6-(3,5-dimethylphenylthio)-5-ethyl-1-(5-oxopentyl)uracil)-4,15-diaza-3-oxopentadecanyl)uridine; C409864:3'-azido-2',3'-dideoxy-5-(N-9-(6-(3,5-dimethylphenylthio)-5-ethyl-1-(5-oxopentyl)uracil)-4,9-diaza-3-oxononanyl)uridine; C409863:6-((3,5-dimethylphenyl)-thio)-5-ethyl-1-(4-(methoxycarbonyl)butyl)uracil; D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D011728:Pyridones; D015215:Zidovudine; D014498:Uracil; D003562:Cytidine; D016047:Zalcitabine; D054303:HIV Reverse Transcriptase