title: Potential multifunctional inhibitors of HIV-1 reverse transcriptase. Novel [AZT]-[TSAO-T] and [d4T]-[TSAO-T] heterodimers modified in the linker and in the dideoxynucleoside region.
abstract: In an attempt to combine the anti-HIV-inhibitory capacity of nucleoside reverse transcriptase (RT) inhibitors (NRTI) and non-nucleoside RT inhibitors (NNRTI), several heterodimer analogues of the previously reported [AZT]-(CH(2))(3)-[TSAO-T] prototype have been prepared. In these novel series, other NRTIs, an expanded range of linkers with different conformational freedom and other attachment sites for these linkers on the base part of the NRTI analogue have been explored. Moreover, in order to circumvent the dependence of the NRTI moiety of the heterodimer on activation by cellular nucleoside kinases, novel heterodimers in which the NRTI is bearing a masked monophosphate group at the 5'-position are described. Among the novel heterodimers, several derivatives show a potent anti-HIV-1 activity, which proved comparable, or even superior, to that of the AZT heterodimer prototype. The nature of the NRTI was important for the eventual anti-HIV-1 activity. In particular, the d4T heterodimer derivative containing a propyl linker between the N-3 positions of the base of TSAO-T and d4T was approximately 5- to 10-fold more inhibitory to HIV-1 than the corresponding AZT heterodimer prototype.
authors.affiliation: Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, 28006 Madrid, Spain, and Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Velázquez
authors.forename: V
authors.initials: V
authors.lastname: Tuñón
authors.forename: M L
authors.initials: ML
authors.lastname: Jimeno
authors.forename: C
authors.initials: C
authors.lastname: Chamorro
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: M J
authors.initials: MJ
authors.lastname: Camarasa
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D019281:Dimerization; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013141:Spiro Compounds / Q000737:chemistry*; D018119:Stavudine / Q000737:chemistry*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry; D014529:Uridine / Q000031:analogs & derivatives; D015215:Zidovudine / Q000737:chemistry*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D015215:Zidovudine; D018119:Stavudine; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine