Synthesis of 3' '-substituted TSAO derivatives with anti-HIV-1 and anti-HIV-2 activity through an efficient palladium-catalyzed cross-coupling approach.
Various synthetic studies for the introduction of several functional groups at position 3' ' of the spiro moiety of TSAO derivatives have been explored. Among them, Stille cross-coupling of 3' '-iodo-TSAO derivatives with different stannanes provided an efficient and straightforward route for the direct and selective functionalization of the 3' '-position of the sultone spiro moiety via carbon-carbon bond formation. The compounds synthesized were evaluated for their inhibitory effect on HIV-1 and HIV-2 replication in cell culture. The introduction of a bromine and particularly an iodine at the 3' '-position conferred the highest anti-HIV-1 activity. In contrast, the presence at this position of (un)substituted vinyl, alkynyl, phenyl, or thienyl groups markedly diminished the anti-HIV-1 activity. Surprisingly, several of the 3' '-alkenyl-substituted TSAO derivatives also gained anti-HIV-2 activity at subtoxic concentrations, an observation that is very unusual for NNRTIs and never observed before for TSAO derivatives. Finally, the anti-HIV-1 activity of some of the 3' '-substituted TSAO derivatives is discussed in light of our recently proposed molecular model of interaction of TSAO derivatives with the interphase between the two subunits of HIV-1 reverse transcriptase.
Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, E-28006 Madrid, Spain.
Esther
E
Lobatón
Fátima
F
Rodríguez-Barrios
Federico
F
Gago
María-Jesús
MJ
Pérez-Pérez
Erik
E
De Clercq
Jan
J
Balzarini
María-José
MJ
Camarasa
Sonsoles
S
Velázquez
D002384:Catalysis; D002460:Cell Line; D003198:Computer Simulation; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D006801:Humans; D010165:Palladium; D011485:Protein Binding; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014529:Uridine / Q000031:analogs & derivatives
D013141:Spiro Compounds; D010165:Palladium; D012194:RNA-Directed DNA Polymerase; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine