title: Synthesis and anti-HIV activity of [AZT]-[TSAO-T] and [AZT]-[HEPT] dimers as potential multifunctional inhibitors of HIV-1 reverse transcriptase.
abstract: In an attempt to combine the HIV-inhibitory capacity of 2',3'-dideoxynucleoside (ddN) analogues and non-nucleoside reverse transcriptase (RT) inhibitors (NNRTI), we have designed, synthesized, and evaluated for their anti-HIV activity several dimers of the general formula [ddN]-(CH2)n-[NNRTI]. These dimers combine in their structure a ddN such as AZT and a NNRTI such as TSAO-T and HEPT linked through an appropriate spacer between the N-3 of the thymine base of both compounds. The [TSAO-T]-(CH2)n-[AZT] dimers proved markedly inhibitory to HIV-1. Also, if AZT was replaced by thymidine in the dimer molecules, potent anti-HIV-1 activity was observed. However, although the compounds proved inhibitory to HIV-1, they were less potent inhibitors than the parent compounds from which they were derived. None of the dimers were endowed with anti-HIV-2 activity. In contrast with the TSAO-T monomers, none of the TSAO-T-containing dimers proved markedly cytotoxic to the cells. There was a clear trend toward decreased antiviral potency with lengthening the methylene spacer in the [TSAO-T]-(CH2)n-[AZT] dimers.
authors.affiliation: Instituto de Química Médica (CSIC), Juan de la Cierva, Madrid, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Velázquez
authors.forename: R
authors.initials: R
authors.lastname: Alvarez
authors.forename: A
authors.initials: A
authors.lastname: San-Félix
authors.forename: M L
authors.initials: ML
authors.lastname: Jimeno
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: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D011108:Polymers; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013941:Thymine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014529:Uridine / Q000031:analogs & derivatives; D015215:Zidovudine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D011108:Polymers; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; C061818:1-((2-hydroxyethoxy)methyl)-6-(phenylthio)thymine; D015215:Zidovudine; D054303:HIV Reverse Transcriptase; D013941:Thymine; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine