title: Novel [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]- 3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2" -dioxide) derivatives with anti-HIV-1 and anti-human-cytomegalovirus activity.
abstract: New [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-d-ribofuranosyl]-3'-spiro-5' '-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide) (TSAO) derivatives substituted at the 4' '-amino group of the spiro moiety with different carbonyl functionalities have been designed and synthesized. Various synthetic procedures, on the scarcely studied reactivity of the 3'-spiroaminooxathioledioxide moiety, have been explored. The compounds were evaluated for their inhibitory effect on both wild-type and TSAO-resistant HIV-1 strains, in cell culture. The presence of a methyl ester (10) or amide groups (12) at the 4''-position conferred the highest anti-HIV-1 activity, while the free oxalyl acid derivative (11) was 10- to 20-fold less active against the virus. In contrast, the presence at this position of (un)substituted ureido or acyl groups markedly diminished or annihilated the anti-HIV-1 activity. Surprisingly, some of the target compounds also showed inhibition of human cytomegalovirus (HCMV) replication at subtoxic concentrations. This has never been observed previously for TSAO derivatives. In particular, compound 26 represents the first TSAO derivative with dual anti-HIV-1 and -HCMV activity.
authors.affiliation: Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: de Castro
authors.forename: Esther
authors.initials: E
authors.lastname: Lobatón
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Pérez-Pérez
authors.forename: Ana
authors.initials: A
authors.lastname: San-Félix
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cordeiro
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: María-José
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Velázquez
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects*; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D054303:HIV Reverse Transcriptase; D013936:Thymidine