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.
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.
de Castro
Sonia
S
Instituto de Química Médica (C.S.I.C.), Juan de la Cierva 3, E-28006 Madrid, Spain.
Lobatón
Esther
E
Pérez-Pérez
María-Jesús
MJ
San-Félix
Ana
A
Cordeiro
Alessandra
A
Andrei
Graciela
G
Snoeck
Robert
R
De Clercq
Erik
E
Balzarini
Jan
J
Camarasa
María-José
MJ
Velázquez
Sonsoles
S
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
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D054303:HIV Reverse Transcriptase; D013936:Thymidine