Novel series of TSAO-T derivatives. Synthesis and anti-HIV-1 activity of 4-, 5-, and 6-substituted pyrimidine analogues.
Several 4-, 5-, and 6-substituted pyrimidine analogues of the new anti-HIV-1 lead compound [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]thymine] -3'-spiro-5''-(4''-amino-1'',2''-oxathiole 2'',2''-dioxide) (TSAO-T) have been prepared and evaluated as inhibitors of HIV-1 and HIV-2 replication in cell cultures. Reaction of 1,2-di-O-acetyl-5-O-benzoyl-3-C-cyano-3-O-mesyl-D-ribofuranose with 5-substituted pyrimidine bases, followed by treatment with Cs2CO3, afforded, stereoselectively, beta-D-ribofuranosyl-3'-spironucleosides. 2',5'-O-Deacylation and subsequent treatment with tert-butyldimethylsilyl chloride gave the TSAO-5-substituted pyrimidine derivatives. Reaction of 5-halogen-TSAO derivatives with nucleophiles gave 6-substituted-TSAO analogues. Treatment of TSAO-pyrimidine analogues with POCl3/1,2,4-triazole and methylamine or di-methylamine afforded the 4-substituted pyrimidine compounds. Several substituted TSAO-thymine, TSAO-uracil, and TSAO-cytosine derivatives were found to be superior to their unsubstituted TSAO congeners with regard to their antiviral and/or cytotoxic properties.
San-Félix
A
A
Instituto de Química Médica (CSIC), Madrid, Spain.
Velázquez
S
S
Pérez-Pérez
M J
MJ
Balzarini
J
J
De Clercq
E
E
Camarasa
M J
MJ
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002478:Cells, Cultured; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014529:Uridine / Q000031:analogs & derivatives
D000998:Antiviral Agents; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D054303:HIV Reverse Transcriptase; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine