Research on L-nucleosides. Synthesis and biological evaluation of a series of L- and D-2',3'-dideoxy-3'-[tris(methylthio)methyl]-beta-pentofuranosyl nucleosides.
Novel nucleoside analogues of both D and L enantiomeric series were prepared by coupling reaction between a 2',3'-dideoxy-3'-modified furanose moiety and four different nucleobases. Though in all cases anomeric mixtures of nucleosides were obtained, the presence of the sterically bulky 3'-tris(methylthio)methyl group allowed a good stereoselectivity level. All the compounds of both enantiomeric series showed high IC(50) values as HSV-1 TK inhibitors and scarce ability to be phosphorylated by HSV-1 TK. In order to overcome possible problems related to the first phosphorylation step and to facilitate the penetration of the molecule through the cellular membrane, a monophosphate prodrug containing a long lipophilic chain was synthesized. No appreciable antiviral activity was exhibited by this molecule.
Mugnaini
Claudia
C
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, via A. Moro, snc, I-53100 Siena, Italy.
Botta
Maurizio
M
Coletta
Massimo
M
Corelli
Federico
F
Focher
Federico
F
Marini
Stefano
S
Renzulli
Michela Lucia
ML
Verri
Annalisa
A
D016475:3T3 Cells; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry*; D018259:Herpesvirus 1, Human / Q000201:enzymology; D020128:Inhibitory Concentration 50; D051379:Mice; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010766:Phosphorylation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D005663:Furans; D009705:Nucleosides; D013937:Thymidine Kinase