Synthesis and biological evaluation of 5R- and 5S-methyl substituted D- and L-configuration 1,3-dioxolane nucleoside analogs.
1,3-Dioxolane and 1,3-oxathiolane nucleoside analogs play an important role in anti-viral and anti-neoplastic chemotherapy. We report here the synthesis of 2-hydroxymethyl-5-methyl-1,3-dioxolanylpurine nucleosides from 4-acetoxy-2-(benzyloxymethyl)-5-methyldioxolane. Dioxolanes of alpha-D-, beta-D-, alpha-L-, and beta-L-configuration were prepared, that included 5-methyl derivatives of both 5R and 5S configuration. Molecular mechanics calculations indicate that the 5S and 5R diastereoisomeric 1,3-dioxolanes possess distinct conformational bias, suggesting that methyl substitution may alter the conformational preference of 1,3-dioxolanes. The ability of the 1,3-dioxolanes to inhibit HCV RNA replication was evaluated in a cell-based, subgenomic replicon assay. In addition, activity against vaccinia and HIV was evaluated in cell-based assays. The 2-hydroxymethyl-5-methyl-1,3-dioxolanes were found to be inactive.
Bera
Sanjib
S
Department of Medicinal Chemistry, Isis Pharmaceuticals, Carlsbad, CA 92008, USA.
Malik
Leila
L
Bhat
Balkrishen
B
Carroll
Steven S
SS
Hrin
Renee
R
MacCoss
Malcolm
M
McMasters
Daniel R
DR
Miller
Michael D
MD
Moyer
Greg
G
Olsen
David B
DB
Schleif
William A
WA
Tomassini
Joanne E
JE
Eldrup
Anne B
AB
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004148:Dioxolanes / Q000138:chemical synthesis* / Q000494:pharmacology; D006151:Guanosine / Q000031:analogs & derivatives*; D006678:HIV / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D012367:RNA, Viral / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014616:Vaccinia virus / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004148:Dioxolanes; D009705:Nucleosides; D012367:RNA, Viral; C098394:dioxolane guanosine; D006151:Guanosine