Synthesis and in vitro activity evaluation of 2',3'-C-dimethyl carbocyclic nucleoside analogues as potential anti-HCV agents.

The first synthetic route of novel 2'(beta),3'(beta)-C-dimethyl carbodine analogues is described. The key intermediate cyclopentenyl alcohol 11(beta) prepared from Weinreb amide 4 via ring-closing metathesis (RCM) and vicinal dihydroxylation. Coupling of 12 with nucleosidic bases via the Pd(0) catalyzed reaction followed by stereoselective dihydoxylation and deprotection afforded the target carbocyclic nucleoside analogues. The synthesized compounds were evaluated as inhibitors of the hepatitis C virus (HCV) in Huh-7 cell line in vitro. However, the nucleosides failed to inhibit HCV RNA replication in the cell-based replicon assay (EC(50) > microM).

Synthesis and antiviral evaluation of novel methyl branched cyclopropyl phosphonic acid nucleosides.

A simple synthetic route for the synthesis of novel methyl branched cyclopropyl phosphonic acid nucleosides is described. The characteristic cyclopropyl moiety 8 was constructed by employing Simmons-Smith reaction as a key step. The condensation of mesylate 11 with natural nucleosidic bases (A,C,T,U) under standard nucleophilic substitution conditions (K2CO3, 18-Crown-6, DMF) and after subsequent hydrolysis resulted in the formation of target nucleosides, 16, 17, 18, and 19. In addition, the antiviral evaluations of the synthesized nucleotides against various viruses were also performed.

Synthesis and biological evaluation of novel 2',3',4'-triply branched carbocyclic nucleosides as potential antiviral agents.

Novel 2',3',4'-triply branched carbocyclic nucleosides were synthesized in this study. The introduction of two methyl groups in the 2'- and 3'-position was accomplished by a Horner-Wadsworth-Emmons reaction and isopropenyl magnesium bromide addition, respectively. The construction of the required 4'-quaternary carbon was carried out using a [3,3]-sigmatropic rearrangement. Bis-vinyls were successfully cyclized using a Grubbs' catalyst II. The natural bases (adenine, cytosine) were efficiently coupled using a Pd(0) catalyst. The antiviral activities of the synthesized compounds were evaluated against HIV-1, HSV-1, HSV-2 and HCMV. Compound 30 displayed moderate anti-HCMV activity (EC50 = 30.1 microg/mL), without exhibiting any cytotoxicity at up to 100 microM.

Novel synthesis of 4'C-aryl-branched acyclic nucleoside using [3,3]-sigmatropic rearrangement.

A very efficient synthetic route for preparing a novel 4'-C-aryl branched-1',2'-seco-2',3'-dideoxy-2',3'-didehydro-nucleoside is described. Mesylate 7 was successfully synthesized via a Horner-Wadsworth-Emmons reaction and a [3,3]-sigmatropic rearrangement, with which an adenine base was coupled by nucleophilic substitution conditions (K2CO3, 18-Crown-6, DMF) to give the target nucleoside 9.

Synthesis and anti-HCMV activity of novel acyclic nucleosides.

A series of novel acyclic nucleosides 10, 11, 21, and 22 were synthesized efficiently starting from D-lactose. The condensation of the mesylate 5 and 16 with an adenine and cytosine base under standard nucleophilic substitution conditions (K2CO3, 18-Crown-6, DMF) afforded a series of acyclic novel nucleosides. Compound 21 displayed moderate anti-HCMV activity in the AD-169 cells (EC50 = 18.5 microg/mL) without exhibiting any cytotoxicity up to 100 microM.

An efficient synthesis of novel carbocyclic nucleosides with use of ring-closing metathesis from D-lactose.

This paper describes an efficient synthetic route for various types of novel carbocyclic nucleosides. The required stereochemistry of the targeted nucleosides was successfully obtained with use of Grubbs cyclization and Trost allylic alkylation from the carbohydrate chiral template "D-lactose".