Synthesis and antiviral activity of novel D- and L-2'-azido-2',3'-dideoxyribofuranosyl-4'-thiopyrimidines and purines

Novel D- and L-2'-azido-2',3'-dideoxyribofuranosyl-4'-thiopyrimidines and purines have been synthesized starting from L-xylose and D-xylose, respectively. Among synthesized compounds tested against several viruses such as HIV-1, HSV-1, HSV-2, and HCMV, D-beta-N6-methyladenine (ent-22a) and D-alpha-N6-methyladenine (ent-22b) analogues were found to exhibit significant anti-HCMV activity.     

Stereoselective synthesis of beta-L-2',3'-dideoxy- and L-2',3'-didehydro-2',3'-dideoxy purine nucleosides

beta-L-2',3'-Dideoxy- and L-2',3'-didehydro-2',3'-dideoxy purine nucleosides have been synthesized via a highly stereoselective method of glycosylation by the condensation of L-2-(phenylselenyl)-2,3-dideoxyribose derivative with silylated heterocyclic base.     

Synthesis of 2',3'-dideoxy-2'-fluoro-L-threo-pentofuranosyl nucleosides as potential antiviral agents

A series of 2',3'-dideoxy-2'-fluoro-L-threo-pentofuranosyl nucleosides has been synthesized as potential antiviral agents. The synthesized compounds were evaluated against HIV-1, HBV, HSV-1, and HSV-2. Among the synthesized analogues, only the cytosine derivative showed moderate antiviral activity against HIV and HBV.     

Synthesis and antiviral evaluation of 2',3'-dideoxy-2'-fluoro-3'- C-hydroxymethyl-beta-D-arabinofuranosyl pyrimidine nucleosides

The synthesis and anti-HBV and anti-HIV activity of a number of 2',3'-dideoxy-2'-fluoro-3'-C-hydroxymethyl-beta-D-arabinofuranosyl pyrimidine nucleosides are reported.     

Synthesis and anti-HIV activity of beta-D-3'-azido-2',3'-unsaturated nucleosides and beta-D-3'-azido-3'-deoxyribofuranosylnucleosides

Since the discovery of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-didehydro-2',3'-dideoxythymidine (d4T) as potent and selective inhibitors of the replication of human immunodeficiency virus (HIV), there has been a growing interest for the synthesis of 2',3'-didehydro-2',3'dideoxynucleosides with electron withdrawing groups on the sugar moiety. Here we described an efficient method for the synthesis of such nucleoside analogs bearing structural features of both AZT and d4T The key intermediate, 3-azido-1,2-bis-O-acetyl-5-O-benzoyl-3-deoxy-D-ribofuranose, 5 was synthesized from commercially available D-xylose in five steps, from which a series of pyrimidine and purine nucleosides were synthesized in high yields. The resultant protected nucleosides were converted to target nucleosides using appropriate chemical modifications. The final nucleosides were evaluated as potential anti-HIV agents.     

Synthesis of 2',3'-dideoxy-3'-C-(hydroxymethyl)-4'-thiopentofuranosyl nucleosides as potential antiviral agent.

1-O-Acetyl-2,3-dideoxy-3-C-(hydroxymethyl)-4-thiofuranose derivative was synthesized from (S,S)-1,4-bis(benzyloxy)-2,3-epoxybutane derived from (+)-diethyl L-tartrate and the enantiomerically pure (E)-5-(2-bromovinyl)-1-[2',3'-dideoxy-3'-C-(hydroxymethyl)-beta-D-4'- thiopentofuranosyl]uracil 4 was obtained via coupling of silylated uracil followed by palladium-mediated coupling of methyl acrylate.     

Synthesis of 2',3'-dideoxy-2',3'-didehydro nucleosides via a serendipitous route

This paper describes a "green" synthesis of 2',3'-unsaturated 2',3'-dideoxynucleosides via an electrochemical reaction. Using this approach d4T, d4U, ddA and ddI can be synthesized in high yields.     

Synthesis and antiviral activity of novel 2',4'-doubly branched carbocyclic nucleosides

A series of 2' and 4'-doubly branched carbocyclic nucleosides 15, 16, 17 and 18 were synthesized starting from simple acyclic ketone derivatives. The required 4'-quatemary carbon was constructed using Claisen rearrangement. In addition, the installation of a methyl group in the 2'-position was accomplished using a Grignard carbonyl addition of isopropenylmagnesium bromide. Bis-vinyl was successfully cyclized using a Grubbs' catalyst II. Natural bases (adenine, cytosine) were efficiently coupled by using Pd(0) catalyst.     

Synthesis and biological evaluation of novel D-2'-azido-2',3'-dideoxyarabinofuranosyl-4'-thiopyrimidines and purines

Novel D-2'-azido-2',3'-dideoxyarabinofuranosyl-4'-thiopyrimidines and purines have been synthesized, starting from L-xylose via azidation at the 2'-position as a key step. Most of the final nucleosides exhibited toxicity-dependent anti-HIV-1 activity, among which D-alpha-adenine analogue was found to be the most cytotoxic.     

Synthesis and biological evaluation of L- and D-configurations of 2',3'-dideoxy-4'-C-methyl-3'-oxacytidine analogues

Novel L- and D-configuration 2',3'-dideoxy-4'-C-methyl-3'-oxacytidine and their 5-fluoro analogues have been synthesized from 1-benzyloxy-2-propanone and L-ascorbic acid in eight steps and evaluated for biological activity.     

Synthesis, antiviral, and antitumor activity of 2-substituted purine methylenecyclopropane analogues of nucleosides

The Z- and E-2-fluoro- and 2-chloropurine methylenecyclopropanes 9a,b and 10a,b as well as enantiomeric Z-isoguanine methylenecyclopropanes 11a,b and their phenyl phosphoralaninate pronucleotides 11c,d were synthesized and their antiviral activity against several viruses was evaluated. Fluoro analogues 9a and 10a were active against human cytomegalovirus but they were cytotoxic at approximately the same concentrations. Chloro derivatives 9b and 10b were non-cytotoxic and effective against Epstein-Barr virus in Daudi cells. Isoguanine analogues 11a-d lacked antiviral activity but pronucleotides 11c,d were substrates for porcine liver esterase. From the group of 9a,b and 10a,b, the fluoro analogues 9a and 10a exhibited antitumor activity but only the Z-isomer 9a had a selective effect.     

Synthesis of 2',3'-dideoxy-3'-fluoro-L-ribonucleosides as potential antiviral agents from D-sorbitol

2',3'-Dideoxy-3'-fluoro-L-ribonucleosides were synthesized as potential antiviral agents. The key intermediate, methyl 5-O-benzoyl-2,3-dideoxy-3-fluoro-L-ribofuranoside, which was prepared from D-sorbitol, was condensed with pyrimidine and purine bases to obtain the respective nucleosides. Among them, the cytosine analogue 2',3'-dideoxy-3'-fluoro-alpha-L-cytidine showed a moderate anti-HBV activity.     

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.     

Synthesis and anti-HCMV activity of novel 2',3', 4'-trimethyl branched carbocyclic nucleosides

This article reports the synthesis of novel 2',3',4'-trimethyl branched carbocyclic nucleosides. The introduction of a methyl group in the 2' and 3'-position was accomplished by sequential Horner-Wadsworth-Emmons reaction and isopropenyl magnesiumbromide addition, respectively. The construction of the 4'-quaternary carbon needed 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 with the use of a Pd(O) catalyst.     

Synthesis of 2',3'-dideoxy-2'-monofluoromethyl azanucleosides

(2S,4S)-Methyl-N-tert-butoxycarbonyl-4-monofluoromethylpyroglutamate 6 was synthesized via a key dehydrofluorination followed by hydrogenation. Compound 6 was converted to (5S,3S)-N-benzyloxycarbonyl-5-tert-butyldimethylsilyloxymethyl-3-monofluoromethyl-2-pyrrolidone 12 over four steps in 62% yield, which was used as a precursor for the synthesis of 2',3'-dideoxy-2'-monofluoromethyl azanucleosides 17-18.     

Design and synthesis of novel 2',3'-dideoxy-4'-selenonucleosides as potential antiviral agents

On the basis of potent anti-HIV activity of 2',3'-dideoxynucleosides (ddNs), their bioisosteric analogues, 2',3'-dideoxy-4'-selenonucleosides (4'-seleno-ddNs) were first synthesized from a chiral template, d-glutamic acid using stereoselective ring-closure reaction of the dimesylate with Se(2-) and Pummerer type condensation of the selenoxide with nucleobases as key steps. X-ray crystallographic analysis indicated that 4'-seleno-ddNs adopted the same C2'-endo/C3'-exo (South) conformation as anti-HIV active ddNs, but did not show anti-HIV activity, indicating that RT seems to prefer the C2'-exo/C3'-endo (North) conformation on binding with their triphosphates.     

Synthesis and biological evaluation of 2',3'-didehydro-2',3'-dideoxy-9-deazaguanosine, a monophosphate prodrug and two analogues, 2',3'-dideoxy-9-deazaguanosine and 2',3'-didehydro-2',3'-dideoxy-9-deazainosine

2',3'-Didehydro-2',3'-dideoxy-9-deazaguanosine (1), its monophosphate prodrug (2), and two analogues, 2',3'-dideoxy-9-deazaguanosine (3) and 2',3'-didehydro-2',3'-dideoxy-9-deazainosine (4), have been synthesized from benzoylated 9-deazaguanosine (5). Basic hydrolysis of 5, selective protection of the 2-amino and 5'-hydroxy functions with isobutyryl and silyl groups, respectively, followed by reaction with thiocarbonyldiimidazole gave the cyclic thiocarbonate, which, upon reaction with triethyl phosphite, followed by deprotection, afforded 1. Treatment of 1 with phenyl methoxyalaninylphosphochloridate and N-methylimidazole gave 2. Catalytic hydrogenation of 1 gave 3. Hydrodediazoniation of 1 with tert-butyl nitrite and tris(trimethylsilyl)silane gave 4. Compounds 1-4 were found to be inactive against the human immunodeficiency virus and exhibited minimal to no cytotoxic activity against the L1210 leukemia, CCRF-CEM lymphoblastic leukemia, and B16F10 melanoma in vitro.     

Synthesis and antiviral activity of D- and L-isodideoxy nucleosides with exocyclic-methylene.

Novel D- and L-isodideoxynucleosides were synthesized starting from D- and L-xylose and evaluated for antiviral activities against HIV-1, HSV-1, HSV-2, HBV and HCMV, respectively.     

Synthesis and antiviral evaluation of unnatural beta-L-enantiomers of 3'-fluoro- and 3'-azido-2',3'-dideoxyguanosine derivatives

3'-fluoro-2',3'-dideoxy- (3) and 3'-azido-2',3'-dideoxy- (4) beta-L-ribofuranonucleoside derivatives of guanine have been synthesized and their antiviral properties examined. All these derivatives were regioselectively and stereospecifically prepared by glycosylation of 2-N-acetyl-6-O-(diphenylcarbamoyl)guanine 5 with a suitable peracylated L-xylo-furanose sugar 6, followed by appropriate chemical modifications. The prepared compounds were tested for their activity against HIV and HBV viruses, but they did not show significant activity.