Synthesis and Biological Evaluation of Pyrimidine and Purine α-L-2′,3′-Dideoxy Nucleosides

Abstract

A series of α-L-2′,3′-dideoxy nucleosides was prepared as potential antiviral agents. The pyrimidine nucleosides were prepared by standard Vorbrüggen coupling reactions. The purine analogues were prepared by enzymatic transfer of the dideoxy sugar from a pyrimidine to a purine base. These compounds were inactive against HIV-1, HBV, HSV-1 and -2, VZV, and HCMV.     

Synthesis of 4-Substituted Pyrimidine 2′,3′-Dideoxynucleosides

Abstract

Reaction of 5′-0-(4,4′-dimethoxytriphenylmethyl)-3′-deoxythy-midine with triphenylphosphine/carbon tetrachloride, followed by deprotection of the 5′-hydroxyl group, afforded the 4-chloro derivative 3 from which some 4-substituted pyrimidin-2(1H)one-2′, 3′-dideoxyribosides were obtained by nucleo-philic substitution under very mild conditions.     

Synthesis and Anti-HIV Activity of Carbocyclic Ring-Enlarged 4′,1′a-Methano Oxetanocin Analogues

Abstract

Synthesis of carbocyclic ring-enlarged 4′,1′ a-methano oxetanocin analogues via completely regioselective opening of cyclic sulfites by sodium azide or purine bases is described.     

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′‐quaternary 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.     

Stannylation Approach to the Synthesis of 2′- and 3′-Substituted Analogues of 2′,3′-Didehydro-2′,3′-dideoxynucleosides

Abstract

Three methods are described for the introduction of a tributylstannyl group to the sp²-carbon of 2′,3′-didehydro-2′,3′-dideoxy nucleosides (d44Ns). The resulting stannylated products serve as versatile intermediates for the synthesis of d4Ns having various types of carbon-substituent.     

Synthesis and Anti-HIV-1 Activity of Base Modified Analogues of 3′-Azido-2′,3′-Dideoxythymidine (AZT)

Abstract

Analogues of AZT have been synthesized by modifications at the 4-position of the base. Two synthetic routes are described. Among the new compounds, 3′-azido-2′, 3′-dideoxy-4-thiouridine 2b exhibited an unexpectedly marked anti-HIV activity on CEM-C113 cell lines.     

Synthesis and Anti-viral Properties of 2′,3′-Dideoxy-3′,4′-dihydroxymethyl Substituted Pyrimidine Nucleoside Analogues

Abstract

Some 2′,3′-dideoxy-3′, 4′-dihydroxymethyl nucleoside analogues have been synthesised starting from diacetone-D-glucose. The 3-C-hydroxymethyl group was introduced by selective hydroboration-oxidation of the 3-C-methylene derivative. The 4-C-hydroxymethyl group was obtained by an aldol condensation followed by in situ cross Canizzaro reduction. Glycosylation using silylated pyrimidine bases furnished the 2′,3′-dideoxy-3′,4′-dihydroxymethyl nucleoside analogues.     

Synthesis of 5′-Substituted Analogues of Carbocyclic 3-Deazaadenosine as Potential Antivirals

Abstract

Various 5′-substituted analogues of carbocyclic 3-deazaadenosine (la), a potent antiviral agent, have been prepared and tested against nine viruses.     

Nucleosides and Nucleotides. 125. Synthesis and Biological Evaluation of 2′,3′-Dideoxy-3′-fluoro-2′-methylidene Pyrimidine Nucleosides

Abstract

Reaction of 2′-deoxy-2′-methylidene-5′-O-trityluridine (1) with diethylamino-sulfur trifluoride (DAST) in CH₂Cl₂ resulted in the formation of a mixture of (3′R)-2′,3′-dideoxy-3′-fluoro-2′-methylidene derivative 3 and 2′,3′-didehydro-2′,3′-dideoxy-2′-fluoromethyl derivative 4 (3:4 = 1:1.5) in 65% yield. A similar treatment of 1-(2-deoxy-2-methylidene-5-O-trityl-β-D-threo-pentofuranosyl)uracil (19) with DAST in CH₂Cl₂ afforded (3′S)-2′,3′-dideoxy-3′-fluoro-2′-methylidene derivatives 20 and 4 in 38% and 17% yields respectively. Transformation of the uracil nucleosides 4, 12, and 20 into cytosines followed by deprotection furnished the corresponding cytidine derivatives 29, 18, and 25, respectively. The corresponding thymidine congener 27 was also synthesized in a similar manner. All of the newly synthesized nucleosides were evaluated for their inhibitory activities against HIV and for their antiproliferative activities against L1210 and KB cells.     

Synthesis and Biological Activity of Sugar-Fluorinated 2′,3′-dideoxy-4′-thioribofuranosyl Nucleosides

Abstract

The efficient DAST fluorination of deoxy-4′-thiopyrimidine nucleosides is reported. The cytidine analogue 3b was marginally effective against HIV.     

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′(β),3′(β)-C-dimethyl carbodine analogues is described. The key intermediate cyclopentenyl alcohol 11(β) 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 (EC₅₀ > μM).     

Synthesis and Antiviral Evaluation of 2′,3′-Dideoxy-2′-fluoro-3′-C-hydroxymethyl-β-D-arabinofuranosyl Pyrimidine Nucleosides

Abstract

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

Synthesis of Novel 2′,3′-Didehydro-2′,3′-dideoxyinosine Phosphoramidate Prodrugs and Evaluation of their Anticancer Activity

An efficient synthesis of 4-chlorophenyl N-alkyl phosphoramidates of 2?′,3?′-didehydro-2?′,3?′-dideoxyinosine employing 4-chlorophenyl phosphoroditetrazolide as a phosphorylating agent is reported. Improved method for the synthesis of 2?′,3?′-didehydro-2?′,3?′-dideoxyinosine starting from inosine is also described. The synthesized phosphoramidates 11–18 were examined for their cytotoxic activity in three human cancer cell lines: cervical (HeLa), oral (KB), and breast (MCF-7) employing sulforhodamine B assay. The highest activity in all investigated cancer cell lines was displayed by phosphoramidate 13 with N-n-propyl substituent.     

Stereospecific Synthesis and Anti-HIV Activity of (Z)2′- and (E)3′-Deoxy-2′(3′)-C-(chloromethylene) Pyrimidine Nucleosides

Abstract

Reaction of 1-[2,5(and 3,5)-di-O-trityl-β-D-erythro-pentofuran-3 (and 2)-ulosyl]uracil derivatives 5 and 6 with (chloromethyl)triphenylphosphorane resulted in the stereoselective formation of (E)-3′- and (Z)-2′-chloromethylene derivatives 7 (69%) and 8 (53%), respectively, deprotection of which gave 9 and 10. Transformation of the uracil nucleoside 7 into cytosine one followed by deprotection yielded 12. The latter was converted into the arabinoside 14. The fully deprotected chloromethylene nucleosides were tested for their activity against HIV-1 and HIV-2.     

Simple Synthesis and Anti-Hiv Activity of Novel 3′-Vinyl Branched Apiosyl Pyrimidine Nucleosides

Novel vinyl branched apiosyl nucleosides were synthesized in this study. Apiosyl sugar moiety was constructed by sequential ozonolysis and reductions. The bases (uracil and thymine) were efficiently coupled by glycosyl condensation procedure (persilyated base and TMSOTf). The antiviral activities of the synthesized compounds were evaluated against the HIV-1, HSV-1, HSV-2, and HCMV. Compound 10β displayed moderate anti-HIV activity (EC₅₀ = 17.3 μg/mL) without exhibiting any cytotoxicity up to 100 μM.     

Synthesis of 5-Substituted 2′-Deoxyuridine-5′- Phosphonate Analogues and Evaluation of their Antiviral Activity

A small series of 5-(hetero)aryl-modified nucleoside phosphonates was synthesized via an 8-step procedure including a Wittig reaction and Suzuki–Miyaura coupling. An unanticipated anomerization during phosphonate deprotection allowed us to isolate both anomers of the 5-substituted 2′-deoxy-uridine phosphonates and assess their antiviral activity against a broad panel of viruses.     

Synthesis and Cytotoxic Activity of Novel 5-Substituted-1-(β-L-Arabinofuranosyl) Pyrimidine Nucleosides

A series of new 5-halogeno-1-(ß-L-arabinofuranosyl)uracils and their cytosine analogues were synthesized by halogenation of ara-L-uridine and ara-L-cytidine, respectively. The 5-(2-thienyl) and 5-halogenothienyl derivatives of both series were also prepared in excellent yields by Stille coupling followed by halogenation. All of these syntheses were based on benzoyl-protected derivatives. In vitro cytotoxicity experiments carried out using L1210 mouse leukemia cells showed that 5-(2-thienyl)-ara-L-uridine was the most potent compound of the new compounds; the majority of the analogues were not effective up to 200 μM concentrations.     

Pyrrolo[2,3-d]Pyrimidine Nucleosides: Synthesis and Antitumor Activity of 7-Substituted 7-Deaza-2′-Deoxyadenosines

Abstract

A one step synthesis, using the nucleoside 7-iodo-2′-deoxytubercidin (2b) in a Pd(0)/Cu(I)-catalyzed cross coupling reaction furnished a series of 7-alkynyl-2′-deoxytubercidin derivatives. The 7-iodo-, 7-chloro- or 7-bromo 2′-deoxytubercidins 2b-d as well as certain 7-alkynyl derivatives show significant activity against several tumor cell lines, with 7-iodo-2′-deoxytubercidin (2b) as the most effective compound.     

Synthetic Nucleosides and Nucleotides. XXX.1 Synthesis and Antiviral Activity of 3′-Azido, 2′,3′-Unsaturated and 2′,3′-Dideoxy Derivatives of E-5-Styryl-2′-Deoxyuridine on Human Immunodeficiency Virus

Abstract

Some new 3′-azido, 2′,3′-unsaturated and 2′,3′-dideoxy 5-styryl analogs of deoxyuridine-related compounds have been synthesized and evaluated against human immunodeficiency virus in vitro. Among these compounds, 3′-azido-2′,3′-dideoxy-5-E-styryluridine (6) and 2′,3′-dideoxy-E-5-styryluridine (9) were found to be active, with ED₅₀ values of 5 and 10 μg/ml respectively.     

Synthesis and Biological Evaluation of Pyrimidine Nucleosides Fused with 3′,4′-Tetrahydrofuran Ring

Abstract

Pyrimidine nucleosides fused with 3′,4′-tetrahydrofuran ring were synthesized, starting from 1,2;5,6-di-O-isopropylidene-D-glucose and assayed for antiviral activities. Thymine analogue 1 and its corresponding 2′-deoxy analogue 3 exhibited high cytotoxicity instead of giving antiviral activities.