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 and Anticancer Activity of 3-(3-Oxoprop-1-enyl)-Substituted Analogues of Carbocyclic Pyrimidine Nucleosides and 2′,3′-Dideoxy Pyrimidine Nucleosides

Abstract

Various 2′, 3′ -dideoxy and carbocyclic pyrimidine nucleosides, and their corresponding 3-(3-oxoprop-1-enyl) derivatives, have been synthesized and evaluated against murine L1210 and P388 leukemias and Sarcoma 180 and human CCRF-CEM lymphoblastic leukemia. Among the compounds tested, 3-(3-oxoprop-1-enyl)-3′ -fluoro-3′ -deoxythymidine (17), 3-(3-oxoprop-1-enyl)-3′ -azido-3′ -deoxythymidine (15) and 3-(3-oxoprop-1-eny!)-(+)-1-[(lα, 3β, 4α)-3-hydroxy-4-(hydroxymethyl)cyclopentyl]-5-methyl-2,4 (lH,3H)pyrimidinedione (6) were found to be the most active with ED₅₀, values of 0.5,0.2,0.1, and 0.3 μM; 1.2, 0.5,1.0 and 1.0 μM; and 0.8,0.7,1.5, and 3.0μM, respectively. Our preliminary findings indicate that the 3-(3-oxoprop-1-enyl) derivative of carbocyclic thymidine is approximately 7 times more active than the 3-(3-oxoprop-1-enyl) derivative of carbocyclic thymine riboside against L1210 leukemia cells in vitro, with ED₅₀ values of 0.8 μM and 5.5 μM, respectively. These findings suggest that the cytotoxicity of these compounds not only is dependent upon the 3-(3-oxoprop-1-enyl)-substituted group, but also may vary with the sugar moiety.     

Design,Synthesis and Antiviral Activity of α-L-Arabinofuranosyl Derivatives of 2-Substituted-5,6-dichlorobenzimidazoles

Abstract

A number of 2-substituted-5,6-dichloro-l-(α-L-arabinofuranosyl)benzimidazoles have been prepared by condensation of 2-bromo-5,6-dichlorobenzimidazole or 2,5,6-trichlorobenzimidazole with tetra-O-acetyl-L-arabinofuranose. 2-Alkylamino derivatives were prepared by a substitution of the 2-chloro group with the appropriate amines. All target compounds were evaluated for activity against HCMV and HSV-1. The 2-chloro and 2-bromo derivatives showed moderate activity against HCMV at non-cytotoxic concentrations.     

Synthesis of 5′-Thioalkyl,Sulfoxide and Sulfone Pyrimidine Nucleosides

Abstract

The preparation of 5′-thioalkyl, sulfoxide and sulfone pyrimidine nucleosides is [4–11] is described. The key steps of this synthesis are the nucleophilic displacements of a chlorine by a thioalkyl sodium salt or the direct introduction of the thioalkyl group under Mitsunobu conditions.     

Nucleosides and Nucleotides. 140. Synthesis and Antileukemic Activity of 5-Carbon-Substituted 1-β-d-Ribofuflranosylimidazole-4-Carboxamides

Abstract

Synthesis of 5-carbon-substituted 1-β-d-ribofuranosylimidazole-4-carboxamides are described. Treatment of 5-iodo derivative 8 with methyl acrylate in the presence of palladium catalyst gave (E)-5-(2-carbomethoxyvinyl)-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxamide (9), followed by appropriate manipulations to afford various 5-carbon-substituted imidazole derivatives 1–7. The antileukemic activities of these imidazole nucleosides are also described.

     

Synthesis of Some Novel 1-(5-Thio-ß-D-glucopyranosyl)-6-azauracil Derivatives - Thiosugar Nucleosides

Abstract

The chemical syntheses of 1-(2,3,4,6-tetra-0-acety]-5-thio-β-D-glucopyranosyl)-6-azauracil (4) and the 5-bromo analogue 6 are described. Deblocking of 4 and 6 with sodium methoxide afforded the free nucleosides 5 and 7, respetively. Treatment of 6 with benzylmercaptan in basic medium led to the formation of 6-benzylthio-1-((2,3,4,6-tetra-0-acetyl-5-thio-β-D-glucopyranosyl)-6-azauracil (8), in good yield, which was deblocked to 9 on treatment with sodium methoxide. Reaction of 6 with benzlamine gave 5-benzylamino-1-(5-thio-β-D-glucopyranosyl)-6-azauracil (10).     

Synthetic Nucleosides and Nucleotides. XX1. Synthesis of Various 1-β-D-Xylofuranosyl-5-Alkyluracils and Related Nucleosides

Abstract

Treatment of D-xylose (1) with 0.5% methanolic hydrogen chloride under controlled conditions followed by benzoylation and acetolysis afforded crystalline 1-O-acetyl-2, 3, 5-tri-O-benzoyl-α-D-xylofuranose (4) in good yield. Coupling of 4 with 2, 4-bis-trimethylsilyl derivatives of 5-alkyluracils (methyl, ethyl, propyl and butyl) (5a-5d), 5-fluorouracil (5e) and uracil (5f) in acetonitrile in the presence of stannic chloride gave 1-(2,3,5-tri-O-benzoyl-β-D-xylofuranosyl)-nucleosides (6a-6f). Saponification of 6 with sodium methoxide afforded 1-β-D-xylofuranosyl-5-substituted uracils (7a-7f). Condensation of 4 with free adenine in similar fashion and deblocking gave carcinostatic 9-β-D-xylofuranosyladenine (7g).     

Synthesis of 1′-C-Cyano Pyrimidine Nucleosides and Characterization as HCV Polymerase Inhibitors

Ribose modified 1′-C-cyano pyrimidine nucleosides were synthesized. A silver triflate mediated Vorbrüggen reaction was used to generate the nucleoside scaffold and follow-up chemistry provided specific ribose modified analogs. Nucleosides and phosphoramidate prodrugs were tested for their anti-HCV activity.     

Synthesis of N-1β-D-Arabinofuranosyl and N-1-2′-Deoxy-β-D-erythro-pentofuranosyl Thieno [3,2-d] Pyrimidine Nucleosides

Abstract

Synthetic methods for 1-(β-D-arabinofuranosyl) and 1-(2-deoxy-β-D-erythro-pentofuranosyl)thieno[3,2-d]pyrimidine-2,4-diones from the orresponding 1-(β-D-ribofuranosyl) nucleoside have been developed in this report. These compounds were tested against HIV-1 in CEM cl 13 cell cultures, but none of them exhibited significant inhibitory activity against this virus.     

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.     

Synthesis and Antiviral Evaluation of Novel 5′-Norcarboacyclic Phosphonic Acid Nucleosides

This article describes a very simple route for synthesizing a novel 5′-norcarboacyclic nucleotides. The condensation of the mesylates 17 and 18 with the natural nucleosidic bases (A,U,T,C) under standard nucleophilic substitution (K₂CO₃, 18-Crown-6, DMF) and deprotection afforded the target nucleotide analogues 27–34. In addition, these compounds were evaluated for their antiviral properties against various viruses.     

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.     

Nucleosides and Nucleotides. 106. Synthesis and Biological Activity of 1-(2-Deoxy-2-hydroxyimino- or Methoxyimino-β-D-erythro-pentofuranosyl)-thymine and -Cytosine§,1

Abstract

Reaction of 1-(3,5-Otetraisopropyldisiloxan-1,3-diyl-β-D-erythro-2-pentofuran-2-ulosyl)uracil (8) with hydroxylamine hydrochloride in pyridine at room temperature for 24 h or at 80°C for 3 h gives the 2′-deoxy-2′-hydroxyiminouridine derivative 9 in good yield. Similarly, oximation of 8 with methoxyamine has been done to obtain 2′-deoxy-2′-methoxyimino derivatives 11 in a high yield. Compound 9 was converted into 1-(2-deoxy-2-hydroxyimino-β-D-erythro-pentofuranosyl)cytosine (3). Cytotoxicity in vitro of these nucleosides against murine leukemia L1210 cells was also examined.     

Nucleosides. II. Synthesis and Properties of 3,4-Diaryl-4,5-dihydro-1-(β-D-ribofuranosyl)-1,2,4-triazole-5-thiones

Abstract

3,4-Diaryl-4,5-dihydro-1,2,4-triazole-5-thiones (1a-c) were silylated to give compounds (2a-c) which were condensed with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (3) in the presence of trimethylsilyl trifluoromethane sulfonate to afford the corresponding nucleosides 4a-c. Treatment of 4a-c with sodium methoxide in methanol at room temperature afforded the debenzoylated nucleosides 5a-c. The reaction of 5a with acetone in the presence of p-toluenesulfonic acid gave the 2′, 3′-isopropylidene derivative (6a). Phosphorylation of 6a with phosphoryl chloride and triethylphosphate followed by treatment with barium hydroxide afforded barium 3,4-diphenyl-4,5-dihydro(β-D-ribofuranosyl)-1,2,4-triazole-5-thione-5′- monophosphate, which gave after lyophilization the free acid (7a)     

Synthesis and Anti-Hiv Activity of 4′-Modified Cyclopentenyl Pyrimidine C-Nucleosides

Novel syntheses of 4′-modified cyclopentenyl pyrimidine C-nucleosides were performed via C-C bond formation using S_N2 alkylation via the key intermediate mesylates 6 and 16, which were prepared from acyclic ketone derivatives. When antiviral evaluation of synthesized compound was performed against various viruses such as HIV-1, HSV-1 and HSV-2, isocytidine analogue 20 showed moderate anti-HIV activity in CEM cell line (EC₅₀ = 13.1 μmol).7     

4′- C -Methyl-β-D-ribofuranosyl Purine and Pyrimidine Nucleosides Revisited

Abstract

In order to evaluate their antiviral properties, a series of 4′-C-methyl-β-D-ribofuranosyl purine and pyrimidine nucleosides has been prepared. Unfortunately, none of these 4′-branched nucleosides showed any antiviral activity or cytotoxcity when tested against HIV, HBV, and Yellow Fever virus.     

Novel Synthesis and Anti-HIV Activity of 4′-Branched Exomethylene Carbocyclic Nucleosides Using a Ring-Closing Metathesis of Triene

The exomethylene of 6 was successfully constructed from the aldehyde 5 using Eschenmoser's reagents. A triene compound 7 was cyclized successfully using Grubbs’ II catalyst to give an exomethylene carbocycle nucleus for the target compound. A Mitsunobu reaction was successfully used to condense the natural bases (adenine, thymine, uracil, and cytosine). The synthesized cytosine analogue 20 showed moderate anti-HIV activity (EC₅₀ = 10.67 μM).     

Photobromination of 1,5-Anhydro-2,3-O-isopropylidene-β-d-ribofuranose and Synthesis of (5R) and (5S)-(5-2H1)-d-Riboses

The photobromination of 1,5-anhydro-2,3-O-isopropylidene-β-d-ribofuranose gave the corresponding (5S)-5-bromo compound. The reduction of the bromide with triphenyltindeuteride gave (5S)-(5-²H₁)-1,5-anhydro-2,3-O-isopropylidene-β-d-ribofuranose, with a chiral purity of 76% at C-5, which was converted to (5R)- and (5S)-(5-²H₁)-d-riboses and other ribofuranose derivatives.