Synthesis of 1′-Deoxypsicofuranosyl-deoxynucleosides as Potential Anti-HIV Agents

Abstract

Various routes to the targets 1, 2, 3, 1-deoxy-psicofuranosyl nucleoside analogues related to anti-HIV agents, are reported. Two routes afforded their 6′-benzylated derivatives 9, 10 and 15. Only the epoxide 12 and deoxynucleosides 19 and 22 were able to be deprotected leading in the first case to 16 and its ring opening derivative 17 and in the second case to 20 and to the target 3.     

Synthesis of 3′-Trifluoromethyl Nucleosides as Potential Antiviral Agents

Abstract

1,2-Di-O-acetyl-3-deoxy-3-trifluoromethyl-5-O-benzoyl-β-D-riboruranose was synthesized from the precursor keto sugar by the use of Ruppert's reagent (CF₃SiMe₃) as the source of a nucleophilic trifluoromethyl group. Coupling of this trifluoromethyl sugar with nucleobases and elaboration gave novel deoxy and dideoxynucleosides. A single crystal X-ray analysis confirmed the structure and stereochemistry. The deoxynucleosides were converted through an elimination reaction to their dideoxydidehydro derivatives.     

Synthesis of 2′,3′-Dideoxy-2′-Fluoro-l-threo-Pentofuranosyl Nucleosides as Potential Antiviral Agents

Abstract

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,Molecular Docking and Biological Evaluation of 2-Aryloxy-N-Phenylacetamide and N′-(2-Aryloxyoxyacetyl) Benzohydrazide Derivatives as Potential Antibacterial Agents

A new class of 2-aryloxy-N-phenylacetamide and N′-(2-aryloxyoxyacetyl) benzohydrazide derivatives with different active moieties were synthesized and screened for their antibacterial activity. Structural characterization of synthesized compounds was performed using HR-MS, ¹H-NMR, and ¹³C-NMR spectral data. Amongst the synthesized compounds, 4-{2-[2-(2-chloroacetamido)phenoxy]acetamido}-3-nitrobenzoic acid ( 3h ) and 2-chloro-N-(2-{2-[2-(2-chlorobenzoyl)hydrazinyl]-2-oxoethoxy}phenyl)acetamide ( 3o ) have shown good antibacterial activity against a selected panel of bacteria. Besides, compounds also exhibited bactericidal activity against P. aeruginosa ( 3h , 0.69 μg/mL) and S. aureus ( 3o , 0.62 μg/mL) as evident by MBC and time-kill kinetics studies. In silico molecular docking and ADMET properties of newly synthesized compounds revealed that compounds could be considered as promising antibacterial agents.     

A Convenient and Stereoselective Synthesis of 2′-Deoxy-β-L-Ribonucleosides

Abstract

2′-Deoxy-β-L-ribonucleosides containing usual bases which are useful as synthons for modified oligodeoxyribonucleotides, were conveniently synthesized by a stereoselective glycosylation procedure. The method is suitable for large-scale preparations.     

Synthesis of 2′,3′-Dideoxy-2′-methylene Pyrimidine Nucleosides as Potential Anti-Human Immunodeficiency Virus (HIV) Agents

Abstract

Several 2′,3′-dideoxy-2′-methylene pyrimidine nucleosides, 2′,3′-dideoxy-2′-methylenecytidine hydrochloride (20), 2′,3′-dideoxy-2′-methyleneuridine (21), and 2′,3′-dideoxy-2′-methylene-5-methyluridine (22), have been synthesized via a multi-step synthesis from uridine and 5-methyluridine, respectively. These compounds were tested for their cytotoxicity against L1210, S-180, CCRF-CEM, and P388 cells in culture and their antiviral activity is under investigation.     

Synthesis of 2′,3′-Dideoxy- and 3′-Azido-2′,3′-dideoxy-pyridazine Nucleosides as Potential Antiviral Agents

Abstract

The synthesis of 4-methoxy-, 4-amino-3-chloro-, and 4-amino-1-(2,3-dideoxy-B-D-glycero-pentofuranosyl)pyridazin-6-one nucleosides, 6,19 and 20 is described. The synthesis of 3,4-dichloropyridazin-6-one (10) was accomplished in 44% overall yield using bromomaleic anhydride (17) as the starting material. The condensation of the silylated base of 10 with the halogenose 12 in the presence of trimethylsilyl triflate as a catalyst afforded a mixture of3,4-dichloro-1-(3,5-di-O-p-toluoyl-2-deoxy-B-D-erythro-pentofuranosyl)pyrridazin-6-one (13) in 67% and its α-anomer 14 in 12% yield, respectively. A series of 3′-sulfonate esters were prepared to explore the synthesis of 3-chloro-4-hydroxy-1-(3-azido-2,3-dideoxy-B-D-erythro-pentofuranosyl) pyridazin-6-one (32) via 6,3-anhydronucleoside analogues. Compounds 15, 19 and 20 were evaluated against human immunodeficiency virus, human cytomegalovirus, and herpes simplex virus type 1 but were inactive.     

Synthesis of O-Benzyl Derivatives of 2′-Deoxy-5-Trifluoromethyluridine for Antitumor Agents

Abstract

A practical synthesis of 3′-O-benzyl-2′-deoxy-5-trifluoromethyluridine was established which involves a selective 3′-O-benzylation of 2′-deoxy-5′-O-trityl-5-iodouridine followed by a cross-coupling with trifluoromethylcopper.     

Synthesis of 2′-Deoxy-6,2′-Ethano-Cyclouridine1 (Nucleosides and Nucleotides. Part 57)

Abstract

Synthesis of a carbon-bridged cyclouridine,2′-deoxy-6,2′-ethano-cyclouridine, was accomplished starting from a 2′-ketouridine via the 2′-deoxy-2′-iodoethyl-5-chlorouridine derivative through a radical cyclization.     

Synthesis and Biological Effects of 5′-Deoxy-5′-(Cyclo-Propylmethylthio)Adenosine

Abstract

A novel synthesis of the nucleoside analog, 5′-deoxy-5′-(cyclopropylmethylthio)adenosine (CPMTA, 1) has been developed. CPMTA is a closely related structural analog of 5′-deoxy-5′-(isobutylthio)-adenosine (SIBA, 2), which has been widely studied and shown to exert a multitude of biological effects. The in vitro and in vivo antitumor (L1210 leukemia) activity of CPMTA has been found to be comparable to that of SIBA, whereas its in vitro antiviral (HSV and VSV) activity is diminished. These agents are being developed as inhibitors of methylation and/or polyamine synthesis.     

Synthesis of 2-(3-Deoxy-β-D-erythropentofuranosyl)-thiazole-4-carboxamide (3′-Deoxytiazofurin)

Abstract

2-(3-Deoxy-β-D-erythropentofuranosyl)-thiazole-4-carboxamide was synthesized in four steps from its β-D-ribofuranosyl nucleoside precursor.     

Synthesis and Anti-HIV Activity of Novel 2′-Deoxy-2′-β-Fluoro-Threosyl Nucleoside Phosphonic Acid Analogues

Novel 2′-deoxy-2′-β-fluoro-threose purine phosphonic acid analogues were designed and racemically synthesized from 2-propanone-1,3-diacetate. Condensation successfully proceeded from a glycosyl donor 9 under Vorbrüggen conditions. Cross-metathesis of vinyl analogues 13 and 23 with diethyl vinylphosphonate yielded the desired nucleoside phosphonate analogues 14 and 24, respectively. Ammonolysis and hydrolysis of phosphonates yielded the nucleoside phosphonic acid analogues 16, 19, 26, and 29. The synthesized nucleoside analogues were subjected to antiviral screening against human immunodeficiency virus (HIV)-1. Adenine analogue 18 exhibited weak in vitro activities against human immunodeficiency virus (HIV)-1.     

Synthesis and Evaluation of 2′-Deoxy-2′-Spirodiflurocyclopropyl Nucleoside Analogs

The preparation of 2′-deoxy-2′-siprodifluorocyclopropany-lnucleoside analogs has been achieved from α-d-glucose in several steps. The key step in the synthesis was the introduction of the difluorocyclopropane through a difluorocarbene type reaction at the 2′-position. Then, a series of novel 2′-deoxy-2′-spirodifluorocyclopropanyl nucleoside analogs were synthesized using the Vorbrüggen method. All the synthesized nucleosides were characterized and subsequently evaluated against hepatitis C and influenza A virus strains in vitro.     

Nucleosides VIII: 1 Synthesis of 2′, 3′-Dideoxy- and 2′, 3′-Didehydro-2′, 3′-Di Deoxyisoguanosine as Potential Antiretroviral Agents

Abstract

2′, 3′-Didehydro-2′, 3′-dideoxyisoguanosine (2) and 2′, 3′- dideoxyisoguanosine (3) have been synthesized by utilizing the Corey-Winter approach starting from isoguanosine. The 6-amino and 5′-hydroxy biprotected isoguanosine derivative was converted to the corresponding 2′, 3′- thionocarbonate, which was heated with triethyl phosphite to afford the 2′,3′- olefinic product. Either a tert-butyldimethylsilyl or a 4, 4′-dimethoxytrityl group was used in the protection of 5′-hydroxy function. Compounds 2 and 3 were found inactive against human immunodeficiency virus (HIV), human cytomegalovirus (HCMV), and herpes simplex virus type 1 (HSV-1).

     

A Direct and Efficient Synthesis of 5′-Deoxy-2′, 3′-

Abstract

A direct and efficient synthesis of 5′-deoxy-2′,3′-O-isopropylideneinosine, 7, from readily available inosine is described. An example of a potentially general synthesis of N -substituted-5′-deoxyadenosines from 7 is also described.     

Synthesis and Physicochemical Properties of 2′-Deoxy- 2′,2″-difluoro-β-D-ribofuranosyl and 2′-Deoxy-2′,2″- difluoro-α-D-ribofuranosyl Oligonucleotides

Abstract

We present procedures for nucleoside and oligonucleotide synthesis, binding affinity (T _m) and structural analysis (CD spectra) of 2′-deoxy-2′,2″-difluoro-α-D-ribofuranosyl and 2′-deoxy-2′,2″-difluoro-β-D-ribofuranosyl oligothymidylates. Possible reasons for the thermal instability of duplexes formed between these compounds and RNA or DNA targets are discussed.     

Molecular Conformation of 2′-Deoxy-2′-methylidene-cytidine: A Potent Antineoplastic Nucleoside

Abstract

2′-Deoxy-2′-methylidenecytidine (DMDC), a potent inhibitor of the growth of tumor cells, was crystallized with two different forms. One is dihydrated (DMDC·2H₂O) and the other is its hydrochloride salt (DMDC·HCLl). Both crystal and molecular structures have been determined by the X-ray diffraction method. In both forms the glycosidic and sugar conformations are anti and C(4′)-exo, respectively, whereas the conformation about the exocyclic bond is trans for DMDC·2H₂O and gauche ⁺ for DMDC·HCl. Proton nuclear magnetic resonance data of DMDC indicate a preference for the anti C(4′)-exo conformation found in the solid state. These molecular conformations were compared with the related pyrimidine nucleosides. When the cytosine bases are brought into coincidence, DMDC displays the exocyclic C(4′)-C(5′) bond located on the very close position to those of pyrimidine nucleosides with typical overall conformations. On the other hand, the hydroxyl O(3′)-H groups are separated by ca. 3 Å in the cases of DMDC and other pyrimidine nucleosides which have the C(2′)-endo sugar conformation. This result may be useful for the implication about the mechanism of the biological activity of DMDC.     

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).     

Intracellular Metabolism and Action of an Antitumor Nucleoside, 2′-C-Cyano-2′-Deoxy-1-β-d-arabinofuranosylcytosine (CNDAC)

Abstract

The mechanism of antitumor activity of 2′-C-cyano-2′-deoxy-1-β-D-arabinofuranosylcytosine (CNDAC) has been examined. Intracellular metabolism of CNDAC using human leukemia cell lines are described. Incorporation of CNDAC triphosphate into DNA and the consequence of this incorporation have been evaluated in vitro using DNA primer extension assay with purified human DNA polymerase α and defined DNA primer/templates.     

Stereoselective Synthesis of 2-Deoxy-2-Fluoroarabinofuranosyl-α-1-Phosphate and Its Application to the Synthesis of 2′-Deoxy-2′-Fluoroarabinofuranosyl Purine Nucleosides by a Chemo-Enzymatic Method

Stereoselective introduction of a phosphate moiety into 2-deoxy-2-fluoroarabinofuranose derivatives at the anomeric position was investigated by two methods. One involved a stereoselective hydrolysis of 1-bromo-derivative, and the consecutive phosphorylation of 2-deoxy-2-fluoro-α-D-arabinofuranose via a phosphoramidite derivative. The other method involved stereoselective α-phosphorylation of the 1-bromo-derivative at the 1-position. The resulting α-1-phosphate was utilized to prepare 2′-deoxy-2′-fluoroarabinofuranosyl purine nucleosides by an enzymatic glycosylation reaction. This chemo-enzymatic method will be applicable to the synthesis of some 2′F-araNs, and three important 2′F-araNs were actually obtained in 30–40% yields from 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinose with high purity.