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.     

Di-ddU-α-Hydroxyphosphonate and α-Hydroxy- α- METHYLPHOSPHONATES as Potential Prodrugs of Antiviral Nucleoside Analogues

Abstract

The synthesis of a potential new prodrug system for the antiviral nucleoside ddU 1 based on α-hydroxybenzylphosphonates 2 and 3 is described. In principle, 2, 3 are able to hydrolyze via different mechanisms yielding ddU H-phosphonate 4 or ddU monophosphate 5, respectively.     

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.     

Acyclic Nucleoside Analogues: III. A Synthesis of New 2′,3′-Dideoxy-2′,3′-Didehydronucleoside Analogues

The coupling of 5-acetoxy-1,1-dimethoxypent-2-ene with cytosine and thymine trimethylsilyl derivatives, as well as the reaction of 5-acetoxy-1-bromopent-2-ene with adenine sodium salt, yielded acyclic analogues of the corresponding nucleosides containing 5-acetoxy groups. They were deprotected with a saturated methanolic solution of ammonia to the target analogues of nucleosides, which were characterized with ¹H NMR, IR, and UV spectra.     

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.     

The 5′-Hydrogen Phosphonate Analog as a Potential Prodrug of 3′-Azido-2′,3′-dideoxythymidine (AZT)

Abstract

A novel synthesis of AZT-5′-H-phosphonate 2, involving decarboxylation of the phosphonoformate intermediate 7, is reported herein. Studies of the metabolism of 2 in U937 cells indicate that 2 is readily converted to AZT-5′-monophosphate.     

Synthetic and Antiviral Studies of Certain Acyclic 3′-Azido-3′-Deoxythymidine (AZT) Analogues

Abstract

A direct alkylation of trimethylsilylated pyrimidines and azapyrimidines with 1-azido-3-benzyloxy-2-chloromethoxypropane gave acyclic analogues of AZT in a good overall yield. None of the compounds exhibited significant antiviral activity against human immunodeficiency virus and herpes simplex virus.     

New Dinucleoside Phosphonate Derivatives as Prodrugs of 3′-Azido-3′-Deoxythymidine and β-L-2′,3′-Dideoxy-3′-Thiacytidine: Synthesis and Anti-HIV Properties

New phosphonate homodimers of 3′-azido-3′-deoxythymidine (AZT) and a phosphonate heterodimer of β-L-2′,3′-dideoxy-3′-thiacytidine (3TC) and AZT were synthesized. The compounds demonstrated moderate anti-HIV activity. Stability of the compounds in human blood serum was studied. A correlation between anti-HIV activity and stability was defined.     

Synthesis and Anti-HIV Activity of Some S-Acyl-2-thioethyl (SATE) Phosphoramidate Derivatives of 3′-Azido-2′,3′-dideoxythymidine

Abstract

The synthesis and in vitro anti-HIV activity of tBuSATE phosphoramidate derivatives of AZT incorporating several methyl-esterified α-aminoacids are reported. The biological evaluation strongly supports the hypothesis that such compounds exert their anti-HIV effects via intracellular delivery of the corresponding 5′-mononucleotide.     

Synthesis of Novel 3′-Hydroxymethyl 5′-Deoxythreosyl Phosphonic Acid Nucleoside Analogues as Potent Antiviral Agents

A very efficient synthetic route to novel 3′-hydroxymethyl 5′-deoxythreosyl phosphonic acid nucleosides was described. The discovery of threosyl phosphonate nucleoside (PMDTA, EC₅₀ = 2.53 μM) as a potent antihuman immunodeficiency virus (anti-HIV) agent has led to the synthesis and biological evaluation of 3′-modified 5′-deoxy versions of the threosyl phosphonate nucleosides. 3′-Hydroxymethyl 5 ′-deoxythreosyl phosphonic acid nucleoside analogues 15, 19, 24, and 28 were synthesized from 1,3-dihydroxyacetone and tested for anti-HIV activity as well as cytotoxicity. The adenine analogue 19 exhibits moderate in vitro anti-HIV-1 activity (EC₅₀ = 10.2 μM).     

Synthesis and Potent Anti-HCMV Activity of 2′,5′,5′-trifluoro-3′-hydroxy-apiosyl Nucleoside Phosphonic Acid Analogues

As antiviral nucleosides containing a fluorine atom at 2′-position are endowed with increased stabilization of glycosyl bond, it was of interest to investigate the influence of three fluorine atoms at 2′- and 5′-positions of apiosyl nucleoside phosphonate analogues. Various pyrimidine and purine 2′,5′,5′-trifluoro-3′-hydroxy-apiose nucleoside phosphonic acid analogues were synthesized from 1,3-dihydroxyacetone. Electrophilic fluorination of lactone was performed using N-fluorodibenzenesulfonimide. Difluorophosphonation was performed by direct displacement of triflate intermediate with diethyl(lithiodifluoromethyl) phosphonate to give the corresponding (α,α-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield nucleoside phosphonate analogues. Deprotection of diethyl phosphonates provided the final phosphonic acid sodium salts. The synthesized nucleoside analogues were subjected to antiviral screening against various viruses.     

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).     

Radical Mediated Synthesis of 3′-α-C-Allenyl-2′,3′-dideoxythymidine as a Non-polar Analogue of AZT

Abstract

The synthesis of the novel modified nucleoside (1) exhibiting the 1,2-propadienyl [allenyl] group at the 3′-α- position is described. The 3′-C-C bond was formed by radical reaction between triphenylprop-2-ynylstannane (2) and the 3′-bromo(iodo)-2′,3′-dideoxynucleoside derivative (3).     

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 of Novel 2′-Spirocyclopropyl-5′- Deoxyphosphonic Acid Furanosyl Nucleoside Analogues as Potent Antiviral Agents

Novel 5′-deoxyfuranosyl purine phosphonic acid analogues with 2 ′-electropositive moiety, such as spirocyclopropanoid, were designed and synthesized from commercially available diethyl malonate. Condensation reaction successfully proceeded from a glycosyl donor 15 at low reaction temperature in Vorbruggen conditions to give desired phosphonate analogues 16b and 23b. The synthesized nucleotide analogues 19, 22, 26, and 29 were subjected to antiviral screening against HIV-1. Adenine phosphonic acid analogue 22 shows significant anti-HIV activity (EC₅₀ = 7.9 μM).     

Novel Acyclic Analogues of 3′-Azido-3′ Deoxythymidine 1-Hydroxy-3-Azido-2-Propoxymethyl Derivatives

Abstract

Starting from glycerol, l-hydroxy-3-Azido-2-pronoxymethyl pyrimidines (T, U, C) are synthesized.     

Synthesis and Antiviral Activity Evaluation of 2′,5′,5′-Trifluoro-Apiosyl Nucleoside Phosphonic Acid Analogs

Racemic synthesis of novel 2′,5′,5′-trifluoro-apiose nucleoside phosphonic acid analogs were performed as potent antiviral agents. Phosphonation was performed by direct displacement of triflate intermediate with diethyl (lithiodifluoromethyl) phosphonate to give the corresponding (α,α-difluoroalkyl) phosphonate. Condensation successfully proceeded from a glycosyl donor with persilylated bases to yield the nucleoside phosphonate analogs. Deprotection of diethyl phosphonates provided the target nucleoside analogs. An antiviral evaluation of the synthesized compounds against various viruses such as HIV, HSV-1, HSV-2, and HCMV revealed that the pyrimidine analogues have significant anti-HCMV activity.     

Stereospecific Synthesis and Antiviral Activities of β-L-2′,3′-Dideoxy-5-chloropyrimidine Nucleoside Derivatives

Abstract

Several 5-chlorouracil and 5-chlorocytosine β-L-dideoxynucleosides were stereospecifically synthesized and their activities against human immunodeficiency virus (HIV) and hepatitis B virus (HBV) were examinated in cell culture.     

Design and Synthesis of Novel 1′,3′-Dioxolane 5′-Deoxyphosphonic Acid Purine Analogues as Potent Antiviral Agents

Electronic parameters of 1′,3 ′-oxygen play significant roles in steering the conformation of nucleoside phosphonic acid analogues. To investigate the relationship of two oxygen atoms with antiviral enhancement, novel 1′,3 ′-dioxolane 5 ′-deoxyphosphonic acid purine analogues were synthesized via de novo acyclic stereoselective route from acrolein and glycolic acid. The synthesized nucleoside phosphonic acid analogues 14 and 19 were subjected to antiviral screening against several viruses, such as HIV-1, HSV-1, HSV-2, and HCMV. The guanine analogue 19 exhibits in vitro anti-HIV-1 activity similar to that of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) in MT-4 cells.