Synthesis of 1′,2′-methano-2′,3′-dideoxynucleosides as potential antivirals

The synthesis of constrained nucleosides has become an important tool to understand the SAR in the interaction between biological and synthetic nucleotides in the context of antisense oligonucleotide therapy. The incorporation of a cyclopropane into a furanose ring of a nucleoside induces some degree of constrain without affecting significantly the steric environment of a nucleoside. Here, we report a new, short and stereocontrolled synthesis of two constrained nucleosides analogues, 1′,2′- methano-2′,3′-dideoxyuridine 9, and the corresponding cytidine analog 12. X-ray crystallography revealed that the furanose ring in the constrained uridine and cytidine analogues was flattened with virtual loss of pseudorotation. The phosphoramidate esters of the novel constrained uridine and cytidine nucleosides, intended as prodrugs, were tested in cell-based assays for viral replication across the herpes virus family and HIV inhibition courtesy of Merck laboratories, Rahway. They were also tested in antiproliferative assays against colorectal and melanoma cell lines. Unfortunately, none of the compounds showed activity in these assays.     

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.     

Catalysts for the self-polymerization of adenosine cyclic 2′,3′-phosphate

Summary When adenosine cyclic 2,3-phosphate is evaporated from solution in the presence of simple catalysts such as aliphatic diamines at alkaline pH, and maintained in a dry state at moderate temperatures (25-85°C), self-polymerization to give oligonucleotides of chainlength up to at least 6 is observed. The products contain an excess of [35]-linkages over [25]-linkages. The effects of different catalysts and reaction conditions on the efficiency of the reaction are described. The prebiological relevance of these reactions is discussed.     

New Approach to the Synthesis of 2′,3′-dideoxyadenosine and 2′,3′-Dideoxyinosine

Abstract

A new approach to the synthesis of 2′,3′-dideoxyadenosine and 2′,3′-dideoxyinosine based on deoxygenation of 2′,3′-di-O-mesylnucleosides was developed.     

Homo Dinucleoside-α-hydroxyphosphonate Diesters as Prodrugs of the Antiviral Nucleoside Analogues 2′,3′-Dideoxythymidine and 3′-Azido-2′,3′-dideoxythymidine

Abstract

The synthesis of a new prodrug system for antiviral nucleosides AZT (1) and ddT (2) based on α-hydroxybenzylphosphonates 3 is described. 3 hydrolyze via different mechanisms yielding the H-phosphonate monoesters 4 or nucleoside monophosphates 5, respectively. 3 were more lipophilic than 1, 2 and showed marked activity against HIV-1/2.     

Acyclic 2′, 3′-Dideoxy-2′,3′-didehydronucleoside 5′-Triphosphates as Termination Substrates of Broad Set of DNA Polymerases

Abstract

O4′-Nor-2′,3′-dideoxy-2′,3′-didehydronucleoside 5′-triphosphates (acyclo-d₄NTP) have been shown to have the properties of effective termination substrates for DNA biosynthesis, catalyzed by several different DNA polymerases.     

Inhibition of anion transport in human red blood cells by 5,5′-dithiobis(2-nitrobenzoic acid)

The uptake of [³²P]phosphate into human red blood cells was inhibited ($\text{K}{}_{\mathrm{<mtext>i</mtext>}}\text{= 0.6}\text{mM}$) by the sulfhydryl reagent 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB). 2-Nitro-5-thiobenzoic acid (NTB), the reduced form of DTNB, was a less potent inhibitor ($\text{K}{}_{\mathrm{<mtext>i</mtext>}}\text{= 7}\text{mM}$). The inhibition of anion transport by DTNB could be reversed by washing DTNB-treated cells with isotonic buffer, or by incubating DTNB-treated cells with 2-mercaptoethanol, which converted DTNB to NTB. DTNB competitively inhibited the binding of 4-[¹⁴C]-benzamido-4′-aminostilbene-2,2′-disulfonate, a potent inhibitor of anion transport ($\text{K}{}_{\mathrm{<mtext>i</mtext>}}\text{= 1?2 μ}\text{M}$), to band 3 protein in cells and ghost membranes. These results suggest that the stilbene-disulfonate binding site in band 3 protein can readily accommodate the organic anion DTNB, and that inhibition by DTNB was not due to reaction with an essential sulfhydryl group.     

Synthesis of 2′,3′-Dideoxy-3′-C-Hydroxymethyl Nucleosides Having the L-Configuration as Potential Inhibitors of HIV

Abstract

Synthesis of 2′,3′-Dideoxy-3′-C-(hydroxymethyl)-α- and β-L-erythro-pentofuranosyl nucleosides of thymine, cytosine and adenine is reported.     

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).

     

Synthesis of 3′,4′-C-Bishydroxymethyl-2′,3′,4′-trideoxy-β-L-threo-pentopyranosyl Nucleosides as Potential Inhibitors of HIV

Abstract

The synthesis of 3′,4′-bishydroxymethyl-2′,3′,4′-trideoxy pentopyranosyl derivatives of thymine, uracil, cytosine, and adenine is described. trans-(3S,4S)-Bis(methoxycarbonyl)cyclopentanone (3) was converted to 1-O-acetyl-3,4-C-bis[(tert-butyldiphenylsiloxy)methyl]-2,3,4-trideoxy-α,β-L-threo-pentopyranose (6), which was subsequently condensed with the silylated purine and pyrimidine bases.     

A Novel Class of 4′-Aza Analogues of 2′,3′-Dideoxynucleosides as Potential Anti-HIV Drugs

Abstract

The 1,3 dipolar cycloaddition approach represents the most valuable strategy for the preparation of isoxazolidine nucleosides. The latter posses more conformational degrees of freedom than the corresponding dideoxyribosides. Side reactions due to the presence of formaldehyde in the reaction media can be avoided by proper derivatization of the vinyl-nucleobase.     

Synthesis of 2′,3′-Didehydro-2′,3′-Dideoxy-3′-C-Methyl Substituted Nucleosides

Abstract

1-(2,3-Dideoxy-3-C-hydroxmethyl-β-D-threo-pentofuranosyl) -,1- (2,3-didehydro-2,3-dideoxy-3-C-hydroxymethyl-β-D-glycero- pentofuranosyl) -and 1-(3-C-azidomethyl-2,3-dideoxy-3-C-hydroxymethyl-β-D-glycero- pentofuranosyl)uracil, thymine and cytosine were synthesized and evaluated for anti-HIV activity. The synthetic strategy was based on an allylic alcohol transposition of the corresponding 3′-C-methylene-nucleoside analogues.     

Synthesis of 2′,3′-Didehydro-2′,3′-dideoxyisoinosine and Oxidation of Fluorescent 2-Hydroxypurine Nucleosides by Xanthine Oxidase

Abstract

The syntheses of 2′,3′-didehydro-2′,3′-dideoxyisoinosine (d4isoI, 4) as well as 7-deaza-2′,3′-didehydro-2′,3′-dideoxyisoinosine (d4c₇isoI, 5) are described. Compounds 4 and 5 show both strong fluorescence. Compound 4 is oxidized by xanthine oxidase to give the corresponding xanthine 2′,3′-dideoxy-2′,3′-didehydronucleosides. A preparative chemo-enzymatic synthesis of 2′-deoxyxanthosine (3) is described.     

Structural Features of 2′,3′-Dideoxy-2′,3′-Didehydrocytidine,A Potent Inhibitor of the HIV (AIDS) Virus

Abstract

The structure and conformation of 2′,3′-dideoxy-2′,3′-didehydrocytidine (2′,3′-dideoxycytidin-2′-ene, d4C), a potent inhibitor of the human immunodeficiency virus, was determined by X-ray crystallography. The nucleoside crystallizes in the orthorhombic space group P2₁2₁2₁ with cell dimensions a = 8.603(1), b = 9.038(1), c = 25.831(2) A and with two independent molecules in the asymmetric unit (Z = 8). Atomic parameters were refined by full-matrix least squares to a final value of R = 0.033 for 2258 observed reflections. The molecules are quite flexible: in molecule A the glycosyl torsion angle (X_CN) is 61.3° and the -CH₂OH side chain is in the gauche ⁺ orientation while in molecule B X_CN = 19.8° and the side chain is trans. The five-membered rings are slightly puckered (～0.1 Å), 04′ being endo in molecule A and exo in molecule B. A mechanism is proposed for the known instability of 2′,3′-unsaturated nucleosides.     

A New Synthesis of 2′,3′-Didehydro-3′-deoxy-3-Alkylthymidine

Abstract

The preparation of 3-alkyl D4T derivatives has been carried out starting from the corresponding 5′-O-t-butyldimethylsilyl-3′-O-methanesulfonylthymidine 2 by way of deprotection-elimination and succesive alkylation reactions.     

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.     

The Use of Acetyl Bromide for the Multigram Synthesis of the Anti-HIV Agent 2′,3′-Didehydro-2′,3′-Dideoxycytidine (d4C)

Abstract

Treatment of uridine (1) with acetyl bromide produced bromoacetate 2 which was reduced with Zn/Cu to give the 2′,3′-unsaturated uridine (d4U; 3). Conversion of the uracil moiety of 3 to thioamide 7 with Lawesson's reagent, followed by amination and deprotection with methanolic ammonia, afforded d4C (9). This multigram scale process for the synthesis of d4C proceeded in 20% yield from uridine.     

A Facile Synthetic Method for 3′-α-Fluoro- 2′,3′-dideoxyadenosine

Abstract

A facile method for the synthesis of 3′-α-fluoro-2′,3′-dideoxyadenosine (5) has been developed using a novel rearrangement of 3′-β-bromine to the 2′-β position during 3′-α fluorination.     

How many pathways for invasion of the red blood cell by the malaria parasite?

Merozoites of the malaria parasite Plasmodium falciparum use several receptors for cellular engagement when they invade human red blood cells. Recently, a merozoite erythrocyte-binding protein, EBA-140, has been identified that specifically binds to glycophorin C on red blood cells. Up to 50% of Melanesians have a deletion in this gene, and the resultant Gerbich-negative red blood cells are relatively resistant to invasion. While discovery of multiple pathways for invasion could confound the search for suitable vaccine targets, they could also be considered in the design of therapeutic interventions that prevent malaria parasites entering red blood cells.