Synthesis of 5′-Deoxy-5′-nucleosideacetic Acid Derivatives

Abstract

The synthesis of several new 5′-deoxy-5′-nucleosideacetic acid derivatives by the reactions of alkoxycarbonylmethylene triphenylphosphoranes with nucleoside 5′-aldehydes is described.     

Incorporation of 5′-N-BOC-2′, 5′-Dideoxynucleoside-3′-O-Phosphoramidites Into Oligonucleotides by Automated Synthesis

Abstract

An efficient method for synthesizing 5′-Boc-5′-amino-2′, 5′- dideoxynucleoside phosphoramidites and conditions for their incorporation in solid-phase oligonucleotide synthesis are presented.     

Synthesis and Incorporation of 2′-O-Methyl-Pseudouridine into Oligonucleotides

Abstract

A short multigram synthesis of 2′-O-methylpseudouridine and its phosphoramidite derivative is described which avoids the use of protecting groups on the nitrogens. A binding study of oligonucleotides containing this modification suggest an increased binding affinity to RNA when compared to oligonucleotides incorporating 2′-O-methyluridine.     

Synthesis of 5′-C-Chain-Extended Uridines by Reaction of 5′-Halonucleosides with Malonic Acid Type Derivatives

Abstract

Reaction of 3-N-benzyl-5′-deoxy-5′-haloderivatives of uridine with the carbanions derived from diethyl malonate, ethyl acetoacetate, ethyl cyanoacetate and malondinitrile afforded the corresponding highly functionalized 5′-C-chain-extended uridines.     

5′-Phosphorylation of Oligonucleotides with Phosphorous Acid in Automated DNA Synthesis

Abstract

Coupling of phosphorous acid in automated DNA synthesis using H-phosphonate methodology leads to 5′-5′ linked dimers and 5′-H-phosphonates. The yield is dependent on the phosphorous acid concentration, chain length of the oligomer, and pore size of the support. 5′-Phosphate oligomers are obtained from the H-phosphonate oligomers by silylation and oxidation.     

New Synthesis of 5-Carboxy-2′-deoxyuridine and Its Incorporation into Synthetic Oligonucleotides

Abstract

5-Carboxy-2′-deoxyuridine is a methyl oxidation product of thymidine. It can be formed by the menadione-mediated photosensitization of thymidine in aerated aqueous solution. Here in we present a new four-step synthesis of the 5-carboxy-2′-deoxyuridine phosphoramidite building block based on the alkaline hydrolysis of 5-trifluoromethyl-2′-deoxyuridine. The phosphoramidite derivative has been incorporated at defined sites into oligonucleotides using the solid phase synthesis approach.     

Synthesis and Antiviral Activity of 5′-O-Sulfamoyluridine Derivatives

Abstract

A series of 5′-O-[[[[(alkyl)oxy]carbonyl] amino] sulfonyl] uridines have been synthesized by reaction of cyclohexanol, palmityl alcohol, 1,2-di-O-benzoylpropanetriol and 2,3,4,6-tetra-O-benzoyl-L-glucopyranose with chlorosulfonyl isocyanate and 2,3′-O-isopropylidene-uridine. Another series of 5′-O-(N-ethyl and N-isopropylsulfamoyl) uridines have been prepared by reaction of 2′,3′-O-isopropylidene and 2′,3′-di-O-acetyluridine with N-ethylsulfamoyl and N-isopropylsulfamoyl chlorides. All compounds were tested against HSV-2, VV, SV and ASFV viruses. 2′,3′-Di-O-acetyl-5′-O-(N-ethyl and N-isopropylsulfamoyl) uridine showed significant activities against HSV-2. 5′-O-[[[[(2,3,4,6-Tetra-O-benzoyl-β-L-glucopyranosyl)oxy]carbonyl]amino] sulfonyl]-2′,3′-O-isopropylideneuridine was very active against ASFV.     

2′-Deoxyisoinosine: Synthesis of a Highly Fluorescent Nucleoside and Its Incorporation into Oligonucleotides

Abstract

The synthesis of 2′-deoxyisoinosine (2a) and the related 2′, 3′- dideoxynucleosides 2b and 3 is reported. The 3′-phosphonate 4b as well as the phosphoramidite 4c were prepared and employed in solid-phase oligonucleotide synthesis.     

Synthesis of 5′-O-Aminothymidine and 5′-Deoxy-5′-Hydrazinothymidine,Novel Nucleoside Derivatives

Abstract

Two novel nucleoside derivatives,5′-0-aminothymidine and 5′-deoxy-5′-hydrazinothymidine were synthesised as potential thymidine kinase inhibitors. The former was made from N-hydroxyu re thane and 5′-0-tosylthymidine and the latter from benzyl carbazate and 5′-0-tosylthymidine.     

Synthesis and Properties of Oligonucleotides Containing 5-Aza-2′-deoxycytidine

Abstract

The preparation of a protected derivative of 5-aza-2′-deoxycytidine carrying the 2-(p-nitrophenyl)ethyl group is described. The new derivative is useful for the preparation of oligonucleotides containing 5-aza-2′-deoxycytidine using a special methodology that avoids the use of ammonia.     

Synthesis of Certain 5′-Substituted Derivatives of Ribavirin and Tiazofurin

Abstract

The synthesis of several 5′-substituted derivatives of ribavirin (1) and tiazofurin (3) are described. Direct acylation of 1 with the appropriate acyl chloride in pyridine-DMF gave the corresponding 5′-O-acyl derivatives (4a-h). Tosylation of the 2′, 3′-O-isopropylidene-ribavirin (6) and tiazofurin (11) with p-toluenesulfonyl chloride gave the respective 5′-O-p-tolylsulfonyl derivatives (7a and 12a), which were converted to 5′-azido-5′-deoxy derivatives (7b and 12b) by reacting with sodium/lithium azide. Deisopropylidenation of 7b and 12b, followed by catalytic hydrogenation afforded 1-(5-amino-5-deoxy-β-D)-ribofuranosyl)-1, 2, 4-triazole-3-carboxamide (10b) and 2 - (5 -amino- 5-deoxy- β-D-ribofuranosyl) thiazole-4-carboxamide (16), respectively. Treatment of 6 with phthalimide in the presence of triphenylphosphine and diethyl azodicarboxylate furnished the corresponding 5′-deoxy-5′-phthaloylamino derivative (9). Reaction of 9 with n-butylamine and subsequent deisopropylidenation provided yet another route to 10b. Selective 5′-thioacetylation of 6 and 11 with thiolacetic acid, followed by saponification and deisopropylidenation afforded 5′-deoxy-5′-thio derivatives of 1-β-D-ribofuranosyl-1, 2, 4-triazole-3-carboxamide (8a) and 2-β-D-ribofuranosylthiazole-4-carboxamide (15), respectively.     

Synthesis and Biological Evaluation of 9-Deazaadenine 5′-Deoxy-6′,6′-Difluoro-Carbocyclic C-Nucleoside Phosphonic Acid Derivatives

The first synthetic route to 5′-deoxy-6′,6′-difluoro-carbocyclic C-nucleoside [9-deazaadenosine, (pyrrolo[3,2-d]pyrimidine)] phosphonic acids from commercially available epichlorohydrin 5 was described. The key C-C bond formation from cyclopentanone to base precursor was performed using the Knoevenagel-type condensation. Synthesized C-nucleoside phosphonic acids were tested for anti-HIV and anti-leukemic activities. They showed moderate cytotoxicity-derived anti-HIV and anti-leukemic activities.     

Synthesis and Properties of Conformationally Rigid Cyclouridylic Acids Having Covalent Bonding Linkers Between the Uracil 5-Position and the 5′-Phosphate Group

Abstract

Conformationally rigid cyclouridylic acid derivatives 2 and 3 having ethylene and propylene bridges, respectively, between the uracil 5-position and the 5′-phosphate group were synthesized. These intramolecularly cyclized compounds have predominantly the ribose pucker of C3′-endo and the g+ orientation around the C4′-C5′ bond.     

Synthesis of 5′-Fluoro-5′-deoxy-and 5′-Amino-5′-Deoxytoyocamycin and Sangivamycin and Some Related Derivatives

Abstract

A series of 5′-substituted analogs of toyocamycin were prepared by condensation of silylated 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidine with protected 5-azido-5-deoxy- or 5-fluoro-5-deoxyribofuranose followed by debromination and deblocking. Alternatively, 5′-azido-5′-deoxytoyocamycin was prepared by azidation of toyocamycin. Conversion of the 5-nitrile function of the toyocamycin derivatives into a carboxamide or a thiocarboxamide gave the corresponding analogs of sangivamycin or thiosangivamycin while reduction of the 5′-azido-5′-deoxy nucleosides provided 5′-amino-5′-deoxy derivatives.     

Synthesis of Oligonucleotides Containing 2′-Deoxyguanosine Adducts of Nitropyrenes

Two different approaches to synthesize oligonucleotides containing the 2 ′-deoxyguanosine adducts formed by nitropyrenes are described. A direct reaction of an unmodified oligonucleotide with an activated nitropyrene derivative is a convenient biomimetic approach for generating the major adducts in DNA. A total synthetic approach, by contrast, involves several synthetic steps, including Buchwald-Hartwig Pd-catalyzed coupling, but can be used for incorporating both the major and minor adducts in DNA in high yield.     

Synthesis of Novel 4′-Cyclopropyl-5′-norcarbocyclic Adenosine Phosphonic Acid Analogues

Novel 4′-cyclopropyl-5′-norcarbocyclic adenosine phosphonic acid analogues were designed and racemically synthesized from propionaldehyde 5 through a de novo acyclic stereoselective route using triple Grignard addition and ring-closing metathesis (RCM) as key reactions. To improve cellular permeability and enhance the anti-HIV activity of this phosphonic acid, SATE phosphonodiester nucleoside prodrug 23 was prepared. The synthesized adenosine phosphonic acids analogues 17, 18, 19, 21, and 23 were subjected to antiviral screening against HIV-1. Compound 23 exhibits enhanced anti-HIV activity than its parent nucleoside phosphonic acid 18.     

A Biotin Phosphoramidite Reagent for the Automated Synthesis of 5′-Biotinylated Oligonucleotides

Abstract

A bis(DMTr)biotin phosphoramidite containing serine and 6-aminohexanol moieties was prepared by a multiple-step reaction, and used successfully in the solid phase synthesis of 5′-biotinylated oligonucleotides.     

New Phosphonoformic Acid Derivatives of 3′-Azido-3′-Deoxythymidine

New 5-alkyl ethoxy- and aminocarbonylphosphonates of 3-azido-3-deoxythymidine (AZT) were synthesized, and their antiviral properties in HIV-1-infected cell cultures and stability to chemical hydrolysis were studied. The AZT 5-aminocarbonylphosphonates were shown to be significantly more stable in phosphate buffer (pH 7.2) than the corresponding ethoxycarbonylphosphonates. The therapeutic (selectivity) index of some of the compounds exceeded that of the parent AZT due to their higher antiviral activity.     

Synthesis of 2′-Deoxyribonucleoside Derivatives of 1-Deazapurine

Abstract

5, 7-Dichloro-3H-imidazo[4, 5-b]pyridine (4) is a versatile base which can be coupled with a variety of sugar moieties and transformed in a series of 7-alkyl(aryl)amino-derivatives by reacting with the corresponding amines. In this paper synthesis, structure elucidation and ADA inhibitory activity of 2′-deoxyribonucleoside derivatives of N⁶-substituted 1-deazaapurines are described.