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 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 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 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.     

Synthesis of Artificially Bent Oligonucleotides by Incorporation of Conformationally Rigid 5′-Cyclouridylic Acid Derivatives

Abstract

This paper describes the design and synthesis of a conformationally rigid dimer building block Umpc3Um having a propylene bridge linked between the uracil 5-position and 5′-phosphate group of pUm. Oligonucleotides incorporating the dimer unit with either the Sp or Rp configuration were synthesized by use of the phosphoramidite approach. The conformational properties of the dimer units and these oligonucleotides were studied in detail.     

The 5′-Nor Aristeromycin Analogues of 5′-Deoxy-5′-Methylthioadenosine and 5′-Deoxy-5′-Thiophenyladenosine

To extend the potential of 5′-noraristeromycin (and its enantiomer) as potential antiviral candidates, the enantiomers of the carbocyclic 5′-nor derivatives of 5′-methylthio-5′-deoxyadenosine and 5′-phenylthio-5′-deoxyadenosine have been synthesized and evaluated. None of the compounds showed meaningful antiviral activity.     

Acycloadenosine Derivatives as Inhibitors of 5′-Deoxy-5′-Methylthioadenosine Phosphorylase (MesADo PASE)

Abstract

Four classes of acyclo amlogs of 5′-methylthioadenosine were synthesized and tested as inhibitors of mammalian methylthicadenosine phosphorylase. Halogenated dihydroxypropyl acycloadenosires were most potent, i.e. K_i = 0.2 - 0.7 uM.     

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.     

Facile Synthesis of Base-Labile 2′-Deoxyribonucleosides: An Improved Synthesis of 2′-Deoxy-5-aza-Cytidine

Abstract

The use of the Fmoc group for the protection of the hydroxy functions of the sugar moiety gave an improved overall yield of 2′-deoxy-5-azacytidine (6β), due to the mildly-basic conditions required for its removal from the protected nucleoside.     

Template-directed oligomerization of 5′-deoxy-5′-nucleosideacetic acid derivatives

5-Deoxy-5-nucleosideacetic acids II–V are isostructural analogues of nucleotides with a carboxylate group in the place of the 5-phosphate group. We have studied their oligomerization in aqueous solution using a water-soluble carbodiimide as the condensing agent in the presence or absence of an appropriate polynucleotide template. Condensation of adenylic acid analogues IIa, IIIa, and Va in the presence of polyuridylic acid were found to be the most efficient reactions. Cyclization of the activated monomers to lactones and the insolubility of the oligomers in aqueous solution were found to be obstacles to the efficient formation of long oligomers.     

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 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 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.     

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 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 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.     

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 and Incorporation of 5″-Amino- and 5′-Mercapto-5′-Deoxy-2′-O-Methyl Nucleosides Into Hammerhead Ribozymes

Abstract

Novel 5′-amino-5′-deoxy-2′-O-methyl uridine, guanosine and adenosine 3′-O-phosphoramidites 5, 11, and 20, as well as protected 5′-mercapto-5′-deoxy-2′-O-methyl uridine 3′-O-phosphoramidite 23 were synthesized from 2′-O-methyl nucleosides. These analogs were incorporated at the 5′-ends of hammerhead ribozymes to evaluate achiral bridging 5′-N- phosphoramidates and 5′-S-phosphorothioates as alternatives for non- bridging phosphorothioates commonly used for end stabilization against nucleases. Oligonucleotide synthesis and deprotection conditions were optimized for better yields of these modified ribozymes.     

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.     

Aldol Reaction of Nucleoside 5′-Carboxaldehydes with Acetone. Synthesis of 5′-C-Chain Extended Thymidine Derivatives

Abstract

Reaction of 3′-0-(t-butyldimethylsilyl)-2′-deoxythymidine-5′-carboxaldehyde and 2′,3′-dideoxythymidine-5′-carboxaldehyde with acetone afforded a 3:2 mixture of the two (5′R)- and (5′S)-5′-acetonylthymidine derivatives.