Synthesis of RNA Fragments Using the H-Phosphonate Method and 2′-(2′-Chlorobenzoyl) Protection

Abstract

The performance of 2′-(2-chlorobenzoyl) protected ribonucleoside H-phosphonates in the synthesis of oligoribonucleotides has been studied.     

A New Efficient Stereoselective Method for the Synthesis of (E)-5-Aminoallyl-Pyrimidine-5′-Triphosphates Using Palladium-Catalyzed Heck Reaction

An efficient overall two-step strategy for the synthesis of (E)-5-aminoallyl-pyrimidine-5′-triphoshate, starting from commercially available pyrimidine-5′-triphosphate is described. The method involves regioselective iodination of pyrimidine-5′-triphosphate, followed by the palladium-catalyzed Heck coupling with allylamine. The catalytic reaction is highly stereoselective and compatible with many functional groups present in the reactants.     

Application of Oxathiaphospholane Method for the Synthesis of Oligodeoxyribonucleotide 5′-O-Conjugates

Abstract

2-Thiono-1,3,2-oxathiaphospholane derivatives of lipophilic alcohols including borneol, cholesterol, menthol and heptadecanol were synthesized and reacted with support-bound oligodeoxyribonucleotides containing free 5′-hydroxyl groups. The reaction is catalyzed by DBU and leads to oligodeoxyribonucleotide conjugates possessing a lipophilic alcohol residue bound at the 5′-end via a phosphorothioate linkage.     

A Novel and Convenient Method for the Synthesis of Free 5′-Thiol Modified Oligonucleotides

Abstract

The synthesis of free 5′-thiol-modified oligonucleotides using a 4,4′,4″-trimethoxytrityl (TMTr)-protected linker and standard Poly-Pak^TM purification has been described.     

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.     

Enantiospecific Synthesis of 5′-Noraristeromycin and its 7-Deaza Derivative and A Formal Synthesis of (-)-5′-Homoaristeromycin

Abstract

Beginning with the treatment of the diacetate of cis-3,5-cyclopentenediol (5) with Pseudomonas cepacia lipase, (-)-5′-noraristeromycin (1) and (-)-7-deaza 5′-noraristeromycin (3) have been prepared. Subjecting 5 to treatment with porcine liver esterase led to an efficient preparation of a substituted cyclopentane precursor which, following literature precedence, can be converted into (-)-5′-homoaristeromycin (4).     

Synthesis of the inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors

Abstract

Inosine 5′-monophosphate dehydrogenase (IMPDH) is important molecular target for potential anticancer, antiviral, antibacterial and immunosuppressive agents. A lot of compounds were obtained to establish their activity toward this enzyme, and to improve therapeutic properties of IMPDH inhibitors used as the drugs. Some of the recently reported analogs exhibited promising results during in vitro and in vivo examinations in comparison to substances applied in clinic. In this review, we describe synthesis and biological activity evaluations of the newly designed IMPDH inhibitors.     

Enzymatic Synthesis of Bis(5′-Nucleosidyl) Tetra- and Triphosphates

The total fraction of aminoacyl-tRNA synthases from Escherichia coli has been shown to catalyze the synthesis of the bis(5′-nucleosidyl) oligophosphates Ap₄AZT, Ap₄d4T, Ap₄3TC, and Ap₄ACV, as well as Ap₃AZT and Ap₃d4T, from [α-³²P]ATP and the corresponding nucleoside-5′-tri(or di)phosphate. The resulting compounds, characterized by HPLC, are resistant to alkaline phosphatase. Ap₄AZT, Ap₄d4T, and Ap₄3TC are formed with approximately equal efficiency, whereas the efficiencies of the synthesis of Ap₄ACV, Ap₃AZT, and Ap₃d4T are three- to fivefold lower.     

The Synthesis and Biological Properties of some Aryl bis(Nucleosid-5′-yl) Phosphates Using Nucleosides with Proven Anti-HIV Activity

Abstract

The synthesis of a series of aryl bis(nucleosid-5′-yl)phosphates in which the nucleosides are either 2′,3′-dideoxy-(d2-) or 2′,3′-didehydro-2′,3′-dideoxy-(d4-) nucleosides is described. These were tested for anti-HIV activity and their efficacy and toxicity compared with the parent nucleosides. Only the 4-(methylsulphonyl)phenyl derivatives of d4T and d2A had any significant activity and had selectivity indices of the same order as the parent nucleosides. These findings can be explained by uptake of the triesters into cells followed by a slow release of nucleoside and nucleotide. In the case of some compounds (such as d2T and d2U) the 5′-monophosphate of which is known to inhibit thymidylate kinase, it is possible that the levels of nucleotide liberated are such that they are not processed into the 5′-triphosphate and hence no antiviral effect is seen.     

Studies on the Chemistry of 5-Acetoxy-6-(Acetoxymethyl)-Uridines: Synthesis of a New type of 5′-Cyclonucleoside1

Abstract

The 5-acetoxy-6-(acetoxymethy1)-uridine derivative 18 is converted in aqueous sodium hydroxide solution into the imidazole cyclonucleoside 22. Compound 22, in which an oxygen bridge links the sugar and base methano groups, represents a new type of 5′-cyclonucleoside.     

The Synthesis of Some 5-Alkyl (Cycloalkyl)-Substituted 2′ -Deoxy-4′-Thiouridines

Abstract

The silylated pyrimidine bases IIa-d were condensed with the benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-d-erythro-pentofuranoside III in acetonitrile under activation by N-iodosuccinimide, giving ca 1.5: 1/α: β anomeric mixtures of the blocked nucleosides IVa-d and Va-d. in yields of 55–58%. After the separation on a silica column the pure anomers were deprotected by BCI₃ or TiCI₄, providing the free nucleosides VIa-d and VIIa,c,d in moderate to good overall yields. The β- or α-anomeric configuration, anti-glycosidic conformation and prevailing C2′endo(S) thiosugar pucker in the synthesized compounds were established by the combined use of the ¹H, ¹³C NMR and X-ray crystallography.

     

Design and Synthesis of 2′-Deoxy-2′-[(1,2,3)Triazol-1-Yl]Uridines Using Click Chemistry Approach

A series of novel nucleosides bearing a 1,2,3-triazole moiety at the 2′-position of the sugar moiety has been synthesized starting from 2′-azidouridine and using the copper (I)-catalyzed Huisgen–Sharpless–Meldal 1,3-dipolar cycloaddition reaction. The reactions proceeded in overall yield of 52–82% and gave almost exclusively the 1,4-disubstituted 1,2,3-triazoles. The 2′-azidouridine was synthesized from uridine in two steps, and reacted with a variety of differently substituted alkynes to give the desired 2′-triazole-substituted uridine derivatives.     

The Synthesis of Some 5-Substituted and 5,6-Disubstituted 2′-Deoxyuridines

Abstract

5-Alkyl(cycloalkyl)-2′-deoxyuridines VIa-VIf were synthesised in high yields by condensation of the corresponding silylated bases with 2-deoxy-3,5-di O-p-toluoyl-D-erthro-pentosyl chloride in chloroform and subsequent deblocking with sodium methoxide in methanol. The β-configuration, anti-glycosidic conformation and C2′-endo (S) sugar pucker of all of these compounds has been established from their ¹H NMR, ¹³C NMR, UV and mass spectra. Under the same conditions, the condensation of silylated 5,6-trimethyleneuracil, resulted in 1:2/α:β anomeric mixture (overall yield 71%) and syn-conformation of the 5,6-trimethylene-2′-deoxyuridine [Xg]. The results of the condensation of the silylated 5,6-dimethyluracil are discussed as well. No significant antiviral activity has been found in testing the synthesised compounds against a range of herpes, influenza and HIV-1 viruses.     

Synthesis of Uridylyl (3′-5′) Uridine Derivatives Containing 5-(Methylamino-Methyl) Uridine as A Modified Nucleoside Found from E. COLI Minor tRNAArg

Abstract

5-(Methylaminomethyl)uridine-containing uridylyl (3′-5′) uridine derivatives (14, 26, and 29), which were the original and modified sequences corresponding to the first letter (position 34) and the 5′-upper ribonucleoside (position 33) in the anticodon loop of minor tRNA^Arg, have been synthesized via 5-(methylaminomethyl)uridine derivatives (4 and 24).     

Glycosylations of Inosine and Uridine Nucleoside Bases and Synthesis of the New 1-(β-D-Glucopyranosyl)-Inosine-5′, 6″-diphosphate

Abstract

Gluco- and ribosylation of the bases of sugar protected inosine and uridine were investigated, obtaining only adducts with β-configuration at the new glycosidic carbon; stereospecific insertion of a sugar moiety at the 1-N of inosine was achieved either using a Mitsunobu approach (for ribosylation) or by direct coupling of 1-δ-bromoglucose 13 with 2′,3′,5′-tri-O-acetylinosine for glucosylation. 1-(β-D-glucosyl)-inosine, chosen as starting substrate for glucosylated analogs of cyclic IDP-ribose, was phosphorylated at the primary hydroxyls and tested in intramolecular pyrophosphate bond formation.     

Synthesis and Biological Activity of BIS(Pivaloyloxymethyl) Ester of 2′-Azido-2′-Deoxyuridine 5′-Monophosphate

Abstract

Bis(pivaloyloxymethyl) ester of 2′-azido-2′-deoxyuridine 5′-monophosphate was prepared as a prodrug to generate 2′-azido-2′-deoxyuridine 5′-diphosphate inside the cell. A synthetic route utilizing stannyl phosphate was adopted in the preparation. The prodrug was evaluated for cell growth inhibition against a variety of tumor cell lines along with 2′-azido-2′-deoxyuridine and 2′-azido-2′-deoxycytidine.     

Synthesis of 2′-Deoxynucleoside 5′-Methylenebis-(phosphonate)s Using 2-(4-Nitrophenyl)ethyl Methylenebis(phosphonate) as the Phosphonylating Agent.

Abstract

2-(4-Nitrophenylethyl) methylenebis(phosphonate) (1) has been prepared by reaction of 2-(4-nitrophenyl)ethyl alcohol with methylenebis(phosphonyl) tetrachloride. Compound 1 was treated with diisopropylcarbodiimide (DIC) to give bicyclic intermediate 2, which in reaction with suitably protected 2′-deoxynucleosides 3 gave P¹,P²-disubstituted methylenebis(phosphonate)s 4. Removal of the nitrophenylethyl group by β-elimination with DBU afforded the corresponding 2′-deoxynucleoside 5′-methylenebis(phosphonate) analogues 5.

     

Synthesis of New Homo and Heterodimers of 2′,3′-Dideoxyinosine (ddi) Using Ester Linkages

Abstract

A series of new homo and heterodimers of ddI has been synthesized. A glutarate diester spacer was used to covalently couple ddI onto ddI, AZT or d4T.     

Synthesis of 8-Bromo- and 8-Azido-2′-deoxyadenosine-5′-O-(1-thiotriphosphate)

Abstract

Treatment of 3′-O-methoxyacetylated 8-bromo-2′-deoxyadenosine (5), with a twofold excess of salicyl phosphorochloridite (6), and subsequent reaction with bis(tri-n-butylammonium) pyrophosphate and oxidation with sulfur followed by removal of the protecting group gives predominantly 8-bromo-2′-deoxyadenosine-5′-O-(1-thiotriphosphate) (7), and minor amounts of the corresponding brominated monothiophosphate. Alternatively, the photoreactive dATP analog 8-azido-2′-deoxyadenosine-5′-O-(1-thiotriphosphate) (11), is obtained by phosphorylation of unprotected 8-azido-2′-deoxyadenosine (9) with a 1.8 molar equivalent excess of thiophosphoryl chloride and bis(tri-n-butylammonium) pyrophosphate. A protection of the nucleobase 6-amino group is not required. The photoaffinity labeling reagent 11, was characterized by ³¹P-NMR and ion-spray mass spectroscopy and its photolysis upon long wavelength UV irradiation was studied. Both α-thioderivatives of 2′-deoxyadenosine triphosphates can be incorporated into plasmid DNA by T7 DNA polymerase. Thus, they can be used for interference studies of protein binding and for cross-linking with amino acids in protein-nucleic acid-complexes.     

A Convenient Synthesis of 9-(5′-DEOXY-β-D-Allofuranosyl)-Adenine (5′-Homoadenosine)

Abstract

The synthesis of 5′-homoadenosine, a chain extended analogue of adenosine, has been developed by coupling the appropriately protected deoxyallofuranose derivative with adenine.