A Short Synthesis of 2′,3′-Didehydro-3′-deoxythymidine

Abstract

Reaction of sodium metal in HMPA-THF with 2,3′-anhydrothymidine la, results in an elimination to give the 2′,3′-unsaturated nucleoside 3a, This process was utilized in a synthesis of the antiviral drug D4T from thymidine.     

Synthesis and evaluation of sulfonylethyl-containing phosphotriesters of 3′-azido-3′-deoxythymidine as anticancer prodrugs

A series of bis(sulfonylethyl) and mono(sulfonylethyl) phenyl phosphotriesters of zidovudine (3′-azido-3′-deoxythymidine, AZT) were synthesized as potential anticancer prodrugs that liberate AZT monophosphate via nonenzymatic β-elimination mechanism. Stability studies demonstrated that all the synthesized prodrugs spontaneously liberate AZT monophosphate with half-lives in the range of 0.07–278.8 h under model physiological conditions in 0.1 M phosphate buffer at pH 7.4 and 37 °C. Analogous to aldophosphamide, the elimination rates were accelerated in the presence of reconstituted human plasma under the same conditions. Among the compounds, 3, 4, 8, and 10 were comparable or superior to AZT against five established human cancerous cell lines in vitro. Moreover, the selected compounds were equally sensitive to both the wild-type osteosarcoma 143B and the thymidine kinase-deficient 143B/TK⁻ cell lines. The findings are consistent with that these compounds deliver AZT monophosphate intracellularly.     

Synthesis and Properties of Some 2′-O-d-Ribofuranosyl-nucleosides

Abstract

A high yield preparation of 9-(2-O-β-d-ribofuranosyl-β-d-ribofuranosyl)-adenine and its pyrimidine analogues has been achieved and their physico-chemical properties were investigated.     

Synthesis of 2′-deoxythymidine by an enzymatic transdeoyrinosylation

Summary 2-Deoxythymidine was synthesized by an enzymatic transdeoxyribosylation of thymine using either (i) dGuo, dCyd or dAdo, or (ii) the mixture of the same 2-deoxynucleosides resulting from enzymatic hydrolysis of DNA as donors of 2-deoxyribofuranose moiety.     

Syntheses,Crystal Structures,and Hydrogen Bonding Patterns of 3′-C-Methylenecarboxylic-3′-deoxythymidine and 3′-C-Methyleneamidilylic-3′-deoxythymidine

Abstract

Thymidine derivatives containing carboxylic acid and amide groups have been synthesized and the hydrogen-bonding patterns of 3′-C-methylenecarboxylic-3′-deoxythymidine 6 and 3′-C-methyleneamidilylic-3′-deoxythymidine 9 have been characterized by using X-ray crystallography.     

Synthesis and Antiviral Evaluation of 3′-Substituted Thymidine Analogues Derived from 3′-Amino-3′-deoxythymidine

Abstract

To assess the structure-activity relationship for antiviral activity, a series of 3′-deoxy-3′-N-functionalized thymidine analogues were synthesized. Several of these thymidine analogues show moderate in vitro activity against HIV-1 and HIV-2.     

Synthesis of 2-acetamido-2-deoxy-3-O-β-d-mannopyranosyl-d-glucose

Condensation of 4,6-di-O-acetyl-2,3-O-carbonyl-α-d-mannopyranosyl bromide with benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-α-d-glucopyranoside (2) gave an α-d-linked disaccharide, further transformed by removal of the carbonyl and benzylidene groups and acetylation into the previously reported benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-α-d-mannopyranosyl)-α-d-glucopyranoside. Condensation of 3,4,6-tri-O-benzyl-1,2-O-(1-ethoxyethylidene)-α-d-glucopyranose or 2-O-acetyl-3,4,6-tri-O-benzyl-α-d-glucopyranosyl bromide with 2 gave benzyl 2-acetamido-3-O-(2-O-acetyl-3,4,6-tri-O-benzyl-β-d-glucopyranosyl)-4,6-O-benzylidene-2-deoxy-α-d-glucopyranoside. Removal of the acetyl group at O-2, followed by oxidation with acetic anhydride-dimethyl sulfoxide, gave the β-d-arabino-hexosid-2-ulose 14. Reduction with sodium borohydride, and removal of the protective groups, gave 2-acetamido-2-deoxy-3-O-β-d-mannopyranosyl-d-glucose, which was characterized as the heptaacetate. The anomeric configuration of the glycosidic linkage was ascertained by comparison with the α-d-linked analog.     

Synthesis and Hybridization Properties of Oligodeoxynucleotides Containing 3′-Deoxy-3′-C-methyleneuridine

Abstract

3′-Deoxy-3′-C-methyleneuridine nucleoside 1 ¹ has been incorporated into oligodeoxynucleotides. Relative to the unmodified references, oligomers containing nucleoside 1 displayed reduced binding affinities towards complementary DNA and RNA with a tendency towards RNA-selective hybridization.     

Chemical and Enzymatic Synthesis and Antiviral Properties of 2′-Deoxy-2′-fluoroguanosine

Abstract

Chemical and enzymatic methods were employed for the synthesis of the title compound, 2′F-Guo 7. High antiviral activity of 2′F-Guo was established in chick embryo cells infected with influenza virus FPV/Rostock/34 (H7N1) and herpes simplex virus (HSV) type I (1C strain).     

Normal coordinate analysis of 2′-deoxythymidine and 2′-deoxyadenosine

The proposed valence force field allows us to reproduce the vibration modes of 2-deoxythymidine and 2-deoxyadenosine. The present calculations are based on the Wilson GF-method and a non-redundant set of symmetrical coordinates. The calculated wavenumbers have been compared to the available Raman and infrared peak positions observed in solid, amorphous or aqueous samples. Moreover, the results obtained with the present force field allow us to assign some of the characteristic vibration modes for the thymidine and adenosine residues involved in DNA double-helical chains.     

Synthesis of 3′-Fluoro-3′-Deoxyribonucleosides; Anti-HIV-1 and Cytostatic Properties

Abstract

It has generally proven difficult to synthesize ribonucleosides with sugar modifications at the 3′ position. We now present a practical route for the synthesis of ribonucleosides with a 3′ fluorine substituent. Nucleosides with the xylo configuration were prepared by sugar-base condensation. Tritylation of the unprotected nucleosides gave a mixture of 2′,5′ and 3′,5′ bistritylated nucleosides which were difficult to characterize. Therefore the necessary precursors were synthesized in a step-wise fashion, starting with selective deprotection of the 2′-acyl group, followed by tritylation. This gave the 2′,5′-tritylated xylonucleosides in good yield. Reaction with diethylaminosulfur trifluoride and deprotection with 80 % acetic acid provided the 3′-fluoro-3′-deoxyribonucleosides 1, 2 and 4. The cytidine derivative was synthesized from 1 by reaction with trifluoromethanesulfonic anhydride followed by ammonia. Treatment of 4 with adenosine deaminase yielded 5.     

Synthesis and Properties of 2′4′- and 3′-5′-Linked Ribodinucleoside Monophosphates Containing 2-Aminoadenosine and Uridine

Abstract

Self complementary diribonucleoside monophosphates containing 2-aminoadenosine (n²A) and uridine (U) residues, (2′-5′) n²ApU (1), (3′-5′) n²ApU (2), (2′-5′) Upn²A (3) and (3′-5′) Upn²A (4), were synthesized by condensation of suitably protected nucleoside and nucleotide units using dicyclohexylcarbodiimide (DCC). The dimers, (3) and (41, were also obtained from uridine 2′,3′-cyclic phosphate and unprotected 2-aminoadenosine using 2,4,6-triisopropylbenzenesulfonyl chloride (TPS-Cl) as the condensing agent. The conformational properties of these dimers were examined by UV, CD and NMR spectroscopy. The results reveal that the 2′-5′ isomers take a stacked conformation, which contains a larger base-base overlap and is more stable against thermal perturbation with respect to the 3′-5′ isomers. The n²ApU isomers have more stacked structure than the Upn²A isomers.     

Synthesis and Properties of O-β-D-Ribofuranosyl-(1″-2′)-Adenosine-5″-O-Phosphate and Its Derivatives

Abstract

The synthesis of O-β-D-ribofuranosyl-(1″-2′)-adenosine-5″-O-phosphate and its suitably protected derivative for oligonucleotide synthesis have been developed.     

Antioxidant Properties of 2-O-β-D-Glucopyranosyl-L-ascorbic Acid

The antioxidant activity of a provitamin C agent, 2-O-β-D-glucopyranosyl-L-ascorbic acid (AA-2βG), was compared to that of 2-O-α-D-glucopyranosyl-L-ascorbic acid (AA-2G) and ascorbic acid (AA) using four in vitro methods, 1,1-diphenyl-picrylhydrazyl (DPPH) radical-scavenging assay, 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS^?+)-scavenging assay, oxygen radical absorbance capacity (ORAC) assay, and 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH)-induced erythrocyte hemolysis inhibition assay. AA-2βG slowly and continuously scavenged DPPH radicals and ABTS^?+ in roughly the same reaction profiles as AA-2G, whereas AA quenched these radicals immediately. In the ORAC assay and the hemolysis inhibition assay, AA-2βG showed similar overall activities to AA-2G and to AA, although the reactivity of AA-2βG against the peroxyl radical generated in both assays was lower than that of AA-2G and AA. These data indicate that AA-2βG had roughly the same radical-scavenging properties as AA-2G, and a comprehensive in vitro antioxidant activity of AA-2βG appeared to be comparable not only to that of AA-2G but also to that of AA.     

Synthesis of 3-O-(2-acetamido-2-deoxy-3-O-β-d-galactopyranosyl-β-d-galactopyranosyl)-1,2-di-O-tetradecyl-sn-glycerol

Stereo- and regio-selective synthesis of 3-O-(2-acetamido-2-deoxy-3-O-β-d- galactopyranosyl-β-d-galactopyranosyl)-1,2-di-O-tetradecyl-sn-glycerol by use of 1,2-di-O-tetradecyl-3-O-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-d-galactopyranosyl)-sn-glycerol as a key intermediate is described.     

Concise and Efficient Synthesis of 3′-O-Tetraphosphates of 2′-Deoxyadenosine and 2′-Deoxycytidine

We describe concise and efficient synthesis of biologically very important 3′-O-tetraphosphates namely 2′-deoxyadenosine-3′-O-tetraphosphate (2′-d-3′-A4P) and 2′-deoxycytidine-3′-O-tetra-phosphate (2′-d-3′-C4P). N⁶-benzoyl-5′-O-levulinoyl-2′-deoxyadenosine was converted into N⁶-benzoyl-5′-O-levulinoyl-2′-deoxyadenosine-3′-O-tetraphosphate in 87% yield using a one-pot synthetic methodology. One-step concurrent deprotection of N⁶-benzoyl and 5′-O-levulinoyl groups using concentrated aqueous ammonia resulted 2′-d-3′-A4P in 74% yield. The same synthetic strategy was successfully employed to convert N⁴-benzoyl-5′-O-levulinoyl-2′-deoxycytidine into 2′-d-3′-C4P in 68% yield.     

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 and Properties of Oligonucleotide Chimeras Containing 5′-Amino-2′-deoxy-2′-fluoroarabinonucleosides

Abstract

Oligonucleotide analogues comprised of 2′-deoxy-2′-fluoro-β-D-arabinose units joined via P3′-N5′ phosphoramidate linkages (2′F-ANA^5′N) were prepared for the first time. Among the compounds prepared were a series of 2′OMe-RNA-[GAP]-2′OMe-RNA ‘chimeras’, whereby the “GAP” consisted of DNA, DNA^5′N, 2′F-ANA or 2′F-ANA^5′N segments. The chimeras with the 2′F-ANA and DNA gaps exhibited the highest affinity towards a complementary RNA target, followed by the 5′-amino derivatives, i.e., 2′F-ANA > DNA > 2′F-ANA^5′N > DNA^5′N. Importantly, hybrids between these chimeras and target RNA were all substrates of both human RNase HII and E.coli RNase HI. In terms of efficiency of the chimera in recruiting the bacterial enzyme, the following order was observed: gap DNA > 2′F-ANA > 2′F-ANA^5′N > DNA^5′N. The corresponding relative rates observed with the human enzyme were: gap DNA > 2′F-ANA^5′N > 2′F-ANA > DNA^5′N.