Deoxyuridine Derivatives Research Articles

5-(Acylethynyl)uracils, 5-(Acylethynyl)-2'-deoxyuridines and 5-(Acylethynyl)-1-(2-hydroxyethoxy)methyluracils. Their synthesis, antiviral and cytotoxic activities

5-(acylethynyl)uracils 4 were synthesized from 5-iodo-2,4-dimethoxypyrimidine 1 through a palladium-catalyzed reaction with acetylenic carbinols 5, subsequent oxidation with manganese dioxide in dichloromethane, demethylation with 6 N hydrochloric acid, followed by treatment with sodium hydroxide in 95% ethanol. The corresponding 5-acylethynyl-2'-deoxyuridines 9 and 5-acylethynyl-1-(2-hydroxyethoxy-methyl)uracils 13 were synthesized following a similar procedure. The 5-acylethynyluracils 4 were cytotoxic against murine L1210 and human T-lymphocyte (Molt 4/C8, CEM) cells. The 2'-deoxyuridine derivatives 9 were less cytotoxic; however the acyclonucleosides 13 were as active as the free bases 4. The compounds did not have antiviral activities at subtoxic concentrations.

Anionically induced formation of anomeric spironucleosides from 1′- C-cyano-2′-deoxyuridine

The reaction of the 1′- C-cyano-2′-deoxyuridine derivative 1 with organolithium reagents can be favorably tuned to give a new class of anomeric spironucleosides.

Exploitation of an unexpected in situ heteroaromatic bromination for the synthesis of a porphyrin functionalized nucleoside

A 2′-deoxyuridine derivative functionalized via an acetylenic junction with a Zn(II) tetraarylporphyrin has been prepared. Is also reported an unexpected in situ bromination of the uracil nucleic base at the C5 position, which occurs during the transformation of a dibromo-olefin into its corresponding acetylenic anion. [Display omitted]

Synthesis and Anti-Virus Activity of Some Nucleosides Analogues

New 3'-, 5'-, 5-bromo-2'-deoxyuridine (3a-g) and 3'-, 5'-thymidine (4a-i) analogues with amino acid and peptide residues were synthesized and evaluated for antiviral activity. The influence of long peptide chains, essential amino acids and the effect of this structural modification on the antiviral activity has been also reported. Three 5-bromo-2'-deoxyuridine derivatives containing glycyl-, glycyl-glycyl- and glycyl-glycyl-glycyl- residues (3a, 3b, 3c) showed a strong activity against the herpes virus PsRV and a moderate one vs. HSV-1. The corresponding thymidine analogues were considerably less effective, and only compounds 4d and 4h showed a borderline effect against PsRV.

ChemInform Abstract: Synthesis of a Novel 2′‐Deoxyuridine Derivative Bearing a Cyanomethoxycarbonylmethyl Group at C‐5 Position and Its Use for Versatile Post‐Synthetic Functionalization of Oligodeoxyribonucleotides.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of a novel 2′-deoxyuridine derivative bearing a cyanomethoxycarbonylmethyl group at C-5 position and its use for versatile post-synthetic functionalization of oligodeoxyribonucleotides

Abstract A novel 2′-deoxyuridine derivative bearing a cyanomethoxycarbonylmethyl group at the C-5 position (1) was synthesized, and its use was examined as a convertible nucleoside for the versatile post-synthesis functionalization of oligodeoxyribonucleotides (ODNs). The ODNs containing 1 reacted with primary monoamines such as heptylamine, histamine, and tyramine as well as d- and polyamines under mild conditions, giving the corresponding derivatized ODNs.

Structure-activity relationship of the affinity of 5-substituted uracil nucleoside analogues for varicella-zoster virus thymidine kinase and their activity against varicella-zoster virus

We investigated structure-activity relationships of 5-substituted uracil nucleoside analogues for their selective antiviral activity against varicella-zoster virus (VZV) and affinity for VZV thymidine kinase (TK). Anti-proliferative activity of the compounds was measured using human lymphoblastoid cells. Most 2′-deoxyribofuranosyluracil, arabinofuranosyluracil (araU) and 2′-deoxy-2′-fluoro-arabinofuranosyluracil derivatives showed selective anti-VZV activity as well as activity against herpes simplex virus types 1 and 2. 2′-Deoxyuridine derivatives showed higher affinity than the corresponding araU analogues. A correlation was seen between the 50% effective doses for VZV and the K i values for VZV TK, except for 5-ethyl-2′-deoxyuridine and 5-ethyl araU that showed relatively high affinity for VZV TK without showing any activity against VZV. 5-Halogenovinyluracil nucleosides showed the highest affinity and the most potent and selective anti-VZV activity. 2′-Deoxy-2′-fluoro-arabinofuranosyluracil derivatives exhibited high anti-VZV potency though they showed relatively low affinity for VZV TK. Some 3′-deoxythymidine analogues having anti-human immunodeficiency virus activity were inactive against herpesviruses.

Synthesis and Biochemical Activity of Hydrophilic Carborane-Containing Pyrimidine Nucleosides as Potential Agents for DNA Incorporation and BNCT

A novel type of hydrophilic 5-tethered carborane-containing 2′-deoxyuridine derivative, SUB-7-DIOL, has been developed. This compound is a potential agent for DNA incorporation and BNCT, because it showed satisfactory aqueous solubility and demonstrated an excellent rate of phosphorylation by human thymidine kinase. This study also demonstrated the importance of tethering a flexible hydrocarbon chain between the carborane cage and the 5-position of the nucleoside, and the effectiveness of a water-solubilizing moiety attached to the carbon atom of the lipophilic carborane cage.

Preparation of Chloro and Sulfanyl Derivatives of 1-(2-Deoxy-4-C-hydroxymethyl-α-L-threo-Pentofuranosyl)uracil

3'-Chloro and 3'-acetylsulfanyl derivatives of 1-(2-deoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)uracil were prepared by reaction of 2,3'-anhydro-1-{5'-O-benzoyl-4'-C-[(benzoyloxy)methyl]-2'-deoxy-α-L-erythro-pentofuranosyl}uracil (3) with hydrogen chloride and thioacetic acid, respectively. The reaction with hydrogen chloride gave a mixture of N-1 and N-3 substituted uracil derivatives 12 and 14. Reaction of 1-{3-O-benzoyl-4-C-[(benzoyloxy)methyl]-2-deoxy-α-L-threo-pentofuranosyl}uracil (7) with thionyl chloride and subsequent debenzoylation afforded 1-(4-C-chloromethyl-2-deoxy-β-D-erythro-pentofuranosyl)uracil (19). Nucleophilic substitution with lithium thioacetate, followed by deacylation, converted 1-{3-O-benzoyl-4-C-[(benzoyloxy)methyl]-2-deoxy-5-O-p-toluenesulfonyl-α-L-threo-pentofuranosyl}uracil (9) into 1-(2-deoxy-4-C-sulfanylmethyl-β-D-erythro-pentofuranosyl)uracil (21). The obtained thiols were oxidized with iodine or air to give 1,1'-[disulfandiylbis(2,3-dideoxy-4-hydroxymethyl-α-L-threo-pentofuranose-3,1-diyl]di(pyrimidine-2,4-(1H,3H)-dione) (17) and 1,1'-[disulfandiylbis(2,5-dideoxy-4-hydroxymethyl-α-L-threo-pentofuranose-5,1-diyl]di(pyrimidine-2,4(1H,3H)-dione) (22). Reaction of 1-{3-acetylsulfanyl-5-O-methanesulfonyl-4-C-[(benzoyloxy)methyl]-2,3-dideoxy-α-L-threo-pentofuranosyl)}uracil (24) with methanolic sodium methoxide afforded 1-(3,5-anhydro-2,3-dideoxy-4-C-hydroxymethyl-3-sulfanyl-α-L-threo-pentofuranosyl)uracil (25). The same reagent was used in the preparation of 1-(3,5-anhydro-2-deoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)uracil (26) from 1-{4-C-[(benzoyloxy)methyl]-2-deoxy-5-O-p-toluenesulfonyl-α-L-threo-pentofuranosyl}uracil (8). From the series of 4'-substituted 2'-deoxyuridine derivatives, synthesized in this study, solely the 4'-chloromethyl derivative 19 and the oxetane derivative 26 exhibited an appreciable activity against HIV-1 and HIV-2.

New synthetic method of 5-formyluracil-containing oligonucleotides and their melting behavior

A new method for the synthesis of 5-foU-containing oligonuleotides by phosphoramidite chemistry and subsequent post-oxidation with sodium periodate was developed. 5-(1,2-Dihydroxyethyl)uracil-containing oligomers, which are readily converted to 5-foU-containing oligomers by sodium periodate oxidation, were synthesized according to the standard β-cyanoethyl phosphoramidite chemistry. The phosphoramidite of a protected 5-(1,2-dihydroxyethyl)-2′-deoxyuridine derivative was prepared from 5-iodo-2′-deoxyuridine in 7 steps. UV melting behavior of these three oligomers demonstrated that the 5-foU-A base pair are less stable than the T-A base pair.

ChemInform Abstract: Synthesis and Biological Activity of O‐Alkyl‐3‐N‐aminoacyloxymethyl‐5‐ fluoro‐2′deoxyuridine Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A proposed mechanism for the mutagenicity of 5-formyluracil

5-Formyluracil is a mutagenic base formed in DNA by oxidation of the thymine methyl group. Whereas the thymine methyl group is electron donating, the formyl group is electron withdrawing, predicting increased ionization of the N-3 imino proton under physiological conditions. The p K a values of a series of 5-substituted uracil and deoxyuridine derivatives have been measured. A linear relationship is observed between the electronic inductive property of the 5-substituent and the p K a value of the corresponding imino proton. The p K a value of 5-formyl-2′-deoxyuridine is close to that of the mutagenic nucleoside analogue 5-bromo-2′-deoxyuridine. In analogy with BrU, it is proposed that the mutagenicity of 5-formyluracil results from enhanced mispairing of the ionized form with guanine during DNA replication.

Synthesis and biological activity of O-alkyl-3-N-aminoacyloxymethyl-5-fluoro-2'-deoxyuridine derivatives.

In an attempt to improve the effectiveness of action of 5-fluoro-2'-deoxyuridine (FUdR), various kinds of O-alkylated water-soluble analogues were synthesized. Antitumor activities against sarcoma 180 (solid) were also evaluated. Some compounds exhibited potent activities. In particular, 3'-O-p-chlorobenzyl-3-N-aminoacyloxy-methylester derivatives were effective over a very wide range of dose and gave extremely large therapeutic ratios compared with known 5-fluorouracil (5-FU) derivations.

Herpes Simplex Virus Thymidine Kinase Gene-Transfected Tumor Cells; Sensitivity to Antiherpetic Drugs

Abstract A series of antiherpetic 5-substituted 2′-deoxyuridine derivatives (i. e. BVDU) and guanine derivatives (i. e. ganciclovir) have been evaluated for their cytostatic activity against murine mammary carcinoma FM3A cell lines that are deficient in cytosol thymidine kinase, but transfected by the herpes simplex virus type 1 (HSV-1)- or type 2 (HSV-2)-specified thymidine kinase gene. Most compounds were endowed with a markedly higher cytostatic activity against the HSV TK gene-transfected tumor cells than against wild-type tumor cells. The principal target for cytostatic activity of the BVDU derivatives proved thymidylate synthase, whereas the guanine derivatives inhibited HSV TK gene-transfected tumor cell proliferation by competing with cellular DNA polymerase(s) and subsequent incorporation into the cellular genome. 1Dedicated to Dr. Yoshihisa Mizuno on the occasion of his 75th birthday. 2This research was supported in part by the Belgian Fonds voor Geneeskundig Wetenschappelijk Onderzoek (Krediet ...

Central nervous system depressant effects of N3-substituted derivatives of deoxyuridine in mice.

N3-Substituted derivatives of deoxyuridine (1) were synthesized and their pharmacological effects were evaluated by intracerebroventricular (i.c.v.) injection in mice. Eleven derivatives, including the methyl (2), ethyl (3), propyl (4), allyl (5), butyl (6), benzyl (7), o, m and p-xylyls (8, 9, 10), alpha-phenylethyl (11) and phenacyl (12) derivatives, of 1 were prepared and their pharmacological effects were evaluated by using hypnotic activity, pentobarbital-induced sleep prolongation, spontaneous activity and motor incoordination as indices of central nervous system (CNS) depressant effects. At a dose of 2.0 mumol/mouse, the values of mean sleeping time induced by 7, 8, 9 and 10 were 23, 35, 29 and 30 min, respectively. Although the alkyl (2-6) derivatives did not cause any hypnotic activity, some derivatives tested (3, 5, 6, 8-12) significantly prolonged the pentobarbital-induced sleeping time. When the CNS depressant effects of phenacyl substituted 1 were compared to that of other oxopyrimidine nucleosides, N3-phenacyluridine (13), N3-phenacylthymidine (14), N3-phenacyl-6-azauridine (15), compounds 12, 13 and 14 (1.0 mumol/mouse, i.c.v.) significantly decreased mouse spontaneous activity. Furthermore, 12-15 (1.0 mumol/mouse, i.c.v.) caused mouse motor incoordination. These results indicate that deoxyuridine derivatives have generally central depressant activity, and the benzyl and xylyl derivatives, but not alkyl derivatives, possess hypnotic activity.

ChemInform Abstract: Novel C5‐Substituted 2′‐Deoxyuridine Derivatives Bearing Amino‐Linker Arms: Synthesis, Incorporation into Oligodeoxyribonucleotides, and Their Hybridization Properties.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and biological evaluation of 5-fluoro-2'-deoxyuridine phosphoramidate analogs.

A series of alkylating phosphoramidate analogs of 5-fluoro-2'-deoxyuridine has been prepared and their growth inhibitory activity evaluated against murine L1210 leukemia and B16 melanoma cells in vitro. These compounds were designed to undergo intracellular release of the phosphoramidate anions, which it was hoped would function as irreversible inhibitors of thymidylate synthase. The expectation was that binding of the nucleoside moiety would be followed by alkylation of the enzyme via the phosphoramidate. The chloride, bromide, iodide, and tosylate analogs were highly potent inhibitors of L1210 cell proliferation, with increased inhibition observed at both higher drug concentrations and longer exposure times. Addition of thymidine completely reversed the inhibition for all compounds, suggesting that these compounds are acting via inhibition of thymidylate synthase. Although the nonalkylating morpholine analog 1f was ca. 50-fold less potent than the methyl(chloroethyl)amino compound, the piperidine analog 1g was only 2-fold less potent, confirming that nitrogen basicity may be as important as the presence of an alkylating group. Addition of thymidine reversed the growth inhibition of the morpholine and piperidine analogs, suggesting that these compounds may also undergo intracellular conversion to 5-fluoro-2'-deoxyuridine 5'monophosphate. The thymidine and deoxyuridine derivatives 2 and 3 showed minimal growth inhibition in the L1210 assay. The alkylating analogs showed modest cytotoxicity against B16 melanoma cells, and the potency of the analogs was more dependent upon the alkylating moiety than on the 5-substituent.

Novel C5-Substituted 2′-Deoxyuridine Derivatives Bearing Amino-Linker Arms: Synthesis, Incorporation into Oligodeoxyribonucleotides, and Their Hybridization Properties

Abstract 2′-Deoxyuridine derivatives bearing several kinds of amino-linker arms at C5 position were synthesized from 5-(methoxycarbonylmethyl)-2′-deoxyuridine and ethylenediamine, 1,6-hexanediamine, or tris(2-aminoethyl)amine. The modified nucleosides were incorporated into oligodeoxyribonucleotides at one or three positions in place of thymidine residues. The thermal stability of the duplexes was investigated. Three incorporations of ethylenediamine or tris(2-aminoethyl)amine at the C5-position increase the duplex stability. The amino-linker arm affected the stability of the duplexes depending on the number of amino groups in the linker arm and the length of the arm. The linker arm improved the nuclease resistance at 5′-side phosphodiester linkage of the modified nucleoside in oligodeoxyribonucleotides.

A deoxyuridine derivative

The structure of N-(4-{1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-2-tetrahydrofuranyl]-2-oxo-1,2-dihydro-4-pyrimidinyloxy}-3,5-dimethylphenyl)acetamide chloroform solvate, C 19 H 23 N 3 O 6 .CHCl 3 , has been determined and its geometrical features are described. This molecule plays an important role in the convertible nucleoside approach, a method of synthetizing oligodeoxynucleotides bearing tethered functionality

Synthesis of 2′-Deoxyuridine Nucleosides with Appended 5-Position Carbonyl Cross-Linking Groups

Abstract A simple modification of Stille type carbonylative coupling conditions resulted in high yield reactions giving new carbonyl appended 2′-deoxyuridine derivatives useful for chemical cross-linking.