Synthesis of nucleoside 3′,5′-cyclic phosphorothioates

A convenient and general method for the synthesis of nucleoside 3′,5′-cyclic phosphorothioates using nucleosides as starting materials is described.A synthesis of nucleoside 3′,5′-cyclic phosphorothioates is described.     

Synthesis of 2-O-ethyl analogues of 3′-azido- and 3′-fluoro-2′,3′-dideoxyuridines and evaluation of their biological activity against HIV

Summary 2-O-Ethyluracil and 2-O-ethylthymine were silylated with 1,1,1,3,3,3-hexamethyldisilazane and condensed in the presence ofTMS triflate with 2,3-dideoxy-3-fluoro-D-erythro-pentofuranoside, 3-azido-2,3-dideoxy-D-erythro-pentofuranoside, and 2,3-dideoxy-3-phthalimido--D-erythro-pentofuranose derivatives to give the corresponding 2-O-ethyl nucleosides. Deprotection with saturated methanolic ammonia afforded the 2,3-dideoxy-3-fluoro-2-O-ethyluridines, whereas 3-azido-2,3-dideoxy-3-O-ethyluridine was obtained by deprotection with tetrabutylammonium fluoride in tetrahydrofuran. 3-Amino-2,3-dideoxy-3-O-ethyluridine could be obtained only by treatment of the corresponding 3-azido nucleoside with triphenylphosphine in pyridine. 3-Deoxy-2-O-ethyl-3-fluorothymidine (6b) showed moderate activity against HIV-1.

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Synthese von 2-O-Ethyl-Analogen von 3-Azido- und 3-Fluor-23-dideoxyuridinen und Bestimmung ihrer biologischen Aktivität gegenüber HIV

Zusammenfassung 2-O-Ethyluracil und 2-O-Ethylthymin wurden mit 1,1,1,3,3,3-Hexamethyldisilazan silyliert und in Gegenwart vonTMS-triflat mit 2,3-Dideoxy-3-fluoro-D-erythro-pentofuranosid, 3-Azido-2,3-dideoxy-D-erythro-pentofuranosid und 2,3-Dideoxy-3-phthalimido--D-erythro-pentofuranosederivaten zu den entsprechenden 2-O-Ethyl-Nucleosiden umgesetzt. Entfernung der Schutzgruppe mit gesättigter methanolischer Ammoniaklösung lieferte 2,3-Dideoxy-3-fluor-2-O-ethyluridin; 3-Azido-2,3-dideoxy-3-O-ethyl-uridin wurde durch Entschützung mit Tetrabutylammoniumfluorid in Tetrahydrofuran erhalten. 3-Amino-2,3-dideoxy-3-O-ethyl-uridin konnte nur durch Behandeln des entsprechenden 3-Azido-Nucleosids mit Triphenylphosphin in Pyridin hergestellt werden. 3-Deoxy-2-O-ethyl-3-fluor-thymidin (6b) zeigt geringe Aktivität gegenüber HIV-1.

     

Synthesis of 4′-substituted 2′-deoxy-4′-thiocytidines and its evaluation for antineoplastic and antiviral activities

4′-Azido- (7), 4′-C-fluoromethyl- (8) 4′-C-ethynyl- (9) and 4′-C-cyano- (10) 2′-deoxy-4′-thiocytidines have been synthesized. In this study, it was found that the isolated yield of 4′-thiouracil nucleoside 13 in a Lewis acid-promoted Vorbrüggen-type glycosidation utilizing 12 was better than that of the electrophilic glycosidation reaction between silylated uracil and 11. This improved result prompted us to perform the glycosidation utilizing 36 and 43 for the synthesis of 37 and 44. Introduction of the azido group was carried out by nucleophilic substitution in the 4′-benzoyloxy derivative 22a. On the other hand, 9 and 10 were synthesized by way of the chemical manipulation of the hydroxymethyl group at the 4′-position of 46.Evaluation of the antineoplastic activity of 2 and 7–10 against human B-cell (CCRF-SB) and T-cell leukemia (Molt-4) cell lines revealed that 4′-azido- (7) and 4′-C-fluoromethyl- (8) derivatives exhibited cytotoxic activity whereas no cytotoxicity was observed in the 4′-C-ethynyl- (9) and 4′-C-cyano- (10) derivatives as well as the parent compound 2. Compound 7 was also found to possess promising antiviral activity against VZV and HSV-1 without any cytotoxity against HEL host cells. It is noteworthy that 7 exhibited potent inhibitory activities against the thymidine kinase-deficient (TK^?) mutant of VZV and HSV-1.     

Synthesis of 2′,3′-Dideoxy-2′-Fluorokanamycin A

2′,3′-Dideoxy-2′-fluorokanamycin A (23) was prepared by condensation of 6-azido-4-0-benzoyl-2,3,6-trideoxy-2-fluoro-α-D-ribo-hexopyranosyl bromide (13) and a protected disaccharide (19). Methyl 4,6-0-benzylidene-3-deoxy-β-D-arabino-hexopyranoside (5) prepared from methyl 4,6-0-benzylidene-3-chloro-3-deoxy-β-D-allo-hexopyranoside (1) by oxidation with pyridinium chlorochromate followed by reduction with Na₂ S₂O₄ was fluorinated with the DAST reagent to give methyl 4,6-O-benzylidene-2,3-dideoxy-2-fluoro-β-D-ribo-hexopyranoside (7). Successive treatment of 7 with NBS, NaN₃ and SOBr₂ gave 13. The structure of the final product (23) was determined by the ¹H and ¹⁹F and shift-correlated 2D NMR spectra.     

Synthesis of 2′,3′-didehydro-3′-deoxythymidine and its activity against HIV

2,3-Didehydro-3-deoxythymidine has been obtained with an overall yield of 10% by the condensation of 1,2-di-O-acetyl-3,5-di-O-benzoyl-D-xylofuranose with bis-(dimethylsilyl)thymine and a series of subsequent transformations. The anti-HIV activity of the compound obtained was studied on the model of MT-4 lymphoid cells primarily infected with HIV-1. It was found that the substance effectively inhibits the reproduction of HIV-1 in a cell culture.Institute of Organic Chemistry, Ural Branch, Russian Academy of Sciences, Ufa. Vector Scientific-Production Association, Kil'tsovo, Novosibirsk Province. Institute of the Chemistry of Plant Substances, Uzbek SSR Academy of Sciences, Tashkent. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 133–136, January–February, 1993.     

Synthesis of 2-fluoro-substituted and 2,6-modified purine 2′,3′-dideoxy-2′,3′-difluoro-d-arabinofuranosyl nucleosides from d-xylose

A series of novel purine-modified 2′,3′-dideoxy-2′,3′-difluro-D-arabinonucleosides, including fluorinated analogs of fludarabine and nelarabine, have been prepared via anion glycosylation reactions of salts of 2-fluoropurine derivatives with the glycosyl bromide. A short and efficient synthetic route to the carbohydrate precursor 5-O-benzoyl-2,3-difluoro-α-d-arabinofuranosyl bromide was developed in five steps from d-xylose. Improved synthesis of methyl 5-O-benzoyl-2,3-difluoro-α-d-arabinofuranoside based upon the study of diethylaminosulfur trifluoride (DAST)-reactions with 5-O-protected methyl D-xylosides was explored using mild reaction conditions on the key step. New peculiarities for selective fluorinations of 5-O-benzoylated α- and β-D-pentofuranosides with DAST leading to the formation of mono and difluoro-furanoside derivatives are reported.     

Synthesis of Steroidal Spiro-1′,2′,4′-triazolidine-3′-thiones

Steroidal ketone thiosemicarbazones (4–6), obtained from the corresponding ketones(1–3), on oxidative cyclization with H₂O₂ at 0°C provide title compounds (7–9), respectively. The structures of these compounds have been established on the basis of their elemental analytical and spectral data.     

An Improved Synthesis of 2′-Hydroxy-3′,4′,6′-trimethoxyacylophenones

A wide variety of 2′-hydroxypolymethoxyacetophenones and propiophenones, e.g. 1a and 1b are used in the synthesis of flavone and ehromone natural products.¹ Repeated attempts to prepare 1a and 1b by reacting 1,2,3,5-tetramethoxybenzene 2 with acetyl or propionyl chlorides and AlCl₃ in ether² gave products which were difficult to purify.³ We traced the problem to ring-ethoxy contaminants which were isolated and tentatively identified as 3a and 3b.     

Synthesis of 2′,3′-dideoxynucleosides from 5-alkoxymethyluracils

Summary A modified synthesis of protected 2,3-dideoxyribose5 starting fromL-glutamic acid (1) is described. Reaction of5 with silylated 5-hydroxymethyluracil7 a and 5-alkoxymethyluracils7 b–e in the presence of trimethylsilyl triflate afforded an anomeric mixture of 2,3-dideoxyuridine derivatives8 a–e and9 a–e. Deprotection with methanolic ammonia and separation by chromatography gave the corresponding nucleosides10 a–e and11 a–e. Treatment of9 b–e with tri(1H-1,2,4-triazol-1-yl)phosphine oxide and subsequent reaction of12 b–e with ammonia in dioxane afforded the cytosine derivatives13 b–e which on treatment with methanolic ammonia gave the corresponding 2,3-dideoxycytidine derivatives14 b–e and15 b–e. In contrast with the parent compounds, these alkoxymethyl derivatives had no appreciable activity against human immunodeficiency virus (HIV-1).

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Synthese von 2,3-Dideoxynucleosiden aus 5-Alkoxymethyluracilen

Zusammenfassung Ausgehend vonL-Glutaminsäure (1) wird eine modifizierte Synthese von geschützter 2,3-Dideoxyribose (5) beschrieben. Reaktion von5 mit silyliertem 5-Alkoxymethyluracilen7 b–e in Gegenwart von Trimethylsilyltriflat ergab anomere Mischungen der 2,3-Dideoxyuridinderivate8 a–e und9 a–e. Abspaltung der Schutzgruppe mit methanolischen Ammoniak und chromatographische Trennung ergab die entsprechenden Nucleoside10 a–e und11 a–e. Behandlung von9 b–e mit Tri(1H-1,2,4-triazol-1-yl)phosphinoxid und nachfolgende Reaktion von12 b–e mit Ammoniak in Dioxan ergab die Cytosinderivate13 b–e, welche nach Behandlung mit methanolischem Ammoniak die entsprechenden 2,3-Dideoxycytidinderivate14 b–e und15 b–e ergaben. Im Gegensatz zur Stammverbindung hatten diese Alkoxymethylderivate keine nennenswerte Wirksamkeit gegen den menschlichen Immunschwächevirus (HIV-1).

     

Synthesis of β-L-2′,3′-Dideoxy-2′-fluoro-3′-hydroxymethylarabinofuranosyl Pyrimidine Nucleosides

β-2′,3′-Dideoxy-2′-fluoro-3′-hydroxymethylarabinofuranosylthymine 10 and cytosine 12 were synthesized from L-xylose and were found to be inactive against HIV-1 in acutely infected lymphocytes.     

Synthesis of 2′-5′,3′-5′ linked triadenylates

2′-5′,3′-5′ Linked triadenylates have been synthesized by direct bisadenylylation of adenosine 2′ and 3′ hydroxyls with an adenosine 5′-phosphorochloridite followed by oxidation.     

Synthesis and evaluation of antiviral activity of 2′-deoxyuridines with 5-methylene-2-thiohydantoin substituents in the 5-position

Summary 1-(2-Deoxy-3,5-bis-O-(4-methylbenzoyl)-D-erythro-pentofuranosyl)-5-formyluracil (4) was synthesized from 5-formyluracil and an appropriate methyl glycoside and condensed with 2-thiohydantoin (5a) and its corresponding 3-phenyl derivative5b to give 5-[1-(2-deoxy-3,5-bis-O-(4-methylbenzoyl)-D-erythro-pentofuranosyl)uracil-5-ylmethylene]-2-thiohydantoins7a and7b, respectively, in 65–70% yield. They were deprotected with sodium methoxide in methanol to give both anomers of the free nucleosides. In a different route 5-formyluracil (1) was condensed with5b and subsequently with an appropriate methyl glycoside to give7b.On leave from Chemistry Department, Faculties of Science and Education, Tanta University, Tanta, Egypt     

Synthesis of 3′,4′-Dimethoxyisoflavone Derivaties

2-(Un)substituted-3,4-dimethoxy-7-hydroxyisoflavones were synthesized. Their derivatives substituted at the phenolic hydroxyl were prepared by alkylation and acylation. Aminomethyl derivatives were also prepared.     

Synthesis of 3-(3′-Acetyl-5′-aroyl-1′,3′,4′-oxadiazolyl-2′)-chromones

A general method has been proposed for synthesizing 3-(3-acetyl-5-aroyl-1,3,4-oxadiazolyl-2)-chromones that has been based on conversion of 3-formylchromones to acylhydrazones and of theacylhydrazones into the heterocyclic chromones.     

A divergent synthesis of d- and l-carbocyclic 4′-fluoro-2′,3′-dideoxynucleosides as potential antiviral agents

d- and l-Carbocyclic 4′-fluoro-2′,3′-dideoxynucleosides have been synthesized from 2, which can be conveniently prepared from 1,2:5,6-di-O-isopropylidene-d-mannitol 1 in eight steps. Ruthenium-catalyzed ring-closing metathesis has been employed in the synthesis of d-nucleosides, whereas the l-series have been obtained through an intramolecular nucleophilic substitution reaction. The Mitsunobu condensation was used as a general tool for the synthesis of both purine and pyrimidine nucleosides.     

Synthesis and mesomorphic properties of 4-methoxyphenyl 4′- n -alkoxy-2′,3′,5′,6′-tetrafluorobiphenyl-1-carboxylates

A novel type of 4-methoxyphenyl 4′-n-alkoxy-2′,3′,5′,6′-tetrafluorobiphenyl-1-carboxylates have been synthesized. Textural observations by polarizing microscopy and DSC measurements of the phase transitions show that all of these compounds are thermotropic liquid crystals with only a nematic mesophase. The relationship between the properties and chemical structures of these compounds is discussed.     

Evaluation of molecularly imprinted polymers using 2′,3′,5′-tri-O-acyluridines as templates for pyrimidine nucleoside recognition

In this paper, we describe the synthesis and evaluation of molecularly imprinted polymers (MIPs), prepared using 2′,3′,5′-tri-O-acyluridines as ‘dummy’ templates, for the selective recognition of uridine nucleosides. The MIPs were synthesised using a non-covalent approach with 2,6-bis-acrylamidopyridine (BAAPy) acting as the binding monomer and ethylene glycol dimethacrylate (EGDMA) as the cross-linking agent. The MIPs were evaluated in terms of capacity, selectivity and specificity by analytical and frontal liquid chromatography measurements. The results obtained in organic mobile phases suggest that the nucleosides are specifically bound to the polymer by the complementary hydrogen bonding motifs of the binding monomer and the nucleoside bases. The MIPs exhibited relatively high imprinting factors for 2′,3′,5′-tri-O-acyluridines, while they did not show any binding capacity for other nucleosides lacking the imide moiety on their base. Moreover, the presence of ester-COO groups in the EGDMA cross-linker may lead to the formation of additional hydrogen bonds with the 2′,3′ and/or 5′-OH of sugar part, allowing enhancement of the recognition of the uridine nucleosides. In aqueous media, results show that the binding is driven by hydrophobic interactions.     

Synthesis and Biological Activity of Novel 2,3-Dihydro-2-phenylsulfonylhydrazono-3-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyl)thiazoles

A series of novel 2,3-dihydro-2-phenylsulfonylhydrazono-3-(2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl) thiazoles were designed and synthesized via the reaction of thiosemicarbazide with chloroaldehyde.Their chemical structures were characterized by 1H and 13C NMR spectroscopy and elemental analysis.The bioassay results indicate that some of these compounds exhibit moderate fungicidal and herbicidal activities.