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We developed new DNA triplexes that contain four base triads T-A·T, A-ψ·CBr, G-PIC·YO, and C-G·Py+, where CBr, YO, Py, ψ, and PIC are 5-bromocytosine, 5-methyl-4-pyrimidone, 2-aminopyridine, the aglycons of deoxypseudouridine, and deoxypseudoisocytidine, respectively. DNA duplex incorporating T-A, A-ψ, G-PIC, and C-G, and triplex forming oligonucleotide incorporating T, CBr, YO, and Py formed the triplex as evaluated by Tm measurements. The triplex formation was successfully applied to the inhibition of transcription of the DNA duplex incorporating T7-promoter sequence modified by the above modified bases.

A general synthesis of hetaryl and aryl C-4(5) linked imidazole C-nucleoside analogues has been developed by the reaction of sugar alkynes with het(aryl) iodides, KMnO4/TBAB oxidation and CoFe2O4 NPs catalyzed muti-component coupling of the corresponding diketones, NH4OAc and aromatic aldehydes in one-pot. The sugar alkynes include pyranosides and furanosides with acid sensitive protecting groups. The het(aryl) iodides comprise iodoaromatics, iodoheterocycles, and sterically hindered iodoheteroaromatics.

The synthesis of novel indolizine C-nucleoside analogues has been achieved by the three-component coupling reaction of sugar alkynes, pyridines and α-bromo carbonyl compounds in one pot. The corresponding products are obtained in good to excellent yields. 49 examples have been given. The synthetic method is convenient, practical and efficient. It is suitable for various substrates including structurally diversified sugar alkynes with sensitive groups. The sugar alkynes include pyranosides, furanosides, and acyclic sugars. A plausible mechanism for the formation of indolizine C-nucleoside analogues has been elucidated.

New [(Indolyl)pyrazolyl]-1,3,4-oxadiazole compounds and their derived thioglycosides as well as the corresponding sugar hydrazones were synthesized. The acyclo C-nucleoside analogs of the oxadiazoline base system were also prepared by reaction of acid hydrazides with aldehydo sugars followed by one pot process encompassing acetylation and cyclization of the synthesized hydrazones. The anticancer activity of the newly synthesized compounds was studied against colorectal carcinoma (HCT116), breast adenocarcinoma (MCF7) and prostate cancer (PC3) human tumor cell lines and a number of compounds showed moderate to high activities.

This article describes a very simple route for synthesizing novel lipophilic phosphate bis(t-bu-SATE) prodrugs of acyclic cyclobutylated C-nucleosides such as isocytosine 12 and 9-deazaadenine 19, which were prepared from 1,1-gem cyclobutyl dicarboxylate. Synthesized compounds were evaluated as potential antiviral agents against HIV virus. Some phosphate SATE prodrugs were more active against HIV than parent nucleosides.

Acid-catalyzed dehydrative cyclization of 5-deoxy- l - manno -pentitol-1-yl)-2-heptulose bisphenylhydrazone and subsequent reflux with copper sulfate gave an anomeric mixture of 4-(5-deoxy-α,β- l -arabinofuranosyl)-2-phenyl-2 H -1,2,3-triazole C-nucleoside analogs. The mixture was separated by chromatography, and the anomeric compositions configurations of the components were determined by CD, NMR, mass spectroscopy, and acylation.

Microwave-assisted synthesis of novel acyclic C-nucleosides of 6-alkyl/aryl-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (5-12) and the 6-aryl-thiomethyl analogues 25-27 has been described. Deblocking of 5-12 and 25-27 afforded the free acyclic C-nucleosides 13-20, and 28-30, respectively. All of the synthesized compounds showed no inhibition against HIV-1 and HIV-2 replication in MT-4 cells. However, 6-(3,4-dichlorophenyl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (6) is a potent inhibitor, in vitro, of the replication of HIV-2. These results suggest that compound 6 should be considered as a new lead in the development of antiviral agent.

The preparation of novel 5-amino or 7-hydroxy substituted pyrazolo[4,3-b]pyridine and pyrazolo[3,4-c]pyridine acyclic C-nucleosides is described. Their synthesis was carried out by condensation of suitably substituted lithiated picolines with 2-benzyloxyethoxymethylchloride followed by pyrazole ring annulation. The compounds were evaluated for their antiviral activity against a wide panel of viruses, but were found inactive at subtoxic concentrations.

A series of 1,3-diaryl-5-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-1H-1,2,4-triazole nucleosides (3a-f) were synthesized via the intermolecular cyclization of hydrazonyl chlorides with peracylated ribofuranosyl cyanide catalyzed by Yb(OTf)3 or AgNO3, respectively. Similarly, the 1,2,4-triazole of glucopyranosyl C-nucleosides 5a,b were prepared from the hydrazonyl chlorides and the nitrile 4. Alternatively, the 1,2,4-triazole N-nucleoside 8 was obtained from cyclization of the unsymmetrical bis[alpha-(4-methoxyphenyl)aminobenzylidene]-hydrazine with peracylated 1-amino-D-manno-pentitol.

A novel efficient and practical approach to the synthesis of 4- or 3-substituted phenyl C-nucleosides has been developed. It consists in coupling of protected halogenose 1 with bromophenylmagnesium bromides followed by acid mediated epimerization to prepare 4- or 3-bromophenyl C-nucleoside intermediates. Their Pd-catalyzed cross-coupling reactions with diverse organometallics followed by deprotection afforded the title nucleoside analogues. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

In connection with my program dealing with the discovery of C-nucleosides1−6 and acyclic-C-nucleosides1, 5 as well as the rapid growth in the literature dealing with their biological activity in th...

Reaction of 2-hydrazinopyridine (1) with D-xylose, D-galactose, D-glucose and D-fructose afforded the corresponding hydrazones mainly in the acyclic forms 2, 3, 6 and 11 with minor amounts of the cyclic structures. Oxidative cyclization of the hydrazones with bromine in methanol resulted in the formation of the 3-(polyhydroxyalkyl)-1,2,4-triazolo[4,3-a]pyridine derivatives 13-15 whose acetylation afforded the acetylated derivatives 16-18. Assignment of 1D and 2D NMR spectral data in addition to 15N NMR experiments led to complete characterization of the products.

Galactopyranosylated olefinic ester (4) on conjugate addition of amines yielded stereoselectively galactopyranosylated amino esters (5–18) in fair to good yield. The selected amino esters (5, 6, 13, and 15–17) on reaction with isocyanates resulted in ureido galactopyranosyl amino esters (19–24) in very good yields. Lactamization of compounds 19–24 with DBU, 4 A MS, and tetrabutylammonium bromide in refluxing toluene gave respective C‐galactopyranosyl dihydropyrimidine‐2,4‐diones (25–30) in respectable yields.

The oxirane ring opening of 3-[(benzyloxy)methyl]-7-oxabicyclo[4.1.0]heptane with sodium salt of diethyl malonate followed by treatment with TsOH gave (3aR*,6R*,7aS*)-6-[(benzyloxy)methyl]hexahydro-1-benzofuran-2(3H)-one (3a) and (3aR*,5R*,7aS*)-5-[(benzyloxy)methyl]hexahydro-1-benzofuran-2(3H)-one (3b). Lactones 3a and 3b were formylated and then treated with thiourea or guanidine to give, after deprotection, racemic 5-[2-hydroxy-4- and 2-hydroxy-5-(hydroxymethyl)cyclohexyl]-2-thiouracil (5a and 5b) or -isocytosine (12a and 12b). Simple transformations of the 2-thiouracil derivative led to uracil (7a and 7b), 4-thiouracil (9a and 9b), and cytosine derivatives (10a and 10b).

A short route to a series of 2′-deoxy-C-nucleosides featuring substituted nucleobases has been developed. The key step is the formation of the cyclized products following Mukaiyama's type amide coupling and a simple dehydration, starting from readily accessible synthons. The epimerization of the C1′-stereogenic center was avoided under mild and controlled conditions.

A combinatorial library of 60C- nucleoside analogs was synthesized by sequential coupling of building blocks followed by cyclative cleavage with DBU in an efficient manner. Only DMSO soluble compounds were tested for their modulatory effect against filarial gamma-glutamyl cysteine synthetase (gamma-GCase) and glutathione-S-transeferases (GSTs). Several compounds were found to be weak inhibitors of filarial gamma-GCase, whereas, most of them stimulated filarial GSTs.

Trifluoroacetic acid has been found to be an efficient and non-oxidative catalyst for the epimerization of pyrene and other C-nucleosides in dichloromethane at ambient temperature. Aspects of the epimerization mechanism are also elucidated.

Synthetic studies of imidazole C-nucleoside derivatives and their application to novel histamine H3- and H4-ligands are described, in which the following items are covered. 1) Stereoselective synthesis of imidazole C-nucleosides via diazafulvene intermediates. 2) Synthesis of tetrahydrofuranylimidazoles using efficient use of a PhSe group and its application to novel histamine H3-ligands. 3) Histamine H3- and H4-agonistic activities of imifuramine derivatives. 4) Efficient synthesis of imifuramine and its stereoisomer via diazafulvene intermediates. 5) Difference between diazafulvene cyclization and intramolecular Mitsunobu reaction of 1, 4-diols.

Direct preparation of 2-amino-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-4H-chromene-3-carbonitrile 2 and 1,2-diamino-1,4,5,6,7,8-hexahydro-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-3-quinolinecarbonitrile 11, which were utilized as starting products for the synthesis of S-nucleoside analogues 10 and 15 and C-nucleoside analogues 12 and 13, is presented in the current study. The antibacterial and antifungal activities of these new compounds were evaluated. The structures of the new products were confirmed on the basis of elemental and spectral analysis results.

Reaction of d -glucono- ( 1 ) or d -galactono- ( 2 ) 1,5-lactones and d - glycero - d -guloheptonic-1,4-lactone ( 11 ) with thiocarbohydrazide ( 3 ) afforded the seco C-nucleosides 4-amino-3-( d -gluco- ( 4 ) or d - galacto - ( 5 ) pentitol-1-yl)-5-mercapto-1,2,4-triazoles and 4-amino-3-( d - glycero - d - gulo -hexitol-1-yl)-5-mercapto-1,2,4-triazole ( 12 ). Their conversions to the 3-(1,2,3,4,5-penta- O -acyl- d - gluco - ( 7 and 9 ) or the d - galacto ( 8 and 10 ) pentitol-1-yl)-6-substituted 1,2,4-triazolo[3,4-b]1,3,4-thiadiazole and 3-(1,2,3,4,5,6-hexa- O -acetyl- d - glycero - d - gulo hexitol-1-yl)-6-methyl-1,2,4-triazolo[3,4- b ]1,3,4-thiadiazole ( 13 ) were achieved under acylative conditions. Reaction of diethyl galactrate ( 17 ) with 3 gave 1,4-bis (4-amino-5-mercapto-1,2,4-triazol-3-yl)- galacto -tetritol ( 18 ), which upon reaction with acetic anhydride gave 1,4-bis(6-methyl-1,2,4-triazolo[3,4- b ]1,3,4-thiadiazol-3-yl)-1,2,3,4-tetra- O -acetyl- galacto -tetritol ( 19 ). When the tetra- O -acetylgalactaric acid ( 15 ) was used instead of 17 , the attack of 3 had taken place on the ester group rather than the carboxylic group, whereby 16 was obtained rather than the tetra- O -acetyl derivative of 18 . The structures were confirmed by using 1 H, 13 C and 2D NMR spectra (DQFCOSY and HMQC) experiments. The vicinal coupling constants were used to deduce the favored conformations.

C-Nucleosides, 4-amino-8-(β- l -ribofuranosyl)pyrazolo[1,5-a]-1,3,5-triazine ( 12 ) and 4-amino-7-(β- l -ribofuranosyl)-5H-pyrrolo[3,2-d]pyrimidine ( l -9-deazaadenosine, 22 ), were synthesized from the key intermediate, 3-dimethylamino-2-(2,3-O-isopropylidene-5-O-trityl- l -ribofuranosyl)acrylonitrile ( 8 ), which was prepared from l -xylose in 11 steps.

Anomeric 2-(α- and β- d -erythrofuranosyl)benzimidazole C-nucleoside analogues 2 and 3 , were prepared from the corresponding epimeric 2-( d - arabino , and d - ribo -tetritol-1-yl)benzimidazole analogues 1 and 4 , respectively. Similarly, 2-(β- l -erythrofuranosyl)benzimidazole 13 was obtained from the precursor 2-( l - arabino -tetritol-1-yl)benzimidazole 12 . The structure and anomeric configuration of the C-nucleoside analogues 2 , 3 , and 13 were determined by acylation, 1 H and 13 C NMR spectroscopy, and mass spectrometry.

Standard Pd-catalyzed cross-coupling reactions proceed chemoselectively at the position of the bromine, whereas nucleophilic substitutions are unselective.

by using thecommercially available 2-amino-6-methylpyrimidin-4(3H)-one (5) as a starting material, and this procedure (Scheme 1)was expected to be very efficient in synthesizing our targetmolecule 3. The treatment of 6 with 2.2 equivalent of N,N-dimethyl-formamide dimethyl acetal at room temperature providedthe corresponding 2-(dimethylamino)methyleneimino deri-vative 8, which was converted to 3-benzyl-2-[(dimethyl-amino)methyleneimino]-5-nitro-6-methylpyrimidin-4-one(9) by treating with benzyl chloride in the presence ofDBU.

The synthesis of 2-deoxy benzamide riboside (XI) proceeds via the preparation of the m-vinyl substituted phenyl exo-alkene key intermediate (VII) which provides the necessary flexibility to access the m-carboxamide substituent, essential to benzamide riboside analogues.

A series of novel 1′-substituted analogues of 4-aza-7,9-dideazaadenosine C-nucleoside are prepared and tested in antiviral assays.

The circular dichroism of a series of acyclic polyhydroxyalkyl benzimidazole C-nucleoside analogs was correlated with the stereochemistry of the chiral carbon atom α to the benzimidazole base moiety. This correlation was used for the assignment of the anomeric configuration of 2-(β-l-erythrofuranosyl) benzimidazole C-nucleoside analogs without a need to have the other anomer on hand, in a similar manner to the correlation obtained for assignment of the anomeric configuration of triazole C-nucleoside analogs.

Synthesis of 4′-C-modified nucleosides and their derivatives, as well as the structure-activity relationship toward hepatitis C virus were discussed.

The synthesis of C-alkynyl glycosides is best performed by treatment of the crude aldehydes derived from building blocks such as (I) with the Bestmann—Ohira compound (II).

The title compounds are tested for their antitumor activity against Ehrlich Ascites Carcinoma cells and the most active compounds are (I), (III), and (VI)— (VIII).

Lipophilic prodrugs of acyclic cyclobutylated C-nucleosides, isocytosine (VI) and 9-deazaadenine (XI), are prepared by applying the bis(SATE) approach.

The title compounds, e.g. (XI) exhibit no activity or cytotoxicity in the HCV (hepatitis-C virus) assay.

C-Glycosylation of two guanine analogues, 9-deaza- and 7-deazaguanine, has been achieved under Friedel-Crafts conditions, providing a direct synthetic route to 9-deazaguanosine (4; 2-amino-7-beta-D-ribofuranosyl-5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one) and 8-beta-D-ribofuranosyl-7-deazaguanine (16), respectively. This electrophilic C-glycosylation was applied successfully to six guanine and substituted-guanine analogues resulting in yields of approximately 50%. This represents the first reported C-ribosylation of preformed nitrogen heterocycles isosteric with guanine. These C-nucleosides were evaluated for their ability to provide protection against a lethal Semliki Forest virus infection in mice, relative to 7-thia-8-oxoguanosine which was used as a positive control. Two of the C-nucleosides, 2-amino-6-chloro-5-methyl-7-beta-D-ribofuranosyl-5H-pyrrolo [3,2-d]pyrimidin-4(3H)-one (12) and the corresponding 6-bromo derivative (13), showed good prophylactic activity in this virus model system.

New dienophiles, 3-acetoxy-2-dimethylphosphonoacrylates, have been prepared and their Diels-Alder reactions with cyclopentadiene investigated. The [4 + 2] adducts thus formed were converted to carbocyclic C-nucleoside precursors by means of reductive retrograde aldol (RRA) reaction.

Photolysis of O-acyl-N-hydroxy-2-thiopyridone, derived from 2-tetrahydrofuryl carboxylic acid or 2,5 -anhydro -D -allonic acid, gave the corresponding C-nucleoside derivatives in the presence of heteroaromatic compounds via radical pathways.