Synthesis of some 3',5'-dideoxy-5'-C-phosphonomethyl nucleosides.

Ammonium [1-(3',5',6'-trideoxy-beta-D-erythro-hexofuranosyl)thymine]-6'- phosphonate (1), ammonium 3',5'-dideoxycytidine-5'-C-methylphosphonate (2) and 3',5'-dideoxyadenosine-5'-C-methyl phosphonic acid (3) have been synthesized and tested for anti-HIV activity. The key steps involved an Arbuzov reaction between triethyl phosphite and 3,5,6-trideoxy-6-iodo-1,2-O-isopropylidene-alpha-D-erythro- hexofuranose (7), followed by condensation with the appropriate nucleoside bases. The substances 1, 2 and 3 have been tested in vitro against HIV.     

Synthetic utility of an isolable nucleoside phosphonium salt

The reaction of O6-benzyl-3',5'-bis- O-( tert-butyldimethylsilyl)-2'-deoxyxanthosine with 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) yielded the nucleoside C-2 tris(dimethylamino)phosphonium hexafluorophosphate salt as a stable, isolable species. This is in contrast to reactions of inosine nucleosides with BOP, where the in situ formed phosphonium salts undergo subsequent reaction to yield O6-(benzotriazol-1-yl)inosine derivatives. The phosphonium salt obtained from the 2'-deoxyxanthosine derivative can be effectively used to synthesize N2-modified 2'-deoxyguanosine analogues. Using this salt, a new synthesis of an acrolein-2'-deoxyguanosine adduct has also been accomplished.     

Nucleic acid related compounds. 116. Nonaqueous diazotization of aminopurine nucleosides. Mechanistic considerations and efficient procedures with tert-butyl nitrite or sodium nitrite

Nonaqueous diazotization-dediazoniation of two types of aminopurine nucleoside derivatives has been investigated. Treatment of 9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-2-amino-6-chloropurine (1) with SbCl(3)/CH(2)Cl(2) was examined with benzyltriethylammonium (BTEA) chloride as a soluble halide source and tert-butyl nitrite (TBN) or sodium nitrite as the diazotization reagent. Optimized yields (>80%) of the 2,6-dichloropurine derivative were obtained with SbCl(3). Combinations with SbBr(3)/CH(2)Br(2) gave the 2-bromo-6-chloropurine product (>60%), and SbI(3)/CH(2)I(2)/THF gave the 2-iodo-6-chloropurine derivative (>45%). Antimony trihalide catalysis was highly beneficial. Mixed combinations (SbX(3)/CH(2)X'(2); X/X' = Br/Cl) gave mixtures of 2-(bromo, chloro, and hydro)-6-chloropurine derivatives that were dependent on reaction conditions. Addition of iodoacetic acid (IAA) resulted in diversion of purine radical species into a 2-iodo-6-chloropurine derivative with commensurate loss of other radical-derived products. This allowed evaluation of the efficiency of SbX(3)-promoted cation-derived dediazoniations relative to radical-derived reactions. Efficient conversions of adenosine, 2'-deoxyadenosine, and related adenine nucleosides into 6-halopurine derivatives of current interest were developed with analogous combinations.     

Enantiomeric syntheses of conformationally restricted D- and L-2', 3'-dideoxy-2',3'-endo-methylene nucleosides from carbohydrate chiral templates

D- and L-2',3'-dideoxy-2',3'-endo-methylene nucleosides were synthesized as potential antiviral agents. The key intermediates 5-O-tert-butyldiphenylsilyl-D- and L-2,3-dideoxy-2, 3-endo-methylenepentofuranoses (20 and 33, respectively) were obtained by selective protection of the D- and L-2,3-dideoxy-2, 3-endo-methylenepentose derivatives 19 and 32 which were prepared from 1,2:5,6-di-O-isopropylidene-D-mannitol and L-gulonic gamma-lactone, respectively, and converted to 5-O-tert-butyldiphenylsilyl-D- and L-2,3-dideoxy-2, 3-endo-methylenepentofuranosyl acetates (21 and 34, respectively) or the chlorides 22 and 35. The acetates and chlorides were condensed with pyrimidine and purine bases by Vorbrüggen conditions or S(N)2-type condensation. Vorbrüggen conditions using the acetates gave mostly alpha-isomers. In contrast, S(N)2-type condensation using the chlorides greatly improved the beta/alpha ratio. From the synthesis, several D- and L-2',3'-dideoxy-2',3'-endo-methylene nucleoside analogues have been obtained, and their structures have been elucidated by NMR spectroscopy and X-ray crystallography. The synthesized D- and L-adenine derivatives were tested as substrates of adenosine deaminase, which indicated that the D-adenosine derivative 4a was a good substrate of a mammalian adenosine deaminase from calf intestinal mucosa (EC 3.5.4.4) while its L-enantiomer 10a was a poor substrate. Either the D-adenine derivative 4a or its L-enantiomer 10a did not serve as an inhibitor of the enzyme.     

Unusual deoxygenation and reactivity studies related to O6-(benzotriazol-1-yl)inosine derivatives

New and unusual developments related to the chemistry of O6-(benzotriazol-1-yl)inosine derivatives are reported. First, a simple, scalable method for their syntheses via the use of PPh3/I2/HOBt has been developed and has been mechanistically investigated by 31P(1H) NMR. Studies were then conducted into a unique oxygen transfer reaction between O6-(benzotriazol-1-yl)inosine nucleosides and bis(pinacolato)diboron (pinB-Bpin) leading to the formation of C-6 (benzotriazol-1-yl)purine nucleoside derivatives and pinB-O-Bpin. This reaction has been investigated by 11B(1H) NMR and compared to pinB-O-Bpin obtained by oxidation of pinB-Bpin. The structures of the C-6 (benzotriazol-1-yl)purine nucleosides have been unequivocally established via Pd-mediated C-N bond formation between bromo purine nucleosides and 1H-benzotriazole. Finally, short and extremely simple synthesis of 1,N6-ethano- and 1,N6-propano-2'-deoxyadenosine are reported in order to demonstrate the synthetic versatility of the O6-(benzotriazol-1-yl)inosine nucleoside derivatives for the assembly of relatively complex compounds.     

6-bromopurine nucleosides as reagents for nucleoside analogue synthesis.

Surprisingly facile direct substitution reactions with acetyl-protected 6-bromopurine nucleosides are described. Included in the series of bromonucleosides studied is the guanosine derivative N(2)-2',3',5'-tetraacetyl-6-bromopurine ribonucleoside, the synthesis of which is reported here for the first time. Brominated nucleosides had not previously been considered optimal substrates for S(N)Ar reactions given the general reactivity trend for halogenated aromatic systems (i.e. F > Cl > Br > I). However, even weakly nucleophilic aromatic amines give high yields of the substitution products in polar solvents with these 6-bromopurine nucleosides. For primary aromatic amines, secondary aliphatic amines, and imidazole, reaction takes place only at C6, with no effect on the acetyl-protected ribose. In addition, we report the first synthesis of 3',5'-di-O-acetyl-6-bromopurine-2'-deoxyribonucleoside and its reaction with an arylamine in MeOH in the absence of added metal catalyst. Thus, C6-arylamine derivatives of both adenosine and 2'-deoxyadenosine can be prepared via simple S(N)Ar reactions with the corresponding 6-bromo precursor. We also describe high yielding and C6-selective substitution reactions with 6-bromonucleosides using alcohol and thiol nucleophiles in the presence of added base (DBU). Finally, C6-bromonucleosides are shown to be readily hydrogenated to give purine or 2-aminopurine products in good yield. This work increases the arsenal of reactions and strategies available for the synthesis of nucleoside analogues as potential biochemical tools or new therapeutics.     

Synthesis of 3'-deoxynucleosides with 2-oxabicyclo[3.1.0]hexane sugar moieties: addition of difluorocarbene to a 3',4'-unsaturated uridine derivative and 1,2-dihydrofurans derived from D- and L-xylose1

Syntheses of 3'-deoxy analogues of adenosine, cytidine, and uridine with a 2,2-difluorocyclopropane ring fused at C3'-C4' are described. Treatment of a 2',5'-protected-3',4'-unsaturated derivative of uridine with difluorocarbene [generated from (CF3)2Hg and NaI] gave a diastereomeric mixture of the 3',4'-difluoromethylene compounds (alpha-L-arabino/beta-D-ribo, approximately 5:4). The limited stereoselectivity for addition at the beta face results from competitive steric hindrance by an allylic 4-methoxybenzyloxy group at C2' on the alpha face and a homoallylic nucleobase at C1' on the beta face. Protected uracil derivatives were converted into their cytosine counterparts via 4-(1,2,4-triazol-1-yl) intermediates. Treatment of 1,2-dihydrofurans derived from D- and L-xylose with difluorocarbene resulted in stereospecific addition at the beta face (anti to the 1,2-O-isopropylidene group on the alpha face). Glycosylations with activated enantiomeric sugar derivatives with the fused difluorocyclopropane ring on the beta face gave protected adenine nucleosides, whereas attempted glycosylation with an alpha-fused derivative gave multiple products. Removal of base- and sugar-protecting groups gave new difluoromethylene-bridged nucleoside analogues.     

Synthesis of C3' modified nucleosides for selective generation of the C3'-deoxy-3'-thymidinyl radical: a proposed intermediate in LEE induced DNA damage

DNA damage pathways induced by low-energy electrons (LEEs) are believed to involve the formation of 2-deoxyribose radicals. These radicals, formed at the C3' and C5' positions of nucleotides, are the result of cleavage of the C-O phosphodiester bond through transfer of LEEs to the phosphate group of DNA oligomers from the nucleobases. A considerable amount of information has been obtained to illuminate the identity of the unmodified oligonucleotide products formed through this process. There exists, however, a paucity of information as to the nature of the modified lesions formed from degradation of these sugar radicals. To determine the identity of the damage products formed via the 2',3'-dideoxy-C3'-thymidinyl radical (C3'(dephos) sugar radical), phenyl selenide and acyl modified sugar and nucleoside derivatives have been synthesized, and their suitability as photochemical precursors of the radical of interest has been evaluated. Upon photochemical activation of C3'-derivatized nucleosides in the presence of the hydrogen atom donor tributyltin hydride, 2',3'-dideoxythymidine is formed indicating the selective generation of the C3'(dephos) sugar radical. These precursors will make the identification and quantification of products of DNA damage derived from radicals generated by LEEs possible.     

O6-(benzotriazol-1-yl)inosine derivatives: easily synthesized, reactive nucleosides

A novel class of O6-(benzotriazol-1-yl)inosine as well as the corresponding 2'-deoxy derivatives can be conveniently prepared by a reaction between sugar-protected or -unprotected inosine or 2'-deoxyinosine nucleosides and 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP). The reaction appears to proceed via a nucleoside phosphonium salt, and in the absence of any additional nucleophile, the released 1-hydroxybenzotriazole undergoes reaction with the formed phosphonium salt leading to the requisite O6-(benzotriazol-1-yl)inosine or 2'-deoxyinosine derivatives. Isolation and characterization of the phosphonium salt as well as analysis by 31P{1H} NMR appear to be consistent with this reaction pathway. The resulting O6-(benzotriazol-1-yl)inosine derivatives are effective as electrophilic nucleosides, undergoing facile reactions with a variety of nucleophiles such as alcohols, phenols, amines, and a thiol. Unusual and challenging nucleoside derivatives such as an aryl-bridged dimer, a nucleoside-amino acid conjugate, and a nucleoside-nucleoside dimer have also been synthesized from the O6-(benzotriazol-1-yl)-2'-deoxyinosine derivative. Finally, a fully protected DNA building block, the O6-(benzotriazol-1-yl)-2'-deoxyinosine 5'-O-DMT 3'-O-phosphoramidite, has been prepared and a preliminary evaluation of its use for DNA modification has been performed. Results from these studies indicate several important facts: A single, simple methodological approach provides a class of stable, isolable ribo and 2'-deoxyribonucleoside derivatives that possess excellent reactivity for SNAr chemistry with a wide range of nucleophiles. Also, a benzotriazolyl nucleoside phosphoramidite appears to be a suitable reagent for incorporation into DNA for purposes of site-specific DNA modification.     

Pyrrolyl-, 2-(2-thienyl)pyrrolyl- and 2,5-bis(2-thienyl)pyrrolyl-nucleosides: synthesis, molecular and electronic structure, and redox behaviour of C5-thymidine derivatives

A series of modified nucleosides based on thymidine have been prepared by Pd-catalysed cross-coupling between N-alkyl-alkynyl functionalised pyrrolyl- (py), 2-(2-thienyl)pyrrolyl- (tp) or 2,5-bis(2-thienyl)pyrrolyl (tpt) groups with 5-iodo-2'-deoxyuridine. The length of the alkyl chain linking the nucleoside and pyrrolyl-containing unit, N(CH(2))(n)C[triple bond, length as m-dash]C-nucleoside (where n = 1-3) was also varied. The compounds have been characterised by (1)H NMR, ES-MS, UV-vis, cyclic voltammetry (CV) and, in some cases, single-crystal X-ray diffraction. Cyclic voltammetry studies demonstrated that all the py-, tp- and tpt-alkynyl derivatives 1-7 can be electrochemically polymerised to form conductive materials. It was found that increasing the N-alkyl chain length in these cases resulted in only minor changes in the oxidation potential. The same behaviour was observed for the tp- and tpt-modified nucleosides 9-12; however, the py-derivative, 8, produced a poorly conducting material. DFT calculations on the one-electron oxidised cation of the modified nucleosides bearing tp or tpt showed that spin density is located on the pyrrolyl and thienyl units in all cases and that the coplanarity of adjacent rings increases upon oxidation. In contrast, in the corresponding pyrrolyl cases the spin density is distributed over the whole molecule, suggesting that polymerisation does not occur solely at the pyrrolyl-Cα position and the conjugation is interrupted.     

Hemicyanine-linked pyrimidine mimics as solvatochromic fluorophores with visible excitation wavelengths

The design of solvatochromic fluorescent nucleosides with visible excitation wavelengths is a goal towards the generation of modified oligonucleotides for fluorimetry-based molecular imaging. Herein, two hemicyanine-linked C5-2′-deoxyuridine nucleosides (PyI-dU and APPy-dU) have been synthesized by first generating hemicyanine-alkyne precursors that were attached via the alkyne moiety to 5-iodo-2′-deoxyuridine (5-I-dU) by Sonogashira coupling. The photophysical properties of the hemicyanine-linked dU probes have been characterized and compared to the corresponding properties of the hemicyanine-alkyne precursors. The nucleoside probe PyI-dU exhibits optical features that mimic the properties of the free hemicyanine-alkyne precursor, while the APPy-dU probe displays more favorable optical properties (longer excitation wavelength, brighter emission in water) than its precursor that is ascribed to π-stacking interactions between the hemicyanine dye with the dU nucleobase. Overall, probe APPy-dU is a superior solvatochromic fluorophore than PyI-dU suggesting its greater utility for fluorescent imaging applications.     

Hydrolysis of 2',3'-O-methyleneadenos-5'-yl bis(2',5'-di-O-methylurid-3'-yl) phosphate, a sugar O-alkylated trinucleoside 3',3',5'-monophosphate: implications for the mechanism of large ribozymes

Hydrolytic reactions of 2',3'-O-methyleneadenos-5'-yl bis(2',5'-di-O-methylurid-3'-yl) phosphate (1), a sugar O-alkylated trinucleoside 3',3',5'-monophosphate, have been followed by RP HPLC over a wide pH range. Under neutral and mildly acidic conditions, the only reaction observed was a pH-independent cleavage of the O-C5' bond of the 5'-linked nucleoside. Under more alkaline conditions nucleophilic attack by hydroxide ion starts to compete. The reaction is first order in [OH(-)] and becomes predominant at pH 10. Each of the 3'-linked nucleosides is displaced 2.9 times as readily as the 5'-linked one. To determine the beta(lg) value for the hydroxide ion catalyzed hydrolysis of 1, two diesters (2a,b) having 2',3'-O-methyleneadenosine (7) and 2',5'-di-O-methyluridine (4) as leaving groups were hydrolyzed under alkaline conditions. Since the beta(lg) value for this reaction is known, DeltapK(a) between 4 and 7 could be calculated. The beta(lg) for the hydrolysis of 1 was estimated to be -0.5 with use of this information. The mechanisms of the partial reactions and the role of leaving group properties in ribozyme reactions of large ribozymes are discussed.     

Synthesis and biological evaluation of 5-substituted-4-nitroimidazole ribonucleosides

The imidazole nucleosides, 4(5)-bromo-5(4)-nitro-1-β-D-ribofuranosylimidazoles, have been prepared via glycosylation of the trimethylsilylated aglycone, 4(5)-bromo-5(4)-nitroimidazole, with tetra-O-acetyl-β-D-ribo-furanose followed by removal of the acetyl protecting groups. The 5-bromo-4-nitro-1-β-D-ribofuranosylimidazole nucleoside was acetonated to produce 5-bromo-4-nitro-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-imidazole which was cyclized to provide the corresponding anhydronucleoside 5,5′-anhydro-4-nitro-5-oxo-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)imidazole. Sodium hydrosulfide treatment of 5-bromo-4-nitroimidazole nucleoside provided 5-mercapto-4-nitro-1-β-D-ribofuranosylimidazole 5-sodium salt which was alkylated with E-1,5-diiodopent-1-ene to yield 5-(E-1-iodo-1-penten-5-yl)thio-4-nitro-1-β-D-ribofuranosylimidazole. The corresponding iodine-125-labeled compound was prepared similarly using radiolabeled diiodopentene. The 5-bromo-4-nitroimidazole, 5-mercapto-4-nitroimidazole, and 5-iodopentenylthio-4-nitroimidazole nucleosides were cytotoxic to Molt-3 cells in vitro at concentrations higher than 10 μg/mL. The radiolabeled 5-iodopentenylthio-4-nitroimidazole nucleoside showed 2-fold higher uptake in a rapidly growing tumor as compared to uptake in a relatively slower growing tumor in mice.     

The 7-nitroindole nucleoside as a photochemical precursor of 2'-deoxyribonolactone: access to DNA fragments containing this oxidative abasic lesion

On the basis of molecular modeling studies, the 7-nitroindole nucleoside 1 was selected as a suitable photochemical precursor for photochemical generation of the C1' deoxyribosyl radical under irradiation, which led to 2'-deoxyribonolactone. The nitro-indole nucleoside derivatives 1a and 1b were prepared and their conformation was determined by X-ray crystallography and NMR spectroscopy. The photoreaction of these nucleosides gave the corresponding deoxyribonolactone derivatives efficiently, with release of 7-nitrosoindole. This reaction was successfully applied to synthesis of oligonucleotides containing the deoxyribonolactone lesion.     

A novel polymer supported approach to nucleoside modification

Polymer-supported O(6)-(benzotriazol-1-yl)inosine derivatives (Pol-I and Pol-dI) have been synthesized reasonably effectively via reaction of nucleoside phosphonium salts with polymer-linked HOBt (Pol-HOBt). In constast to solution chemistry, use of polymer-supported BOP (Pol-BOP) did not lead to efficient nucleoside loading. Presence of the nucleosides on the support could be readily detected by MAS NMR. Exposure of the polymer-supported nucleosides, Pol-I and Pol-dI, to alcohol, phenol, thiol and amine nucleophiles caused cleavage from the support leading directly to the C-6 modified nucleoside analogues. To our knowledge, these are the first examples of the application of such technology for nucleoside modification. Where possible, results of reactions with the polymer-supported nucleosides are compared to those from solution chemistry, providing insight into the differences between the two techniques. These new polymer-supported nucleosides can be conveniently utilized for diversity-oriented synthesis.     

Artificial nucleosides possessing metal binding sites at the 3'- and 5'-positions of the deoxyribose moieties

This paper describes a convenient synthetic procedure for nucleoside mimics, 1-6, in which the 3',5'-hydroxy groups of natural 2'-deoxythymidine or 2'-deoxyadenosine are replaced by thiol, amine, or alkylthiol groups. Such nucleosides would be built up into a single DNA strand with cooperative participation of metal coordination, where internucleoside linkages are replaced by metal complexation motifs. The X-ray crystal structure and complexation behaviors of 3',5'-dithiothymidine, 1, with Au(I) are also reported.     

Efficient one-step Suzuki arylation of unprotected halonucleosides,using water-soluble palladium catalysts

Modification of nucleosides to give pharmaceutically active compounds, mutagenesis models, and oligonucleotide structural probes continues to be of great interest. The aqueous-phase modification of unprotected halonucleosides is reported herein. Using a catalyst derived from tris(3-sulfonatophenyl)phosphine (TPPTS) and palladium acetate, 8-bromo-2'-deoxyguanosine (8-BrdG) is coupled with arylboronic acids to give 8-aryl-2'-deoxyguanosine adducts (8-ArdG) in excellent yield in a 2:1 water:acetonitrile solvent mixture. The TPPTS ligand was found to be superior to water-soluble alkylphosphines for this coupling reaction. The coupling chemistry has been extended to 8-bromo-2'-deoxyadenosine (8-BrdA) and 5-iodo-2'-deoxyuridine (5-IdU), as well as the ribonucleosides 8-bromoguanosine and 8-bromoadenosine. Good to excellent yields of arylated adducts are obtained in all cases. With use of tri(4,6-dimethyl-3-sulfonatophenyl)phosphine (TXPTS), the Suzuki coupling of 8-BrdA and 5-IdU can be accomplished in less than 1 h at room temperature. This methodology represents an efficient and general method for halonucleoside arylation that does not require prior protection of the nucleoside.     

Vertical excitation energies for ribose and deoxyribose nucleosides

Vertical excitation energies for DNA and RNA nucleosides are determined with electron structure calculations using the time-dependent density functional theory (TDDFT) method at the B3LYP/6-311++G(d,p) level for nucleoside structures optimized at the same level of theory. The excitation energies and state assignments are verified using B3LYP/aug-cc-pVDZ level calculations. The nature of the first four excited states of the nucleosides are studied and compared with those of isolated bases. The lowest npi* and pipi* transitions in the nucleoside remain localized on the aromatic rings of the base moiety. New low-energy npi* and pisigma* transitions are introduced in the nucleosides as a result of bonding to the ribose and deoxyribose molecules. The effect on the low-lying excited state transitions of the binding to phosphate groups at the 5'- and 3',5'-hydroxyl sites of the uracil ribose nucleoside are also studied. Some implications of these calculations on the de-excitation dynamics of nucleic acids are discussed.     

Pyrrolo-dC oligonucleotides bearing alkynyl side chains with terminal triple bonds: synthesis, base pairing and fluorescent dye conjugates prepared by the azide-alkyne "click" reaction

5-(Octa-1,7-diynyl)-2'-deoxyuridine was converted into the furano-dU derivative 7 by copper-catalyzed cyclization; the pyrolodC-derivative 3 was formed upon ammonolysis. The bicyclic nucleosides 3 and 7 as well as the corresponding non-cyclic precursors 4 and 6 all containing terminal C[triple bond]C bonds were conjugated with the non-fluorescent 3-azido-7-hydroxycoumarin 5 employing the copper(I)-catalyzed Huisgen-Sharpless-Meldal cycloaddition "click reaction". Strongly fluorescent 1H-1,2,3-triazole conjugates (30-33) are formed incorporating two fluorescent reporters-the pyrdC nucleoside and the coumarin moiety. Oligonucleotides incorporating 6-alkynyl and 6-alkyl 7H-pyrrolo[2,3-d]pyrimidin-2(3H)-one nucleosides (3 and 2f) have been prepared by solid-phase synthesis using the phosphoramidite building blocks 10 and 13 ; the pyrrolo-dC oligonucleotides are formed during ammonia treatment. The duplex stability of oligonucleotides containing 3 and related derivatives was studied. Oligonucleotides with terminal triple bonded nucleosides such as 3 are more stabilizing than those lacking a side chain with terminal unsaturation; open-chain derivatives (4) are even more efficient. The click reaction was also performed on oligonucleotides containing the pyrdC-derivative and the fluorescence properties of nucleosides, oligonucleotides and their coumarin conjugates were studied.     

A Direct Synthesis for a New Series of 2‐Oxo(thioxo)nicotinonitrile Nucleosides as Antimicrobial Agents

A facile synthesis of a new series of cyclic and acyclic nucleosides of polyfunctionalized 2‐oxo(thioxo)nicotinonitrile derivatives 1 and 2 was performed. Glycosylation of 2‐pyridone 1 and 2‐thiopyridone 2 with glycosyl/galactosyl bromides in the existence of KOH afforded the N‐nucleoside and S‐nucleoside analogues 3 , 5 , 7 , and 9 , respectively. Deacetylation of nucleosides 3 , 5 , 7 , and 9 gave the deacetylated nucleosides 4 , 6 , 8 , and 10 , respectively. Alkylation of 2‐pyridone 1 with glycone analogues [namely, 4‐bromobutyl acetate, (2‐acetoxyethoxy)methyl bromide, 3‐chloropropane‐1,2‐diol, and allyl and / propargyl bromides] in the existence of K₂CO₃ afforded the corresponding O‐acyclic nucleoside analogues 11 , 13 , and 15–17 , respectively. Finally, treating of compounds 11 and 13 with a small amount of Et₃N tolerated the 6‐hydroxy deacetylated derivatives 12 and 14 , respectively. The synthesized nucleosides and alkylated products were tested against Gram (+ve) (Staphylococcus aureus and Bacillus cereus) and (Pseudomonas aeruginosa and Escherichia coli) as Gram (?ve) and Fungi (Aspergillus flavus and Aspergillus niger) and showed moderate antibacterial and antifungal activity.