Synthesis of Novel Branched Nucleoside Dimers Containing a 1,2,3-Triazolyl Linkage

Abstract

Three branched nucleoside dimers containing a 1,2,3-triazole linkage have been synthesized using 1,3-dipolar cycloaddition of N-3 or C-5 acetylene nucleosides with 3′-azido-3′-deoxythymidine.     

Stereoselective reduction of 2-azido-1-phenylethanone derivatives by whole cells of marine-derived fungi applied to synthesis of enantioenriched β-hydroxy-1,2,3-triazoles

Several marine-derived fungi were evaluated by the bioreduction of 2-azido-1-phenylethanone 1, and the strains A. sydowii CBMAI 935 and M. racemosus CBMAI 847 were selected for the reduction of 2-azido-1-phenylethanone derivatives 2–4. Whole cells of A. sydowii CBMAI 935 promoted the reduction of 2-azido-1-phenylethanones 1–4 with high selectivities to yield the (S)-2-azido-1-phenylethanols 1a–4a. Bioreduction of compounds 1–4 by M. racemosus CBMAI 847 led to (R)-2-azido-1-phenylethanols for 1, 2 and 4 and (S)-2-azido-1-phenylethanol 3. Enantiomerically enriched 2-azido-1-phenylethanols 1a–4a and phenylacetylene 5 were applied in the synthesis of β-hydroxy-1,2,3-triazoles using CuSO₄ and sodium ascorbate leading to regioselective formation of enantioenriched 1,4-disubstituted 1,2,3-triazole compounds 1b–4b.     

Assignment of 13C Chemical Shifts of α-D-Ribonucleoside Sugar Carbons by 1J(CH) Coupling Constants

Abstract

The ¹J(CH) coupling constant of C-1 in nucleosides is increased compared to those of the other carbons of the sugar moiety. Applying this to several D-ribonucleosides the signals C-4′/C-1′of these a-anomers are reversed to those of the 8-counterparts (C-1′/C-4′). This phenomenon and the broadening of the C-3′ signal compared to that of C-2′ establishes the seauence C-4′,1′,2′,3′,5′ (increasing field) for a number of α-D-ribonucleosides.     

Synthesis and Anti-HIV Activity of β-D-3′-Azido-2′,3′-unsaturated Nucleosides and β-D-3′-Azido-3′-deoxyribofuranosylnucleosides

Since the discovery of 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) as potent and selective inhibitors of the replication of human immunodeficiency virus (HIV), there has been a growing interest for the synthesis of 2′,3′-didehydro-2′,3′-dideoxynucleosides with electron withdrawing groups on the sugar moiety. Here we described an efficient method for the synthesis of such nucleoside analogs bearing structural features of both AZT and d4T. The key intermediate, 3-azido-1,2-bis-O-acetyl-5-O-benzoyl-3-deoxy-D-ribofuranose, 5 was synthesized from commercially available D-xylose in five steps, from which a series of pyrimidine and purine nucleosides were synthesized in high yields. The resultant protected nucleosides were converted to target nucleosides using appropriate chemical modifications. The final nucleosides were evaluated as potential anti-HIV agents.     

Synthesis and Activity of Modified Cytidine 5′-Monophosphate Probes for T4 RNA Ligase 1

We describe the synthesis of a series of unique base modified ligation probes such as p(5′)C-4-ethylenediamino 3, p(5′)C-4-biotin 4, and pre-adenylated form A(5′)pp(5′)C-4-biotin 6 and tested their biological activity with T4 RNA ligase 1 using a standard pCp probe 1 as a control. The intermolecular ligation assay was developed using a 5′-FAM labeled 24 mer single-stranded (ss) RNA and the average ligation efficiencies for pCp 1, p(5′)C-4-ethylenediamino 3, p(5′)C-4-biotin 4, and pre-adenylated form A(5′)pp(5′)C-4-biotin 6 were found to be 44%, 81%, 39% and 16% respectively, as determined using a denaturing gel analysis. Furthermore, confirmation of the ligation activity of the biotinylated probes to the RNA substrate was confirmed by streptavidin conjugation and analysis by nondenaturing gel electrophoresis. These results strongly suggest that the new probes are valid substrates for T4 RNA ligase 1 and therefore could be useful for developing a miRNA detection system that includes rapid isolation, efficient labeling and detection of miRNAs on sensitivity-enhanced microarrays.     

Imidazole Nucleosides IV Nucleosides of 5 (4)-Formamido-imidazole-4 (5)carboxamide

Abstract

Nucleosides of 5(4)-aminoimidazole-4(5)-carboxamide were formylated with sodium formate, formic acid and acetic anhydride to the β-D-ribo-, α-D-arabino-, α-L-arabino- and β-D-xylofuranosides of 5-formamidoimidazole-4-carboxamide, and to the β-D-ribo-, β-D-arabi-no-, α-D-arabino- and α-L-arabinopyranosides of 4-formamidoimidazole-5-carboxamide.     

Synthesis of 5′-Fluoro-5′-deoxy-and 5′-Amino-5′-Deoxytoyocamycin and Sangivamycin and Some Related Derivatives

Abstract

A series of 5′-substituted analogs of toyocamycin were prepared by condensation of silylated 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidine with protected 5-azido-5-deoxy- or 5-fluoro-5-deoxyribofuranose followed by debromination and deblocking. Alternatively, 5′-azido-5′-deoxytoyocamycin was prepared by azidation of toyocamycin. Conversion of the 5-nitrile function of the toyocamycin derivatives into a carboxamide or a thiocarboxamide gave the corresponding analogs of sangivamycin or thiosangivamycin while reduction of the 5′-azido-5′-deoxy nucleosides provided 5′-amino-5′-deoxy derivatives.     

Nucleosides and Nucleotides. 98. Synthesis and Antitumor Activities of 5-Ethynylimidazole-4-carboxamide and -carbonitrile Derivatives

Abstract

5-Ethynyl-1-(2-deoxy-β-D-ribofuranosyl)imidazole-4-carbonitrile (4) and -carboxamide (5) and 5-ethynyl-1-(5-deoxy-β-D-ribofuranosyl)imidazole-4-carbonitrile (11) and -carboxamide (12) have been synthesized from the corresponding 5-iodo derivatives 2 and 7 by a palladium-catalyzed cross-coupling reaction with (tri-methylsilyl)acetylene. The aglycons, 5-ethynylimidazole derivatives 14 and 15 were synthesized by the hydrolytic cleavage of the corresponding nucleosides. The antileukemic activity of these nucleosides and base analogues are also described.     

Biotransformation of mestanolone and 17-methyl-1-testosterone by Rhizopus stolonifer

Abstract

Microbial transformation of mestanolone (1) using the plant pathogenic fungus, Rhizopus stolonifer, resulted in the production of two known metabolites, identified as 11α-hydroxymestanolone (3) and 6α-hydroxymestanolone (4). Transformation of 17-methyl-1-testosterone (2) by R. stolonifer yielded two known metabolites, methandrostenolone (5) and 11α,17β- dihydroxy-androsta-1,4-diene-3-one (6). These transformations included α-hydroxylations at C-11 and C-6, dehydrogenation at C-4, androsta and a demethylation at C-17 positions. Structures of transformed products were determined using spectroscopic techniques.     

Analysis of some partly and fully esterified oligogalactopyranuronic acids by p.m.r. spectrometry at 220 MHz

The p.m.r. spectra of mono-, di-, tri-, tetra-, and penta-galactopyranuronic acids (1–5), the corresponding fully esterified methyl esters (6–10), the partly esterified di- (11) and tri-galactopyranuronic acids (12, 13), and the unsaturated di-, tri-, and tetra-galactopyranuronic acids (14–16) were measured on solutions in D₂O at 220 MHz at a pH of 1 and 6. Observation of doublets (J 4 Hz) in the range δ 4.90–5.05 p.p.m. indicates the site of esterification in the non-reducing or reducing sugar residue. Esterification of the sugar residue at the non-reducing end can be deduced from both the presence of a methyl resonance peak at δ 3.80 and the indifference of the signal at δ 4.35 (H-4) to the change in pH. The δ values and coupling constants confirm that all the d-galacturonic acid residues have the CI conformation and are α-(1→4)-linked. In the unsaturated oligogalactopyranuronic acids, the double bond is located between C-4 and C-5 of the sugar unit at the non-reducing end. The 4-deoxyhex-4-enopyranosyluronic acid residue occurs in the ²H₁(d) conformation. Compound 11 was identified as O-(α-d-galactopyranosyluronic acid)-(1→4)-(methyl α,β-d-galactopyranuronate). Compounds 12 and 13 each consisted of a mixture of the three possible isomers; preference for the site of esterification decreases in the order reducing sugar unit, non-reducing sugar unit, sugar unit at the non-reducing end.     

Synthesis of the conjugation ready, downstream disaccharide fragment of the O-PS of Vibrio cholerae O:139

The linker-equipped disaccharide, 8-amino-3,6-dioxaoctyl 2,6-dideoxy-2-acetamido-3-O-β-d-galactopyranosyluronate-β-d-glucopyranoside (10), was synthesized in eight steps from acetobromogalactose and ethyl 4,6-O-benzylidene-2-deoxy-2-trichloroacetamido-1-thio-β-d-glucopyranoside. The hydroxyl group present at C-4^II in the last intermediate, 8-azido-3,6-dioxaoctyl 4-O-benzyl-6-bromo-2,6-dideoxy-2-trichloroacetamido-3-O-(benzyl 2,3-di-O-benzyl-β-d-galactopyranosyluronate)-β-d-glucopyranoside (9), is positioned to allow further build-up of the molecule and, eventually, construction of the complete hexasaccharide. Global deprotection (9→10) was done in one step by catalytic hydrogenolysis over palladium-on-charcoal.     

The X-ray Crystal and Molecular Structure of 5-Amino-1-(2,3:5,6-Di-O-isopropylidene-α-D-mannofuranosyl) Imidazole-4-carboxamide

Abstract

5-Amino-1-(2,3:5,6-di-O-isopropylidene-α-D-mannofuranosyl) imidazole-4-carboxamide (ADIMIC) crystallizes with six molecules in a hexagonal unit cell of space group P6_3.. The imidazole ring is closely planar, the furanose ring pucker is O1′ endo-C4′ exo, and the dioxolane rings are puckered C6′ endo-O6′ exo and C7′ endo-O3′ exo. In addition to an intramolecular hydrogen bond from the 5-amino hydrogen to the 4-carboxamide oxygen, a circuit of intermolecular hydrogen bonds links nearly coplanar imidazole rings.     

Structure-Activity Relationships of Tiazofurin Analogs: Synthesis and Computational Studies of 4′-Thio Derivatives of Thiophenfurin and Furanfurin

Abstract

The synthesis and computational studies of 5-(4-thio-β-D-ribofuranosyl)-furan-3-carboxamide (furanthiofurin) and 5-(4-thio-β-D-ribofuranosyl)thiophene-3-carboxamide (thiophenthiofurin) are reported.     

Novel Analogues of Tiazofurin by Lawesson Reagent Effected Cyclization

Abstract

2-Benzylthiazole-4-carboxamide 4 and 5-(β-D-ribofuranosylamino) thiazole-4-carboxamide 10 were synthesized from phenylacetylamino- and formylamino cyanoacetic acid esters 1a and 1b, respectively. The ribosylation reaction leading to 10 gave rise also to its α anomer as a minor product.     

Chemical modification of the sugar part of methyl acarviosin: synthesis and inhibitory activities of nine analogues.

Nine analogues of methyl acarviosin (1), the core structure of acarbose and its homologues, the 6-hydroxy-(2), 6-azido-(3), 6-amino- (4), 6-acetamido-(5), 6-methoxy-(6), 6-hydroxy-2-O-methyl-(8), and 6-hydroxy-3-O-methyl derivatives (9), including the 5-methoxycarbonyl analogue (7) and 3,6-anhydro derivative (10) of 2, were synthesized by chemical modification of the sugar part of 2 derived by condensation of methyl 3,4-anhydro-alpha-D-galactopyranoside (17) and 4,7:5,6-di-O-isopropylidenevalienamine (26) or by direct coupling between 26 and the 6-substituted methyl 3,4-anhydro-alpha-D-galactopyranoside derivatives. Compounds 2 and 8 show notable inhibitory activity against yeast alpha-D-glucosidase almost comparable to that of 1. Introduction of a polar substituent at C-6 of 1 decreases the inhibitory activity. Interestingly, inversion of the conformation of the sugar part of 1 by introduction of the 3,6-anhydro bridge elicits almost no effect on the inhibitory activity.     

Synthesis of New 5″-Sulfonylamido Derivatives of 3″-Azido-3″-Deoxythymidine (AZT)

Abstract

A series of 5′-N-methanesulfonyl derivatives of 3′-azido-5′-(alkylamino)-3′,5′-dideoxythymidine was synthesised. The first step of the synthesis involved the reaction of 1-(2,5-dideoxy-5-O-tosyl-β-D-threo-pentofuranosyl)thymine 1 with an appropriate amine to give 1-[5-(alkylamino)-2,5-dideoxy-β-D-threo-pentofuranosyl]thymines 2a-e and 1-(2,5-dideoxy-β-threo-pent-4-enofuranosyl)thymine 3 as a by-product. Compounds 2a-e were treated with an excess of methanesulfonyl chloride to yield intermediates 1-[5-(dimethylamino)-3-O-methanesulfonyl-2,3,5-trideoxy-β-D-threo-pentofuranosyl]-thymine 4a and 1-[5-(N-alkyl-N-methanesulfonyl)-3-O-methanesulfonyl-2,3,5-trideoxy-β-D-threo-penfuranosyl]thymines 4b-e. The reaction of 4a-e with lithium azide in dimethyl-formamide afforded the final compounds 1-[3-azido-5-(N-methyl-N-methanesulfonyl)-2,3,5-trideoxy-β-D-erythro-penofuranosyl]thymine 5a and 1-[3-azido-5-(N-alkyl-N-methanesulfonyl)-2,3,5-trideoxy-β-D-erythro-penofuranosyl]thymines 5b-e. The independent synthesis of 4′,5′-unsaturated product 3 was also described.     

Synthesis of Certain 5′-Substituted Derivatives of Ribavirin and Tiazofurin

Abstract

The synthesis of several 5′-substituted derivatives of ribavirin (1) and tiazofurin (3) are described. Direct acylation of 1 with the appropriate acyl chloride in pyridine-DMF gave the corresponding 5′-O-acyl derivatives (4a-h). Tosylation of the 2′, 3′-O-isopropylidene-ribavirin (6) and tiazofurin (11) with p-toluenesulfonyl chloride gave the respective 5′-O-p-tolylsulfonyl derivatives (7a and 12a), which were converted to 5′-azido-5′-deoxy derivatives (7b and 12b) by reacting with sodium/lithium azide. Deisopropylidenation of 7b and 12b, followed by catalytic hydrogenation afforded 1-(5-amino-5-deoxy-β-D)-ribofuranosyl)-1, 2, 4-triazole-3-carboxamide (10b) and 2 - (5 -amino- 5-deoxy- β-D-ribofuranosyl) thiazole-4-carboxamide (16), respectively. Treatment of 6 with phthalimide in the presence of triphenylphosphine and diethyl azodicarboxylate furnished the corresponding 5′-deoxy-5′-phthaloylamino derivative (9). Reaction of 9 with n-butylamine and subsequent deisopropylidenation provided yet another route to 10b. Selective 5′-thioacetylation of 6 and 11 with thiolacetic acid, followed by saponification and deisopropylidenation afforded 5′-deoxy-5′-thio derivatives of 1-β-D-ribofuranosyl-1, 2, 4-triazole-3-carboxamide (8a) and 2-β-D-ribofuranosylthiazole-4-carboxamide (15), respectively.     

Hydroxylation of (+)-menthol by Macrophomina phaseolina

Abstract

Biotransformation of (+)-menthol with Macrophomina phaseolina led to hydroxylations at C-1, C-2, C-6, C-7, C-8 and C-9, with the C-8 position being preferentially oxidized. The resulting metabolites were identified as 8-hydroxymenthol (2), 6R-hydroxymenthol (3), 1R-hydroxymenthol (4), 9-hydroxymenthol (5), 2R,8-dihydroxymenthol (6), 8S,9-dihydroxymenthol (7), 6R,8-dihydroxymenthol (8), 1R,8-dihydroxymenthol (9) and 7,8-dihydroxymenthol (10). Metabolites 6–10 are described here for the first time. Their structures were characterized by spectroscopic analysis.     

Synthesis of 3′-Deoxy-3′ and 5′-Deoxy-5′-[4-(Purin-9-yl/Pyrimidin-1-yl) methyl-1,2,3-Triazol-1-yl]thymidine via 1,3-Dipolar Cycloaddition

Abstract

Synthesis of new 3′-deoxy-3′ and 5′-deoxy-5′-[(4-(purin-9-yl/pyrimidin-1-yl)methyl-1,2,3-Triazol-1-yl]thymidine 8a-g 10a-g from 3′-azido-3′-deoxy-5′-O-monomethoxytrityl-thymidine and 5′-azido-5′deoxythymidine respectively are described. The key step is the 1,3-dipolar cycloaddition between the azido group and N-9/N-1-propargylpurine/pyrimidine derivatives.     

NMR study of dideoxynucleotides with anti-human immunodeficiency virus (HIV) activity

The molecular structures of 3′-azido-2′,3′-dideoxyribosylthymine 5′-triphosphate (AZTTP), 2′,3′-dideoxyribosylinosine 5′-triphosphate (ddITP), 3′-azido-2′,3′-dideoxyribosylthymine 5′-monophosphate (AZTMP) and 2′,3′-dideoxyribosyladenine 5′-monophosphate (ddAMP) have been studied by NMR to understand their anti-HIV activity. For ddAMP and ddITP, conformations are almost identical with their nucleoside analogues with sugar ring pucker equilibriating between C3′-endo (∼75%) and C2′-endo (∼25%). AZTMP and AZTTP on the other hand show significant variations in the conformational behaviour compared with 3′-azido-2′,3′-dideoxyribo-sylthymine (AZT). The sugar rings for these nucleotides have a much larger population of C2′-endo (∼75%) conformers, like those observed for natural 2′-deoxynucleosides and nucleotides. The major conformers around C5′-O5′, C4′-C5′ and the glycosidic bonds are the β^t, γ⁺ and anti, respectively.