Biotransformation of heterocyclic dinitriles by Rhodococcus erythropolis and fungal nitrilases

2,6-Pyridinedicarbonitrile (1a) and 2,4-pyridinedicarbonitrile (2a) were hydrated by Rhodococcus erythropolis A4 to 6-cyanopyridine-2-carboxamide (1b; 83% yield) and 2-cyanopyridine-4-carboxamide (2b; 97% yield), respectively, after 10 min. After 118 h, the intermediates 1b or 2b were transformed into 2,6-pyridinedicarboxamide (1c; 35% yield) and 2,6-pyridinedicarboxylic acid (1d; 60% yield) or 2-cyanopyridine-4-carboxylic acid (2c; 64% yield), respectively. The nitrilase from Fusarium solani afforded cyanocarboxylic acids 1e and 2c after 118 h (yields 95 and 62%, respectively). 3,4-Pyridinedicarbonitrile (3a) and 2,3-pyrazinedicarbonitrile (4a) were inferior substrates of nitrile hydratase and nitrilase.     

Synthesis of Carbocyclic 1-[4-(Hydroxymethyl)cyclopent-2-enyl]-1,2,4-triazole-3-carboxamide and Its Derivatives

Abstract

The synthesis of carbocyclic 1-[4-(hydroxymethyl)cyclopent-2-enyl]-1,2,4-triazole-3-carboxamide (6a) and its derivatives was achieved from triol 10 in excellent overall yield. This route involves a Pd(0)-catalyzed coupling reaction as a key step.     

Design and Synthesis of Heterocyclic Carboxamides as Natural Nucleic Acid Base Mimics

Abstract

A series of heterocyclic carboxamides have been designed as mimics for the natural nucleic acid bases. The nucleosides 1-(2′-deoxy-β-d-ribofuranosyl)imidazole-4-carboxamide (1), 1-(2′ -deoxy-β-d-ribofuranosyl)pyrazole-3-carboxamide (2), and 1-(2′ -deoxy-β-d-ribofuranosyl)pyrrole-3-carboxamide (3) were synthesized and their structures confirmed by spectroscopic and analytical means.

     

Isolation and Identification of 1-Ribosyl Pyridone Nucleosides from Human Urine

Abstract

1-Ribosylpyridin-4-one-3-carboxamide with lesser amounts of 1-ribosylpyridin-2-one-5-carboxamide have been isolated quantitatively from human urine using ion exchange column chromatography. Absorption spectra and mass spectrometry were used in the identification.     

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.     

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.     

Ambiguous Base Pairing of 1-(2-Deoxy-β-D-Ribofuranosyl)imidazole-4-carboxamide During PCR

Abstract

The use of 5′-triphosphate of 1-(2-deoxy-β-D-ribofuranosyl)imidazole-4-carboxamide (dYTP) in DNA amplification reaction in place of dATP or dGTP yielded mutations frequencies of 3–4×10^?2 per base per amplification. A reasonable proportion of transversions (11–15%) was observed in the absence of deletions and insertions.     

Triazole and Imidazole Reversed Nucleosides of L-Idose and D-Glucose

Abstract

6-azido-6-deoxy-gluco-(galacto)pyranose and 5-azido-5-deoxy-glucofuranose derivatives were used to obtain reversed nucleoside analogues with either the 5-aminoimidazole-4-carboxamide or 5-amino-1,2,3-triazol-4-carboxamide groups attached, through the N-1 site, to the C-6′ (C-5′) site of the sugar. When deprotected some of these compounds cyclised spontaneously to form a bond between the exocylic nitrogen and the anomeric carbon of the sugar.     

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.     

The Synthesis of Coformycin from 5-Amino-1-β-D-ribofuranosylimidazole-4-carboxamide

Abstract

A convenient synthesis of cotormycin from commercially available 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide is described.     

A Novel Imidazole Nucleoside Containing a Diaminodihydro-S-triazine as a Substituent: Inhibitory Activity Against the West Nile Virus NTPase/Helicase

The attempted synthesis of a ring-expanded guanosine (1) containing the imidazo[4,5-e][1,3]diazepine ring system by condensation of 1-(2′-deoxy-β-D-erythropentofuranosyl)-4-ethoxycarbonylimidazole-5-carbaldehyde (2) with guanidine resulted in the formation of an unexpected product, 1-(2′-deoxy-β-D-erythropentofuranosyl)-5-(2,4-diamino-3,6-dihydro-1,3,5-triazin-6-yl)imidazole-4-carboxamide (7). The structure as well as the pathway of formation of 7 was corroborated by isolation of the intermediate, followed by its conversion to the product. Nucleoside 7 showed promising in vitro anti-helicase activity against the West Nile virus NTPase/ helicase with an IC ₅₀ of 3-10 μg/mL.     

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.     

Synthesis,Antitumor Activity and Crystallographic Studies of Analogues of Tiazofurin

Abstract

The syntheses and antitumor activity of 2-β-D-ribofuranosylfuran-4-carboxamide (furanfurin) and 2-β-D-ribofuranosylthiophene-4-carboxamide (thiophenfurin) are reported. The X-ray structure of ethyl 2-β-D-ribofuranosylthiophene-4-carboxylate, precursor of thiophenfurin, is also presented. Only thiophenfurin showed activity as an antitumor agent both in vitro and in vivo.     

An Unusual Iodine Monochloride Chlorination of an Imidazole Nucleoside

Abstract

The reaction of iodine monochloride with the imidazole nucleoside, 5-amino-1-(2,3,5-tri-0-acetyl-α-D-ribofuranosyl)imidazole-4-carboxamide, provides the 2-chloroimidazole nucleoside in good yield.     

Synthesis of functionalized amino acid derivatives as new pharmacophores for designing anticancer agents

A new series of functionalized amino acid derivatives N-substituted 1-N-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyl-5-oxazolidine carboxamide (1-17) and 1-N-substituted-3-amino-2-hydroxy-3-phenylpropane-1-carboxamide (18-34) were synthesized and evaluated for their in vitro cytotoxicity against human cancer cell lines. Compound 6 has shown interesting cytotoxicity (IC₅₀ = 5.67 μm) in ovarian cancer, while compound 10 exhibited promising cytotoxicity in ovarian (IC₅₀ = 6.1 μm) and oral (IC₅₀ = 4.17 μm) cancers. These compounds could be of use in designing new anti-cancer agents.     

Ring-Opening of 3-β-D-Ribofuranosyl-3,7,8,9-Tetrahydropyrimido [1,2-i]Purin-8-ol and Preparation of 2-Thio- and 2-aza-Adenosine Derivatives

The adduct 3-β-D-ribofuranosyl-3,7,8,9-tetrahydropyrimido[1,2-i]purin-8-ol (2), obtained from adenosine and epichlorohydrin, underwent ring fission at basic conditions. The initial ring-opening took place at C2 of the pyrimidine unit resulting in 2-(5-amino-1-β-D-ribofuranosyl-imidazol-4-yl)-1,4,5,6-tetrahydropyrimidin-5-ol (3). Also the tetrahydropyrimidine ring of 3 could be opened resulting in 5-amino-1-(β-D-ribofuranosyl)-imidazole-4-(N-3-amino-2-hydroxyl-propyl)-carboxamide (4). In hot acid conditions, 2 was both deglycosylated and ring-opened yielding 2-(5-amino-imidazol-4-yl)-1,4,5,6-tetrahydropyrimidin-5-ol (7) as the final product. When reacting 3 with CS₂ or HNO₂ ring-closure took place and 3-β-D-ribofuranosyl-3,4,7,8,9-pentahydropyrimido[1,2-i]purin-8-ol-5-thione (5), and 3-β-D-ribofuranosyl-imidazo[4,5-e]-3,7,8,9-tetrahydropyrimido[1,2-c][1,2,3]triazine-8-ol (6), respectively, were obtained. Also, the pyrimidine ring of the epichlorohydrin adduct with adenine, 10-imino-5,6-dihydro-4H,10H-pyrimido[1,2,3-cd]purin-5-ol (10), underwent ring fission and the product was identified as 3-hydroxy-1,2,3,4-tetrahydroimidazo[1,5-a]pyrimidine-8-carboximidamide (11).     

Synthesis of Certain 4-Substituted-1-β-D-Ribofuranosyl-3-Hydroxypyrazoles Structurally Related to the Antibiotic Pyrazofurin

Abstract

Several 4-substituted-1-β-D-ribofuranosyl-3-hydroxypyrazoles were prepared as structural analogs of pyrazofurin. Glycosylation of the TMS derivative of ethyl 3(5)-hydroxypyrazole-4-carboxylate (3) with 1-0-acetyl-2,3,5-tri-0-benzoyl-D-ribofuranose in the presence of TMS-triflate gave predominantly ethyl 3-hydroxy-1-(2,3,5-tri-0-benzoyl-β-D-ribofuranosyl)pyrazole-4-carboxylate (4a), which on subsequent ammonolysis furnished 3-hydroxy-1-β-D-ribofuranosylpyrazole-4-carboxamide (5). Benzylation of 4a with benzyl bromide and further ammonolysis gave 3-benzyloxy-1-β-D-ribofuranosylpyrazole-4-carboxamide (8a). Catalytic (Pd/C) hydrogenation of 8a afforded yet another high yield route to 5. Saponification of the ester function of ethyl 3-benzyloxy-1-β-D-ribofuranosylpyrazole-4-carboxylate (7b) gave the corresponding 4-carboxylic acid (6a). Phosphorylation of 8a and subsequent debenzylation of the intermediate 11a gave 3-hydroxy-1-β-D-ribofuranosylpyrazole-4-carboxamide 5′-phosphate (11b). Dehydration of 3-benzyloxy-1-(2,3,5-tri-0-acetyl-β-D-ribofuranosyl)pyrazole-4-carboxamide (8b) with POCl₃ provided the corresponding 4-carbonitrile derivative (10a), which on debenzylation with Cl₃SiI gave 3-hydroxy-1-(2,3,5-tri-0-acetyl-β-D-ribofuranosyl)pyrazole-4-carbonitrile (13). Reaction of 13 with H₂S/pyridine and subsequent deacetylation gave 3-hydroxy-1-β-D-ribofuranosylpyrazole-4-thiocarboxamide (12b). Similarly, treatment of 13 with NH₂OH afforded 3-hydroxy-1-β-D-ribofuranosylpyrazole-4-carboxamidoxime (14a), which on catalytic (Pd/C) hydrogenation gave the corresponding 4-carboxamidine derivative (14b). The structural assignment of these pyrazole ribonucleosides was made by single-crystal X-ray analysis of 6a. None of these compounds exhibited any significant antitumor or antiviral activity in cell culture.     

Nucleosides and Nucleotides. 140. Synthesis and Antileukemic Activity of 5-Carbon-Substituted 1-β-d-Ribofuflranosylimidazole-4-Carboxamides

Abstract

Synthesis of 5-carbon-substituted 1-β-d-ribofuranosylimidazole-4-carboxamides are described. Treatment of 5-iodo derivative 8 with methyl acrylate in the presence of palladium catalyst gave (E)-5-(2-carbomethoxyvinyl)-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxamide (9), followed by appropriate manipulations to afford various 5-carbon-substituted imidazole derivatives 1–7. The antileukemic activities of these imidazole nucleosides are also described.

     

Imidazole-4-Carboxamide and 1,2,4-Triazole-3-Carboxamide Deoxynucleotides as Simplified DNA Building Blocks with Ambiguous Pairing Capacity

Abstract

2′-Deoxynucleosides of imidazole-4 (or 1,2,4-triazole-3)-carboxamide, ethyl imidazole-4 (or 1,2,4-triazole-3)-carboxylate were synthesized by enzymatic glycosylation using N-deoxyribosyltransferase from a lactobacterium. The base pairing properties of Y and V when placed opposite the natural DNA bases as well as their self were evaluated by thermal denaturation experiments. DNA templates containing imidazole-4-carboxamide base were used in elongation reaction catalysed by Klenow fragment.     

Synthesis and anticonvulsant activity of 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues

A series of fourteen 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues were synthesized and evaluated for anticonvulsant activity according to the Antiepileptic Drug Development Programme (ADD) protocol. Some of the synthesized compounds showed significant activity in minimal clonic seizure model (6 Hz psychomotor seizure test). 3-(4-Fluorophenyl)-N-(4-bromophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4c) was found to be the most active compound of the series showing 75% (3/4, 0.25–2.0 h) and 50% (2/4, 4.0 h) protection against minimal clonic seizure at 100 mg/kg without any toxicity. 3-(Pyridin-4-yl)-N-(4-chlorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4f) showed protection in maximal electroshock (MES) seizure and subcutaneous metrazol (scMET) seizure at 300 mg/kg.