Researches on Pyrimidines. Cxvii. A Method for the Synthesis of Nucleosides

Hilbert, Guido E.; Johnson, Tommy

doi:10.1021/ja01374a045

Cited by 153 publications

(54 citation statements)

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“…Pathway b of Scheme 3 proposes the formation of two different cyclized intermediates, which could ultimately form 2Ј-OAADPr. In the latter pathway, a water molecule attacks after the formation of a 1Ј-2Ј-cyclic acetoxonium intermediate (62,63). Future studies will be directed at differentiating these two mechanisms.…”

Section: Mechanism Of Nicotinamide Inhibition and Transglycosidation-mentioning

confidence: 99%

Mechanism of Nicotinamide Inhibition and Transglycosidation by Sir2 Histone/Protein Deacetylases

Jackson

Schmidt

Oppenheimer

et al. 2003

Journal of Biological Chemistry

223

266

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Silent information regulator 2 (Sir2) enzymes catalyze NAD؉ -dependent protein/histone deacetylation, where the acetyl group from the lysine ⑀-amino group is transferred to the ADP-ribose moiety of NAD ؉ , producing nicotinamide and the novel metabolite O-acetyl-ADPribose. Sir2 proteins have been shown to regulate gene silencing, metabolic enzymes, and life span. Recently, nicotinamide has been implicated as a direct negative regulator of cellular Sir2 function; however, the mechanism of nicotinamide inhibition was not established. Sir2 enzymes are multifunctional in that the deacetylase reaction involves the cleavage of the nicotinamide-ribosyl, cleavage of an amide bond, and transfer of the acetyl group ultimately to the 2-ribose hydroxyl of ADP-ribose. Here we demonstrate that nicotinamide inhibition is the result of nicotinamide intercepting an ADP-ribosyl-enzyme-acetyl peptide intermediate with regeneration of NAD ؉ (transglycosidation). The cellular implications are discussed. A variety of 3-substituted pyridines was found to be substrates for enzyme-catalyzed transglycosidation. A Brö nsted plot of the data yielded a slope of ؉0.98, consistent with the development of a nearly full positive charge in the transition state, and with basicity of the attacking nucleophile as a strong predictor of reactivity. NAD ؉ analogues including ␤-2-deoxy-2-fluororibo-NAD ؉ and a His-to-Ala mutant were used to probe the mechanism of nicotinamide-ribosyl cleavage and acetyl group transfer. We demonstrate that nicotinamide-ribosyl cleavage is distinct from acetyl group transfer to the 2-OH ribose. The observed enzyme-catalyzed formation of a labile 1-acetylated-ADP-fluororibose intermediate using ␤-2-deoxy-2-fluororibo-NAD ؉ supports a mechanism where, after nicotinamide-ribosyl cleavage, the carbonyl oxygen of acetylated substrate attacks the C-1 ribose to form an initial iminium adduct.The acetylation state of histones is intimately coupled to transcription, DNA repair, and replication and is governed by the competing enzymatic activities of histone acetyltransferases and histone deacetylases (reviewed in Refs. 1-3). Recently a new family of histone deacetylases has emerged and is referred to as the silent information regulator 2 (Sir2) 1 family of histone/protein deacetylases (reviewed in Refs. 4 -6) or Sirtuins (7). This family is highly conserved from prokaryotes to humans (7), and there is evidence suggesting that the scope of Sir2 activity extends beyond histone deacetylation and involves other protein targets throughout the cell. In yeast, at least five Sir2-like proteins have been identified. The founding member, yeast Sir2 (ySir2), is required for all major silenced loci (reviewed in Ref. 4). A Sir2 homologue from Salmonella enterica was shown to up-regulate acetyl-CoA synthetase, through deacetylation of a critical lysine residue (8, 9). In humans, seven Sir2 homologues have been identified to date (7). Of these seven, human SIRT2 (hSIRT2) has been identified as a cytosolic protein (10) that deacetylates ␣-tubuli...

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Section: Mechanism Of Nicotinamide Inhibition and Transglycosidation-mentioning

confidence: 99%

Mechanism of Nicotinamide Inhibition and Transglycosidation by Sir2 Histone/Protein Deacetylases

Jackson

Schmidt

Oppenheimer

et al. 2003

Journal of Biological Chemistry

223

266

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“…The target compound was synthesized in analogy to described procedures [1][2][3][4][5][6]. 2-Thiouracil was silylated with hexamethyldisilazane (HMDS) in the presence of ac atalytic amount of trimethylsilyl chloride.…”

Section: Source Of Materialsmentioning

confidence: 99%

Crystal structure of 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-hydroxymethyltetrahydrofuran- 2-yl)-2-propylsulfanyl-1H-pyrimidin-4-one, C12H18N2O5S

Euler¹,

Kirfel²,

El‐Tayeb³

et al. 2009

Zeitschrift für Kristallographie - New Crystal Structures

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Source of materialThe target compound was synthesized in analogy to described procedures [1][2][3][4][5][6]. 2-Thiouracil was silylated with hexamethyldisilazane (HMDS) in the presence of ac atalytic amount of trimethylsilyl chloride. After excess HMDS was distilled off, the raw product was reacted with 1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose in dichloroethane in the presence of tin(IV)chloride [1]. Hydrolysis with saturated aqueous sodium hydrogen car-, which was subsequently alkylated with 1-iodopropane in dichloromethane in the presence of triethylamine as described for the homologous ethyl derivative [5]. The benzoyl groups were removed by reaction with asaturated solution of ammonia in methanol [6] yielding the title compound 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-hydroxymethyltetrahydrofuran-2-yl)-2-propylsulfanyl-1H-pyrimidin-4-one, which was purified by column chromatography (dichloromethane/methanol, 5:1). Crystals were obtained by dissolution of 50 mg of the pure compound in 3mlofacetone followed by the addition of 7mlofn-hexane and slow evaporation of the solvent over aperiod of several months at room temperature. Experimental detailsOwing to sufficient resonant scattering from the sulfur and oxygen atoms, the data allowed for the determination of the absolute structure of the title compound (x(Flack) =0.01(6), R1=0.039). Across check refinement of the enantiomer yielded (x(Flack) = 0.98(6), R1=0.040). The majority of the Hatoms could be determined from difference Fourier calculations. The hydrogens bonded to C18 and C19 were treated as 'riding' due to the thermal displacements of their carrier atoms. DiscussionThe crystal structure contains 4symmetry equivalent molecules per unit cell. All intramolecular bond lengths are normal. The main part of the molecule consists of an almost planar aromatic system (C2, N6, C7, N8, C9, C10, C11, S16, O20) with an r.m.s. deviation from the least squares plane of 0.034 Å.Asecond plane, which is defined by S16, C17, C18, C19 with r.m.s. =0.0009 Å,is tilted by 87.7(1)°against the first mentioned plane. The packing scheme of the molecules is characterized by stacking of puckared layers of the main molecular planes approximately perpendicular to [130] and [130], respectively, with an dihedral angle of 80.9(1)°. Within the layers, the molecules are held together by two O-H···O hydrogen bonds, extending from the acceptors O13 and O15 to the common donator O20. The hydrogen bond H13-O13···O20 with d =2.683(1) Å is significantly shorter and thus stronger than H15-O15···O20 with d =2.756(2) Å.O13 and O15 belong to different adjacent molecules in the same layer. The layers are connected by Van der Waals bonds. The shortest distance between layers is d =3.70(1) Å.

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“…Lumazine [2][3][4][5][6][7][8][9][10][11] and isopterin nucleosides 12 can be regarded as structural analogs of the pyrimidine nucleosides whereas the many pteridin-7-one N 8 -nucleosides [13][14][15][16][17][18][19][20][21][22][23] are structurally related to the purine nucleosides. The syntheses could be achieved either by a classical Hilbert-Johnson reaction 24 , the mercury salt method by Fox and Davoll 25 , the Hilbert-Johnson-Birkofer silyl procedure 26,27 or the silyl variant by Vorbrüggen 28 .…”

Section: Introductionmentioning

confidence: 99%

“…Ribosylations of 6,7-dimethylpterin (3) led with the halosugar 10 and HgO/HgBr 2 to 3-(2,3,5-tri-O-benzoyl-ß-Dribofuranosyl)-6,7-dimethylpterin (13) in 14% yield whereas the use of 11 and BF 3 -catalysis formed the N 1 -riboside (20) in 14% as the main reaction product besides 8% of the N 3 -isomer (13). The ribosylation reaction have also been extended to 6-methylpterin (4) yielding with 11 and BF 3 small amounts of the N 1 - (21) and N 3 -riboside (14), with 7-methyl-pterin (5) the N 3 -riboside ( (15) in 6% yield and with 7-tert.butylpterin (8) again a mixture of N 1 - (24) and N 3 -riboside (18). A highly unpleasant reaction was encountered with pterin (1) itself which led after a tedious isolation and purification process only to 10% yield of the 1-(2,3,5.tri-O-benzoyl-ß-Dribofuranosyl)pterin (25).…”

Section: Introductionmentioning

confidence: 99%

Syntheses and properties of pterin ribonucleosides

Pfadler¹,

Pfleiderer²

2008

Arkivoc

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Several pterin derivatives (1-8) have been ribosylated in form of their trimethylsilyl derivatives (9) with 1-bromo-(10) and 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (11) under the catalysis of HgO/HgBr 2 , BF 3 -etherate and trimethylsilyl triflate, respectively. Mixtures of the N-1-(19-25) and N-3-ribofuranosides (12-18) which are difficult to be separated were obtained. Debenzoylation by the Zemplen method led to the free pterin-nucleosides (28-30). A second approach starting from 2-methylthio-4(3H)pteridinones (31-33) gave again mixtures of the N-1-(35-37) and N-3-ribonucleosides (38-40). The 2-methylthio function in 35-37 can easily be substituted by various amines leading after subsequently debenzoylation to the N-2-substituted pterin-ribonucleosides (41-50). The structural assignments were based on comparisons of the UV spectra with the corresponding N-methyl substituted model substances. 1 H-NMR-spectra functioned as additional structural proof.

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Researches on Pyrimidines. Cxvii. A Method for the Synthesis of Nucleosides

Abstract: Nov., 1930 RESEARCHES ON PYRIMIDINES. CXVII 4489 light yellow oil at 216-218' (5 mm.). This ester was more readily prepared from the phenol and benzoyl chloride by the pyridine method.

Cited by 153 publications

References 0 publications

Mechanism of Nicotinamide Inhibition and Transglycosidation by Sir2 Histone/Protein Deacetylases

Mechanism of Nicotinamide Inhibition and Transglycosidation by Sir2 Histone/Protein Deacetylases

Crystal structure of 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-hydroxymethyltetrahydrofuran- 2-yl)-2-propylsulfanyl-1H-pyrimidin-4-one, C12H18N2O5S

Syntheses and properties of pterin ribonucleosides

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