Der synthetische Aufbau der Harnsäure, des Xanthins, Theobromins, Theophyllins und Caffeïns aus der Cyanessigsäure

Traube, Wilhelm

doi:10.1002/cber.19000330352

Cited by 105 publications

(34 citation statements)

References 3 publications

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“…In the past, several strategies for the synthesis of purines and substituted xanthines have been established 19–23. In order to introduce two triply deuterated methyl residues into the xanthine nucleus at positions N‐3 and N‐7, a published procedure for the generation of 7‐substituted 1‐methylxanthines24 was adapted and modified as follows: 156 mg of xanthine (1 mmol) were added to 40 mL of a mixture of MSTFA/ammonium iodide/ethanethiol (1000:2:6, v/w/v), which contains the in situ generated trimethyliodosilane (TMIS).…”

Section: Methodsmentioning

confidence: 99%

Electrospray ionization mass spectrometric characterization and quantitation of xanthine derivatives using isotopically labelled analogues: an application for equine doping control analysis

Thevis

Opfermann

Krug

et al. 2004

Rapid Comm Mass Spectrometry

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Isotope-dilution mass spectrometry has been employed successfully in numerous fields of analytical chemistry enabling the establishment of fast and reliable procedures. In equine sports, xanthine derivatives such as caffeine and theobromine are prohibited, and doping control laboratories analyze horse urine specimens regarding these illicit performance-enhancing drugs. Theobromine has to exceed a threshold level of 2 microg/mL, hence a robust and reliable quantitation is required. Stably deuterated theobromine and caffeine were synthesized by the reaction of xanthine or theobromine with iodomethane-d3 in the presence of N-methyl-N-trimethylsilyltrifluoroacetamide or potassium carbonate in acetonitrile, respectively. Both compounds were characterized by nuclear magnetic resonance spectroscopy and electrospray ionization tandem mass spectrometry, and a robust and fast assay for the qualitative and quantitative analysis of theobromine in equine urine samples was validated. Urine specimens were extracted by means of solid-phase extraction cartridges, and concentrated extracts were analyzed by liquid chromatography interfaced to a triple-quadrupole mass spectrometer. In addition, the dissociation behavior of deuterated analogues to caffeine and theobromine allowed proposals for fragmentation routes of xanthine derivatives after atmospheric pressure ionization and collisionally activated dissociation.

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Section: Methodsmentioning

confidence: 99%

Electrospray ionization mass spectrometric characterization and quantitation of xanthine derivatives using isotopically labelled analogues: an application for equine doping control analysis

Thevis

Opfermann

Krug

et al. 2004

Rapid Comm Mass Spectrometry

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“…[22] 6-Aminouracil derivatives (R)-1 a, (S)-1 a, and 1 b were obtained as previously described. [23] Alkylation of these compounds at N3 (corresponding to xanthine N1) was carried out in N,N-dimethylformamide in the presence of potassium carbonate by using propyl iodide at room temperature.…”

Section: Chemistrymentioning

confidence: 99%

Improving Potency, Selectivity, and Water Solubility of Adenosine A₁ Receptor Antagonists: Xanthines Modified at Position 3 and Related Pyrimido[1,2,3‐cd]purinediones

et al. 2006

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The structure-activity relationships of xanthine derivatives related to the adenosine A(1) receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 1,3-dipropyl-8-(3-noradamantyl)xanthine (KW3902) were investigated by focusing on variations of the 3-substituent. Aromatic residues were well tolerated by the A(1) receptor in that position. A moderate effect of stereochemistry was found for the 3-(1-phenylethyl)-substituted analogue of DPCPX (S>R) at A(1) and A(3) receptors, whereas the opposite stereoselectivity was observed at the A(2) receptor subtypes. A 3-hydroxypropyl substituent was found to be optimal for high A(1) affinity and selectivity. The most potent compound of the present series was 1-butyl-3-(3-hydroxypropyl)-8-(3-noradamantyl)xanthine (10 c), which exhibits a K(i) value of 0.124 nM at rat, and 0.7 nM at human adenosine A(1) receptors, combined with high selectivity (>>200-fold) versus the other receptor subtypes. The similarly potent 8-cyclopentyl-3-(3-hydroxypropyl)-1-propylxanthine was converted into a water-soluble phosphate prodrug, which may become a useful pharmacological tool for in vivo studies. 8-Alkyl-2-(3-noradamantyl)pyrimido[1,2,3-cd]purine-8,10-diones, which can be envisaged as xanthine analogues with a fixed 3-propyl substituent, were identified as a new class of potent, selective adenosine A(1) receptor antagonists. For example, compound 14 (8-butyl-substituted) exhibits a K(i) value of 13.8 nM at human A(1) receptors. A selection of the most potent compounds was investigated in [(35)S]GTPgammaS binding assays and showed inverse agonistic activity. Their efficacy was generally lower than that of the full inverse agonist DPCPX, and depended on subtle structural changes. Some of the new compounds belong to the most potent and selective A(1) antagonists described to date.

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“…1,3-Dimethyluric acid (10) was obtained by way of a four-step sequence from commercially available 9, as described in the literature. [17] Radio-labelled 11 was purified by column chromatography to yield a product with a specific activity of 3.5 mCi mg…”

Section: Resultsmentioning

confidence: 99%

Extraction of Radio‐Labelled Xanthine Derivatives by Artificial Receptors: Deep Insight into the Association Behaviour

Bomkamp

Siering

Landrock

et al. 2007

Chemistry A European J

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Association constants for the interaction of almost insoluble substrates with triphenylene ketal-based receptors in toluene have been determined by means of an extraction method employing the corresponding radio-labelled substrates. Flexible and more polar receptors tend to aggregate and exhibit inferior extraction qualities. Binding constants in toluene were found to be in the range 10(5)-10(7) m(-1), which is significantly higher than in dichloromethane. X-ray analyses indicate the direct participation of a water molecule in the binding process, which may account for the surprisingly small effect of moisture in the solvent on the stability of the complexes.

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Der synthetische Aufbau der Harnsäure, des Xanthins, Theobromins, Theophyllins und Caffeïns aus der Cyanessigsäure

Cited by 105 publications

References 3 publications

Electrospray ionization mass spectrometric characterization and quantitation of xanthine derivatives using isotopically labelled analogues: an application for equine doping control analysis

Electrospray ionization mass spectrometric characterization and quantitation of xanthine derivatives using isotopically labelled analogues: an application for equine doping control analysis

Improving Potency, Selectivity, and Water Solubility of Adenosine A₁ Receptor Antagonists: Xanthines Modified at Position 3 and Related Pyrimido[1,2,3‐cd]purinediones

Extraction of Radio‐Labelled Xanthine Derivatives by Artificial Receptors: Deep Insight into the Association Behaviour

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Der synthetische Aufbau der Harnsäure, des Xanthins, Theobromins, Theophyllins und Caffeïns aus der Cyanessigsäure

Cited by 105 publications

References 3 publications

Electrospray ionization mass spectrometric characterization and quantitation of xanthine derivatives using isotopically labelled analogues: an application for equine doping control analysis

Electrospray ionization mass spectrometric characterization and quantitation of xanthine derivatives using isotopically labelled analogues: an application for equine doping control analysis

Improving Potency, Selectivity, and Water Solubility of Adenosine A1 Receptor Antagonists: Xanthines Modified at Position 3 and Related Pyrimido[1,2,3‐cd]purinediones

Extraction of Radio‐Labelled Xanthine Derivatives by Artificial Receptors: Deep Insight into the Association Behaviour

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Improving Potency, Selectivity, and Water Solubility of Adenosine A₁ Receptor Antagonists: Xanthines Modified at Position 3 and Related Pyrimido[1,2,3‐cd]purinediones