- Imidazopyridine- and purine-thioacetamide derivatives: Potent inhibitors of nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1)
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Nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) belongs to the family of ecto-nucleotidases, which control extracellular nucleotide, nucleoside, and (di)phosphate levels. To study the (patho)physiological roles of NPP1 potent and selective inhibitors with drug-like properties are required. Therefore, a compound library was screened for NPP1 inhibitors using a colorimetric assay with p-nitrophenyl 5′-thymidine monophosphate (p-Nph-5′-TMP) as an artificial substrate. This led to the discovery of 2-(3H-imidazo[4,5-b]pyridin-2-ylthio)-N-(3,4-dimethoxyphenyl)acetamide (5a) as a hit compound with a Ki value of 217 nM. Subsequent structure-activity relationship studies led to the development of purine and imidazo[4,5-b]pyridine analogues with high inhibitory potency (Ki values of 5.00 nM and 29.6 nM, respectively) when assayed with p-Nph-5′-TMP as a substrate. Surprisingly, the compounds were significantly less potent when tested versus ATP as a substrate, with Ki values in the low micromolar range. A prototypic inhibitor was investigated for its mechanism of inhibition and found to be competitive versus both substrates.
- Chang, Lei,Lee, Sang-Yong,Leonczak, Piotr,Rozenski, Jef,De Jonghe, Steven,Hanck, Theodor,Müller, Christa E.,Herdewijn, Piet
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p. 10080 - 10100
(2015/02/05)
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- Purines. LXX. An extension of the 'Phenacylamine route' to the syntheses of the 7-N-oxides of 6-mercaptopurine and 6-methylthiopurine, and antileukemic activity of some purine N-oxides
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A full account is given of the first syntheses of 6-mercaptopurine 7-N-oxide (4) and 6-methylthiopurine 7-N-oxide (5), The synthesis of 4 followed a 'phenacylamine route', which started from condensation of 4,6-dichloro-5-nitropyrimidine (15) with N-(4-methoxybenzyl)phenacylamine to form the phenacylaminopyrimidine derivative (11) and proceeded through conversion into the mercapto derivative, intramolecular cyclization between the NO2 nitrogen atom and the phenacyl carbanion to give 6-mercapto-9-(4-methoxybenzyl)purine 7-N-oxide (12), and removal of the 4-methoxybenzyl group, S-Methylation of 12 and removal of the 4-methoxybenzyl group afforded 5, The location of the oxygen function in 4, 5, and 12 was confirmed by X-ray crystallographic analysis of 5 · H2O, which was shown to exist in the N(7)-OH form (19). A UV spectroscopic approach suggested that the neutral species of 4 exists in H2O as the N(7)-OH tautomer (21), whereas that of 5 exists as an equilibrated mixture of the N(7)-oxide (5) and the N(7)-OH (19) tautomers. In the in vitro bioassay of antileukemic activity against murine L5178Y cells, the N-oxides 4 and 12 were found to be weakly cytotoxic.
- Fujii,Ogawa,Itaya,Date,Inagaki,Nohara
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p. 408 - 413
(2007/10/02)
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- Method for the selection of genetically transformed cells and compounds for use in the method
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A method for selecting from a population of cells genetically transformed cells into which a desired nucleotide sequence has been introduced, wherein in the transformed cells the desired nucleotide sequence or a co-introduced nucleotide sequence induces or increases a positive effect of a compound or nutrient supplied to the population of cells, thereby allowing the transformed cells to be identified or selected from non-transformed cells, e.g. for the preparation of genetically transformed plants not containing as a selection marker a non-native nucleotide sequence coding for toxin, antibiotic or herbicide resistance; as well as novel glucuronide compounds, including cytokinin glucuronide compounds, for use in the method.
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