- Improved imide receptors by imprinting using pyrimidine-based fluorescent reporter monomers
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(Chemical Equation Presented) Optically responsive receptors toward imides based on 6-substituted 2,4-bis(acrylamido)pyrimidines are presented. The monomers were readily prepared in good yield. Solution binding to 1-benzyluracil (BU) monitored by 1H NMR appeared lower than a previously reported pyridine-based monomer. However, as indicated by 1H NMR and IR spectral investigations, the association strength was demonstrated to be "masked" by dimerization of the pyrimidine-based monomer units. Thus, from dilution experiments, a dimerization constant of 731 M-1 was estimated for the pyrimidine-based monomer 2,4-bis(acrylamido)-6- piperidinopyrimidine whereas for the pyridine-based monomer 2,6-bis(acrylamido) pyridine, no self-association was observed. This precluded an accurate determination of the binding constant for BU to the former monomer whereas for the latter a binding constant of 757 M-1 was measured. Despite the strong self-association, the novel monomer was shown to lead to enhanced imprinting effects when compared to imprinted polymers prepared analogously, but using the pyridine-based monomer as the recognition element. This was attributed to a higher intrinsic binding affinity exhibited by the pyrimidine based host monomer vis a vis the guest and the existence in the former of more than one interaction site for the guest. The monomers exhibited fluorescence emission informative of the mode of monomer incorporation in the polymer and the presence of guest species. Thus, the fluorescence was rapidly and selectively quenched upon template addition, with the degree of quenching correlating with binding affinity and the amount of template bound to the polymer.
- Manesiotis, Panagiotis,Hall, Andrew J.,Sellergren, Boerje
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- 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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- Synthesis of novel 5-amino-thiazolo[4,5-d]pyrimidines as E. coli and S. aureus SecA inhibitors
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An efficient synthesis of a library of 5-amino-thiazolo[4,5-d]pyrimidines is reported. Regioselective displacements of chlorines, as well as regioselective diazotation reactions are described, which allow the introduction of structural diversity on the sc
- Jang, Mi-Yeon,Jonghe, Steven De,Segers, Kenneth,Anné, Jozef,Herdewijn, Piet
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experimental part
p. 702 - 714
(2011/02/28)
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- Synthesis and in vitro evaluation of 2-amino-4-N-piperazinyl-6-(3,4- dimethoxyphenyl)-pteridines as dual immunosuppressive and anti-inflammatory agents
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Screening of a pteridine-based compound library led to the identification of compounds exhibiting immunosuppressive as well as anti-inflammatory activity. Optimization afforded a series of 2-amino-4-N-piperazinyl-6-(3,4- dimethoxyphenyl)pteridine analogues. The most potent congeners in this series displayed low nM IC50 values in the Mixed Lymphocyte Reaction (MLR) assay. In addition, these compounds also have potent anti-inflammatory activity as measured in the Tumor Necrosis Factor (TNF) assay.
- De Jonghe, Steven,Marchand, Arnaud,Gao, Ling-Jie,Calleja, Agnes,Cuveliers, Eva,Sienaert, Ilse,Herman, Jean,Clydesdale, Gavin,Sefrioui, Hassane,Lin, Yuan,Pfleiderer, Wolfgang,Waer, Mark,Herdewijn, Piet
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scheme or table
p. 145 - 149
(2011/02/25)
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- 5-ARYL-SUBSTITUTED DIHYDROPYRIDOPYRIMIDINES AND DIHYDROPYRIDAZINES AND USE THEREOF AS MINERAL CORTICOID ANTAGONISTS
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The present application relates to novel aryl-substituted heterobicyclic compounds, a process for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for the manufacture of medicaments for the treatment and/or prop
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Page/Page column 20
(2010/03/02)
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- Synthesis and biological evaluation of 5-substituted O4- alkylpyrimidines as CDK2 inhibitors
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CDK2 inhibitory structure-activity relationships have been explored for a range of 5-substituted O4-alkylpyrimidines. Variation of the 5-substituent in the 2,6-diaminopyrimidine series confirmed the 5-nitroso substituent as optimal, and showed that 5-formyl and 5-acetyl substituents were also tolerated at this position. A series of O4-alkyl-N 2-aryl-5-substituted-6-aminopyrimidines revealed interesting structure-activity relationships. In the 5-nitroso series, the optimum O 4-alkyl substituents were cyclohexylmethyl or sec-butyl, combined with a 2-sulfanilyl group. By contrast, in the N2-arylsulfonamido-5- formyl series, the cyclohexylmethyl compound showed relatively poor activity compared with the sec-butyl derivative (22j, (R)-4-(4-amino-6-sec-butoxy-5- formylpyrimidin-2-ylamino)benzenesulfonamide; CDK2 IC50 = 0.8 nM). Similarly, in the N2-arylsulfonamido-5-(hydroxyiminomethyl) series the O4-sec-butyl substituent conferred greater potency than the cyclohexylmethyl (23c, (rac)-4-(4-amino-6-sec-butoxy-5-(hydroxyiminomethyl) pyrimidin-2-ylamino)benzenesulfonamide; CDK2 IC50 = 7.4 nM). The 5-formyl derivatives show selectivity for CDK2 over other CDK family members, and are growth inhibitory in tumour cells (e.g.22j, GI50 = 0.57 μM).
- Marchetti, Francesco,Cano, Celine,Curtin, Nicola J.,Golding, Bernard T.,Griffin, Roger J.,Haggerty, Karen,Newell, David R.,Parsons, Rachel J.,Payne, Sara L.,Wang, Lan Z.,Hardcastle, Ian R.
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supporting information; experimental part
p. 2397 - 2407
(2010/07/09)
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- Immunosuppressive effects of pteridine derivatives
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This invention relates to a group of trisubstituted and tetrasubstituted pteridine derivatives, their pharmaceutically acceptable salts, N-oxides, solvates, dihydro- and tetrahydroderivatives and enantiomers, possessing unexpectedly desirable pharmaceutical properties, in particular which are highly active immunosuppressive agents, and as such are useful in the treatment in transplant rejection and/or in the treatment of certain inflammatory diseases. These compounds are also useful in preventing or treating cardiovascular disorders, allergic conditions, disorders of the central nervous system and cell proliferative disorders.
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- Thiono and Dithio Esters, 42. - Synthesis and Properties of Cyanoacetic Thionoesters
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Malononitrile (1) can be transformed into the cyanoacetic thionoesters 3 via the imidoester hydrochlorides 2 by thiolysis.The ethyl ester 3a condenses with benzylamine by H2S elimination to form the imidoester 7 and with piperidine by elimination of ethan
- Mueller, Hans-Georg,Hartke, Klaus
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p. 879 - 884
(2007/10/02)
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