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Marine Peuchmaur Marie-Agnès Lacour Jean Sévalle Vincent Lisowski Youness Touati-Jallabe Fabien Rodier Jean Martinez Frédéric Checler Jean-François Hernandez 《Bioorganic & medicinal chemistry》2013,21(4):1018-1029
The 3-alkoxy-7-amino-4-chloro-isocoumarins JLK-6 and JLK-2 have been shown to markedly reduce the production of Amyloid β-peptide (Aβ) by Amyloid-β Precursor Protein (APP) expressing HEK293 cells by affecting the γ-secretase cleavage of APP, with no effect on the cleavage of the Notch receptor. This suggested that these compounds do not directly inhibit the presenilin-dependent γ-secretase complex but more likely interfere with an upstream target involved in γ-secretase-associated pathway. The mechanism of action of these compounds is unknown and there are high fundamental and therapeutical interests to unravel their target. Isocoumarin compounds were previously shown to behave as potent mechanism-based irreversible inhibitors of serine proteases, suggesting that the JLK-directed target could belong to such enzyme family. To get further insight into structure–activity relationships and to develop more potent isocoumarin derivatives, we have synthesized and evaluated a series of isocoumarin analogues with modifications at positions 3, 4 and 7. In particular, the 7-amino group was substituted with either acyl, urethane, alkyl or aryl groups, which could represent additional interaction sites. Altogether, the results highlighted the essential integrity of the 3-alkoxy-7-amino-4-chloro-isocoumarin scaffold for Aβ-lowering activity and supported the involvement of a serine protease, or may be more generally, a serine hydrolase. The newly reported 7-N-alkyl series produced the most active compounds with an IC50 between 10 and 30 μM. Finally, we also explored peptide boronates, a series of reversible serine protease inhibitors, previously shown to also lower cellular Aβ production. The presented data suggested they could act on the same target or interfere with the same pathway as isocoumarins derivatives. 相似文献
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Extracts prepared from old cow lymphoid cells (OCE) inhibit the primary and secondary in vitro responses to SRBC of mouse spleen cells. The active factor in OCE is a protein of 10,000–15,000 MW, and it does affects neither lymphocyte stimulation by Con A and LPS, nor cell viability. Various experiments suggest that OCE and its active factor interfere with mechanisms of differentiation of lymphocytes into antibody-producing cells. In the present state of purification the amount of product corresponding to 50% inhibition of the immune response is about 0.3 μg/ml. 相似文献