Further characterization of a putative serine protease contributing to the ¦Ã-secretase cleavage of ¦Â-amyloid precursor protein

详细信息    查看全文

• 作者：Marine Peuchmaur^a ; ^&dagger ; ; ^¡¬ ; Marie-Agnè ; s Lacour^a ; ^&Dagger ; ; ^¡¬ ; Jean Sé ; valle^b ; ^§ ; ; Vincent Lisowski^a ; Youness Touati-Jallabe^a ; Fabien Rodier^a ; ^¶ ; ; Jean Martinez^a ; Fré ; dé ; ric Checler^b ; Jean-Franç ; ois Hernandez^a ; ^{jean-francois.hernandez@univ-montp1.fr}
• 关键词：A¦Â ; Amyloid ¦Â-peptide ; AICD ; APP intracellular domain ; APP ; Amyloid-¦Â Precursor Protein ; BACE ; beta-site APP cleaving enzyme ; DCM ; dichloromethane ; DMSO ; dimethylsulfoxide ; ESI ; electrospray ionization ; EtOAc ; ethyl acetate ; FBS ; fetal bovine serum ; GS
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：15 February, 2013
• 年：2013
• 卷：21
• 期：4
• 页码：1018-1029
• 全文大小：853 K

文摘

The 3-alkoxy-7-amino-4-chloro-isocoumarins JLK-6 and JLK-2 have been shown to markedly reduce the production of Amyloid ¦Â-peptide (A¦Â) by Amyloid-¦Â Precursor Protein (APP) expressing HEK293 cells by affecting the ¦Ã-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 ¦Ã-secretase complex but more likely interfere with an upstream target involved in ¦Ã-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 A¦Â-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 ¦ÌM. Finally, we also explored peptide boronates, a series of reversible serine protease inhibitors, previously shown to also lower cellular A¦Â production. The presented data suggested they could act on the same target or interfere with the same pathway as isocoumarins derivatives.