Synthesis of new 3-alkoxy-7-amino-4-chloro-isocoumarin derivatives as new beta-amyloid peptide production inhibitors and their activities on various classes of protease.
A series of new 7-substituted-4-chloro-3-alkoxy isocoumarin derivatives were synthesized and evaluated as inhibitors of representative classes of proteases: serine protease (alpha-chymotrypsin, trypsin), cysteine protease (Caspase-3), and aspartyl protease (HIV-protease), 20S proteasome and also as inhibitors of amyloid peptide gamma-secretase-mediated production. Protease inhibition selectivity is directly related to the structure of the substituent at the 7-position of the isocoumarin nucleus. 7-Nitro-isocoumarin derivatives (4c, 4d, 4f) are potent alpha-chymotrypsin inhibitors but slightly active or inactive on HIV-protease, as well as on cysteine protease. In contrast, only derivatives bearing a free amino (5d, 5f) or a substituted amino group (6f) at the 7-position of the isocoumarin nucleus, were found weakly active or inactive on alpha-chymotrypsin, trypsin, Caspase-3 and HIV-protease, but prevent gamma-secretase-mediated production of Abeta 40/42 amyloid peptides, which is known to be involved in Alzheimer's disease. Moreover, the most active compounds on beta-amyloid peptide production [JLK6 (5d), JLK2 (5f) and JLK7 (6f)] show only weak or moderate inhibitory activity on the 20S proteasome. The obtained results suggest that the described new isocoumarin analogues could be of interest, since compounds like JLK6 (5d), JLK2 (5f) and JLK7 (6f) can be considered as possible hits for the development of new agents directed towards Alzheimer's disease.
Bihel
Frédéric
F
INSERM U-382, Developmental Biology Institute of Marseille (CNRS-INSERM-Univ. Méditerranée- AP Marseille), Laboratoire de Chimie Biomoléculaire, Faculté des Sciences de Luminy, case 907, 13288 Marseille Cedex 09, France.
Quéléver
Gilles
G
Lelouard
Hugues
H
Petit
Agnès
A
Alvès da Costa
Cristine
C
Pourquié
Olivier
O
Checler
Frédéric
F
Thellend
Annie
A
Pierre
Philippe
P
Kraus
Jean Louis
JL
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016282:Aspartic Acid Endopeptidases; D002478:Cells, Cultured; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology*; D003546:Cysteine Endopeptidases; D015195:Drug Design; D010450:Endopeptidases / Q000145:classification / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D003374:Coumarins; D009097:Multienzyme Complexes; D010446:Peptide Fragments; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D046988:Proteasome Endopeptidase Complex