Structure-activity relationships for naturally occurring coumarins as β-secretase inhibitor.
The present study was demonstrated to evaluate the effects of naturally occurring coumarins (NOCs) including simple coumarins, furanocoumarins, and pyranocoumarins on the inhibition of β-secretase (BACE1) activity. Of 41 NOCs examined, some furanocoumarins inhibited BACE1 activity, but simple coumarins and pyranocoumarins did not affect. The most potent inhibitor was 5-geranyloxy-8-methoxypsoralen (31), which has an IC(50) value of 9.9 μM. Other furanocoumarin derivatives, for example, 8-geranyloxy-5-methoxypsoralen (35), 8-geranyloxypsoralen (24), and bergamottin (18) inhibited BACE1 activity, with the IC(50) values <25.0 μM. Analyses of the inhibition mechanism by Dixon plots and Cornish-Bowden plots showed that compounds 18, 31 and 35 were mixed-type inhibitor. The kinetics of inhibition of BACE1 by coumarins 24 was non-competitive inhibitors.
Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University, Kowakae, Higashiosaka-shi, Osaka 577-8502, Japan.
Shinsuke
S
Marumoto
Mitsuo
M
Miyazawa
D000078223:5-Methoxypsoralen; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry*; D011564:Furocoumarins / Q000737:chemistry; D007700:Kinetics; D008730:Methoxsalen / Q000031:analogs & derivatives / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship
D003374:Coumarins; D011564:Furocoumarins; D011480:Protease Inhibitors; D000078223:5-Methoxypsoralen; D053829:Amyloid Precursor Protein Secretases; C068337:bergamottin; D008730:Methoxsalen