Structure-activity relationships for naturally occurring coumarins as β-secretase inhibitor

Shinsuke Marumoto; Mitsuo Miyazawa

doi:10.1016/j.bmc.2011.12.002

Structure-activity relationships for naturally occurring coumarins as β-secretase inhibitor

Bioorg Med Chem. 2012 Jan 15;20(2):784-8. doi: 10.1016/j.bmc.2011.12.002. Epub 2011 Dec 8.

Authors

Shinsuke Marumoto¹, Mitsuo Miyazawa

Affiliation

¹ Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University, Kowakae, Higashiosaka-shi, Osaka 577-8502, Japan.

PMID: 22222157
DOI: 10.1016/j.bmc.2011.12.002

Abstract

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.

MeSH terms

5-Methoxypsoralen
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Coumarins / chemical synthesis
Coumarins / chemistry*
Furocoumarins / chemistry
Kinetics
Methoxsalen / analogs & derivatives
Methoxsalen / chemistry
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry*
Structure-Activity Relationship

Substances

Coumarins
Furocoumarins
Protease Inhibitors
5-Methoxypsoralen
Amyloid Precursor Protein Secretases
bergamottin
Methoxsalen