Biotransformation of isoimperatorin and imperatorin by Glomerella cingulata and beta-secretase inhibitory activity.
Biotransformation studies conducted on the furanocoumarins isoimperatorin (1) and imperatorin (3) have revealed that 1 was metabolized by Glomerella cingulata to give the corresponding reduced acid, 6,7-furano-5-prenyloxy hydrocoumaric acid (2), and 3 was transformed by G. cingulata to give the dealkylated metabolite, xanthotoxol (4) in high yields (83% and 81%), respectively. The structures of the new compound 2 have been established on the basis of spectral data. The metabolites 2 and 4 were tested for the beta-secretase (BACE1) inhibitory activity in vitro, and metabolite 2 slightly inhibited the beta-secretase activity with an IC(50) value of 185.6+/-6.8 microM. The metabolite 4 was less potent activity than compounds 1-3. In addition, methyl ester (2Me), methyl ether (2a) and methyl ester and ether (2aMe) of 2 were synthesized, and investigated for the ability to inhibit beta-secretase. Compound 2aMe exhibited the best beta-secretase inhibitory activity at the IC(50) value 16.2+/-1.2 microM and found to be the 2aMe showed competitive mode of inhibition against beta-secretase with K(i) value 11.3+/-2.8 microM.
Marumoto
Shinsuke
S
Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University, Kowakae, Higashiosaka-shi, Osaka 577-8502, Japan.
Miyazawa
Mitsuo
M
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001711:Biotransformation; D004365:Drugs, Chinese Herbal / Q000378:metabolism / Q000494:pharmacology; D011564:Furocoumarins / Q000378:metabolism* / Q000494:pharmacology*; D020081:Phyllachorales / Q000378:metabolism*
D004365:Drugs, Chinese Herbal; D011564:Furocoumarins; C055542:isoimperatorin; D053829:Amyloid Precursor Protein Secretases; C031534:imperatorin