BACE1 inhibitory effects of lavandulyl flavanones from Sophora flavescens.
In order to access beta-secretase (BACE1), and enzyme strongly implicated in the cause of Alzheimer's disease, inhibitors must possess sufficient lipophilicity to traverse two lipid bilayers. Current drug candidates, which are almost totally peptide-derived, are thus inefficient because cell permeability presents a serious limiting factor. In this study, lipophilic alkylated (C(10)-C(5)) flavanones from Sophora flavescens were examined for their inhibitory effects against beta-secretase. Lavandulyl flavanones (1, 2, 5, 6, and 8) showed potent beta-secretase inhibitory activities with IC(50)s of 5.2, 3.3, 8.4, 2.6, and 6.7microM, respectively, while no significant activity was observed in the corresponding hydrated lavandulyl flavanones (4 and 7) and prenylated flavanone (3). As we expected, lavandulyl flavanones reduced Abeta secretion dose-dependently in transfected human embryonic kidney (HEK-293) cells. In kinetic studies, all compounds screened were shown to be noncompetitive inhibitor.
Hwang
Eun Mi
EM
Department of Physiology, Institute of Health Science, and Medicinal Research Center for Neural Dysfunction, Gyeongsang National University School of Medicine, Jinju 660-751, Republic of Korea.
Ryu
Young Bae
YB
Kim
Hoi Young
HY
Kim
Dong-Gyu
DG
Hong
Seong-Geun
SG
Lee
Jin Hwan
JH
Curtis-Long
Marcus J
MJ
Jeong
Seong Hun
SH
Park
Jae-Yong
JY
Park
Ki Hun
KH
D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics; D002460:Cell Line; D044950:Flavanones / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D029909:Sophora / Q000737:chemistry*; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D044950:Flavanones; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human