Synthesis and structure-activity relationships of berberine analogues as a novel class of low-density-lipoprotein receptor up-regulators.
Berberine (BBR, 1) is a novel cholesterol-lowering agent that up-regulates low-density-lipoprotein receptor (LDLR) expression through a mechanism different from that of statins. Because of the unique mode of action and good safety record, BBR provoked our interest to do structure modification at different domains for its cholesterol-lowering activity. Nineteen BBR analogues with substituents on the benzene ring D were synthesized in the present study. The analysis of structure-activity relationship (SAR) indicated that the two methoxyl groups in an ortho-distribution on this benzene ring afforded a good activity. Among the 19 analogues, compound 8j bearing a methoxyl at both 10- and 11-position showed an increased LDLR up-regulatory activity in respect to BBR, and therefore has been selected as a promising cholesterol-lowering drug candidate for further evaluation.
Yang
Peng
P
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Song
Dan-Qing
DQ
Li
Ying-Hong
YH
Kong
Wei-Jia
WJ
Wang
Yan-Xiang
YX
Gao
Li-Mei
LM
Liu
Shu-Yu
SY
Cao
Rui-Qiang
RQ
Jiang
Jian-Dong
JD
D001554:Benzene; D001599:Berberine / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy; D007477:Ions; D008055:Lipids; D008956:Models, Chemical; D020871:RNA Stability / Q000187:drug effects; D011973:Receptors, LDL / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D055672:Static Electricity; D013329:Structure-Activity Relationship; D015854:Up-Regulation
D007477:Ions; D008055:Lipids; D011973:Receptors, LDL; D001599:Berberine; D001554:Benzene