title: Synthesis and structure-activity relationships of berberine analogues as a novel class of low-density-lipoprotein receptor up-regulators.
abstract: 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.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.forename: Dan-Qing
authors.initials: DQ
authors.lastname: Song
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Li
authors.forename: Wei-Jia
authors.initials: WJ
authors.lastname: Kong
authors.forename: Yan-Xiang
authors.initials: YX
authors.lastname: Wang
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Gao
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Liu
authors.forename: Rui-Qiang
authors.initials: RQ
authors.lastname: Cao
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
mesh_terms: 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
chemical_list: D007477:Ions; D008055:Lipids; D011973:Receptors, LDL; D001599:Berberine; D001554:Benzene