title: Berberine analogues as a novel class of the low-density-lipoprotein receptor up-regulators: synthesis, structure-activity relationships, and cholesterol-lowering efficacy.
abstract: Twenty-nine derivatives of berberine (1) or pseudoberberine (2) were designed, semisynthesized, and evaluated for their up-regulatory activity on the low-density-lipoprotein receptor (LDLR) expression. SAR analysis revealed that (i) the methylenedioxy group at the 2- and 3-position is an essential element to keep the activity, (ii) the 7-position quaternary ammonium and planar structure of the compound are activity-required, and (iii) addition of electron-donating groups at the 7- or 13-position reduced the activity. Of the compound 1 analogues, compound 2 exhibited an increased activity on LDLR expression compared to 1. In the hyperlipidemic rats, compound 2 (100 (mg/kg)/day) reduced blood CHO and LDL-c by 42.6% and 49.4%, respectively, more efficient than 1 did (p < 0.01 for both). The results were confirmed in the hyperlipidemic mice. LD(50) of 2 in mice was over 5000 mg/kg (oral). We consider compound 2 a promising cholesterol-lowering drug candidate.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Li
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.forename: Wei-Jia
authors.initials: WJ
authors.lastname: Kong
authors.forename: Yan-Xiang
authors.initials: YX
authors.lastname: Wang
authors.forename: Chang-Qin
authors.initials: CQ
authors.lastname: Hu
authors.forename: Zeng-Yan
authors.initials: ZY
authors.lastname: Zuo
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Gao
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Gao
authors.forename: Yan-Chun
authors.initials: YC
authors.lastname: Feng
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Du
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Dan-Qing
authors.initials: DQ
authors.lastname: Song
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001599:Berberine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*; D013329:Structure-Activity Relationship; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D012333:RNA, Messenger; D011973:Receptors, LDL; D001599:Berberine; D002784:Cholesterol