Berberine analogues as a novel class of the low-density-lipoprotein receptor up-regulators: synthesis, structure-activity relationships, and cholesterol-lowering efficacy.
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.
Li
Ying-Hong
YH
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Yang
Peng
P
Kong
Wei-Jia
WJ
Wang
Yan-Xiang
YX
Hu
Chang-Qin
CQ
Zuo
Zeng-Yan
ZY
Wang
Yue-Ming
YM
Gao
Hong
H
Gao
Li-Mei
LM
Feng
Yan-Chun
YC
Du
Na-Na
NN
Liu
Ying
Y
Song
Dan-Qing
DQ
Jiang
Jian-Dong
JD
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*
D012333:RNA, Messenger; D011973:Receptors, LDL; D001599:Berberine; D002784:Cholesterol