Synthesis and biological evaluation of berberine analogues as novel up-regulators for both low-density-lipoprotein receptor and insulin receptor.
Berberine (BBR) is a natural compound with up-regulating activity on both low-density-lipoprotein receptor (LDLR) and insulin receptor (InsR). This one-drug-multiple-target characteristic might be suitable for the treatment of metabolic syndrome. In searching for up-regulators effective for both LDLR and InsR expression, the structure-activity relationship (SAR) analysis for BBR analogues was done. Fourteen BBR analogues were designed, synthesized and biologically evaluated. SAR analysis revealed that appropriate modifications on the phenyl ring A or D of BBR might retain the up-regulatory activities on the expression of both LDLR and InsR. Among these compounds, compound 13a bearing 9-methoxy and 10-hydroxyl on the ring D showed promising activities on either LDLR or InsR gene expression. The 10-hydroxyl of 13a could be an arm to connect proper chemical groups for optimizing drug-bioavailability in vivo. Thus, 13a could be considered to be a parent compound to make pro-drugs for either blood lipids or glucose.
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Yan-Xiang
YX
Wang
Yu-Ping
YP
Wang
Hao
H
Zhang
Wei-Jia
WJ
Kong
Ying-Hong
YH
Li
Fei
F
Liu
Rong-Mei
RM
Gao
Ting
T
Liu
Jian-Dong
JD
Jiang
Dan-Qing
DQ
Song
D001599:Berberine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015854:Up-Regulation
D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D011973:Receptors, LDL; D001599:Berberine; D011972:Receptor, Insulin