Design, synthesis, and biological activity of 9-O-cinnamoylberberines as novel lipid-lowering agents

Abstract

Berberine possesses a wide spectrum of lipid regulation, and yet it has poor physicochemical property and cytotoxicity as a drug candidate. In order to alleviate the problems, a total of twenty-one 9-O-cinnamoylberberines and twenty 9-O-cinnamoyltetrahydroberberines were designed, synthesized, and evaluated by in vitro cell viability experiment and four classical lipid-lowering assays involving with total cholesterol, triglyceride, low density lipoprotein cholesterol, and high density lipoprotein cholesterol. A structure–activity relationship study of these compounds resulted in the discovery of two promising candidate molecules (5p and 7u). Compound 5p displayed the most potent inhibitory effect for TG formation, with the inhibitory rates of 40.5% and 76.8% in 3T3-L1 cells and HepG2 cells, respectively. Compound 7u exhibited the most promoting activity for the production of HDLC, with the increasing rates of 52.6% and 70.5% in both models, respectively. These two attractive compounds can be further investigated as new lipid-lowering agents in follow-up researches.

Graphical Abstract

Keywords:

• Berberine
• lipid-lowering
• cholesterol
• triglyceride
• natural product modification

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Funding

This work was supported by the Project for Young Teachers of Nanjing Forestry University (grant number: CX2017005), a Project Funded by the National First-class Disciplines (PNFD).