Discovery of C-9 Modified Berberine Derivatives as Novel Lipid-Lowering Agents

Abstract

Berberine (BBR), a kind of quaternary ammonium benzylisoquinoline alkaloids with multiple pharmacological activities, has been regarded as a promising lipid-lowering agent in the field of drug repurposing. Particularly, the chemical modification at the C-9 position of BBR can remarkably improve its lipid-lowering efficacy. In this study, thirteen novel BBR derivatives were rationally designed, synthesized, and evaluated by preliminary pharmacological tests. The results showed that most compounds exhibited more potent hypolipidemic activities when compared with BBR and simvastatin. Among these compounds, compound 2h-1 and 2h-2 exhibited better activity profiling in these four tests involving with inhibition of total cholesterol (TCHO), triglyceride (TG), and low-density lipoprotein cholesterol (LDLC) and the increase of high-density lipoprotein cholesterol (HDLC). Correspondingly, the BBR analogs with 9-O-cinnamic moiety probably exhibited potent lipid-lowering activity, and should be exploited as an important versatile template for the development of BBR-like lipid-lowering agents.

Berberine: A Multi-Target Natural PCSK9 Inhibitor with the Potential to Treat Diabetes, Alzheimer’s, Cancer and Cardiovascular Disease

“…92 Another compound, 2h-1, was found to reduce TC by >50% and TG by 70% in HepG2 cells compared to controls. 124 8-cetylberberine is another analog which lowered total cholesterol and LDL-C by 48% and 22%, respectively, in hyperlipidemic mice. 125 While each of these compounds offer a distinct method for increasing efficacy and bioavailability, the majority of berberine analogs with improved bioavailability and potency show increased lipophilicity compared to berberine.…”