Structure-activity relationship of berberine derivatives for their glucose-lowering activities

Natural product berberine (BBR) has anti-diabetic activity, both in preclinical studies as well as in clinical trials. This study was designed to discover new BBR derivatives with better glucose-lowering efficacy. Thirty-five derivatives were selected from our derivative library and screened for their activities on glucose consumption in HL-7702 cells. Among these derivatives, compound 3e with amide bond and amidogen at 9-position showed an inspiring potency of 33.3-42.1% stronger than BBR when administered at an equal molar concentration. Compound 3f, a pro-drug of berberrubine (M1), which possessed an ester bond at 9-position, showed no activity on glucose consumption in vitro, although it had promising glucose-lowering activity in KK-Ay mice. The results suggest that the amide bond at 9-position is essential to maintain the activity of BBR on glucose consumption, the introduction of electron-donating groups such as amidogen at 9-position may be a viable strategy to enhance BBR's potency, and preparation of pro-drugs may be useful to enhance the in vivo glucose-lowering efficacies of BBR derivatives.