Design and synthesis of novel saponin-triazole derivatives in regulation of adipogenesis

Saponins associated with Panax notoginseng (Burk.) F.H. Chen are recognized as an effective medicine for the treatment of a variety of diseases. However, the clinical applications of some high-yield saponins are limited due to weak pharmacological activities. In this study, 36 saponin-1,2,3-triazole derivatives of ginsenosides Rg1/Rb1 and notoginsenoside R1 were synthesized and evaluated for anti-adipogenesis activity in vitro. The findings have revealed that the ginsenosides Rg1-1,2,3-triazole derivative a17 exhibits the greatest adipogenesis inhibitory effect. The structure-activity relationships (SARs) analysis has demonstrated that the introduction of an amidyl-substituted 1,2,3-triazole to the saponin side chain in a Click reaction can enhance anti-adipogenesis activity. Moreover, several other derivatives also display a general adipogenesis inhibition. Compound a17 exhibited more potent activity when compared with the starting ginsenoside Rg1. Mechanistic studies have indicated that a17 exhibited a dose-dependent inhibition of adipogenesis in vitro, with a concurrent reduction in the expressions of the PPARγ, FAS and FABP4 adipogenesis regulators. The results establish the potential of the ginsenoside Rg1-1,2,3-triazole derivative a17 as an inhibitor for adipocyte differentiation, and a possible therapeutic candidate for the treatment of obesity and related metabolic disorders. Our findings can serve as the basis for future research directed at effective therapeutic strategies for a range of metabolic syndromes.