Synthesis and biological evaluation of geniposide derivatives as inhibitors of hyperuricemia, inflammatory and fibrosis.

Hyperuricemia is a metabolic disease caused by abnormal purine metabolism in the body. Long-term high levels of uric acid in the body will lead to gout and kidney disease. Xanthine oxidase (XOD) is a key enzyme in the pathogenesis of hyperuricemia. In this context, a series of geniposide derivatives were designed, synthesized and evaluated as xanthine oxidase inhibitors. Most of these compounds exhibited potent XOD inhibitory activities in vitro , and representatives 6a , 6c , 6g and 6j were found to be the most potent inhibitors against the enzyme with IC 50 values of 2.15 ± 1.03, 1.37 ± 0.26, 4.14 ± 0.79 and 1.86 ± 0.13 μM, which were 33.03–158.37 fold more active than geniposide, respectively. Compounds 6a , 6c , 6g and 6j were evaluated in hyperuricemia mice, and the results demonstrated that compound 6c showed the strongest anti-hyperuricemia and renal protective activity in vivo. Subsequently, the molecular mechanism of compound 6c was studied in this investigation. In vitro cell experiments showed that compound 6c inhibited the inflammation of HK-2 cells under high uric acid conditions by inhibiting the expressions of TGF-β, TNF-α and IL-1β, and reduced the cell fibrosis by decreasing the expressions of α-SMA and Collagen I. The results of the mice experiments indicated that compound 6c efficiently decreased the level of serum uric acid (SUA) in hyperuricemia mice by inhibiting the XOD activity. Moreover, compound 6c effectively reduced the urate accumulation in the kidney and simultaneously decreased inflammation by regulating the expression of the TLR4/IκBα/NF-κB signaling pathway. In addition, consistent with cell experiments, compound 6c also reduced renal fibrosis in hyperuricemia mice, which may be due to compound 6c inhibiting the expression of inflammatory factor TGF-β. Furthermore, a molecular docking study was performed to gain insight into the binding mode of compound 6c with XOD. These results suggest that compound 6c has the potential to be developed into a novel medicine to reduce blood uric acid and treat renal diseases caused by hyperuricemia. [Display omitted] • 42 novel geniposide derivatives were designed and synthesized for the purpose of discovering an efficient XOD inhibitor. • Compound 6c was the most potent XOD inhibitor in vitro , showing 117.81-fold more active than that of geniposide. • Compound 6c effectively inhibited XOD activity in hyperuricemic mice. • Compound 6c could regulate the TLR4/IκBα/NF-κB signal pathway, thereby reducing the level of inflammatory factors. • Compound 6c could inhibit renal fibrosis by reducing the expression of TGF-β. [ABSTRACT FROM AUTHOR]