Synthesis and bioactivity evaluation of novel nuciferine derivatives with antihyperuricemia and nephroprotective effects.

Scheme 1. Synthesis of nuciferine derivative 1a-1r,2a-2l. Reagents and conditions: (a) 48% HBr solution, glacial acetic acid, 70 °C; (b) Et 3 N, N 2 , CH 2 Cl 2 , 25℃, 1h; (c) NaH, N 2 , DMF, 0 °C, 2h. [Display omitted] • The inhibition effect of compound 1j (104.46 ± 4.07%) was roughly the same as benzbromarone (101.44 ± 6.21%) in UA-induced HK-2 cells model; • Compound 1j inhibited the expression of URAT1 and GLUT9 through repressing PI3K/Akt pathway in HK-2 cells; • Compound 1j can promote the excretion of uric acid and thereby increase the fraction of uric acid excretion in vivo ; • Compound 1j can ameliorate renal inflammation and reduce the level of renal inflammatory factors; • Compound 1j shows nephroprotective effect through regulate TLR4/IκBα/NF-κB signaling pathway; Hyperuricemia is a common metabolic disease with a series of complications. Nuciferine, a typical aporphine alkaloid natural compound extracted from the leaves of Nelumbo nucifera Gaertn., was confirmed to have an antihyperuricemia effect. In the present study, 30 novel nuciferine derivatives were designed and synthesized. The effects of all derivatives on the regulation of URAT1 were studied in a uric acid-induced HK-2 cell model with benzbromarone as a positive control. The results indicated that Compound 1j showed the optimal URAT1 inhibitory activity through repressing PI3K/Akt pathway in HK-2 cells and the inhibitory effect was similar to that of benzbromarone. In addition, in vivo experiments demonstrated that Compound 1j could reduce uric acid levels and ameliorate kidney damage in hyperuricemic mice. On the one hand, Compound 1j could inhibit the expression of URAT1 and GLUT9 to increase the uric acid excretion index. On the other hand, Compound 1j could regulate the TLR4/IκBα/NF-κB signaling pathway to reduce the levels of inflammatory cytokines, thereby alleviating kidney damage. Meanwhile, a molecular docking assay revealed the potential molecular binding power (-9.79 kcal/mol) between Compound 1j and URAT1, which was more tightly bound than the lead compound nuciferine (-7.44 kcal/mol). Based on these results, Compound 1j may be a future drug for the development of new potential antihyperuricemia and nephroprotective drug candidates. [ABSTRACT FROM AUTHOR]