Licochalcone A Derivatives as Selective Dipeptidyl Peptidase 4 Inhibitors with Anti-Inflammatory Effects.

A set of 22 analogs of licochalcone A was designed and synthesized to explore their potentials as dipeptidyl peptidase 4 (DPP4) inhibitors with anti-inflammatory effects. The anti-DPP4 effects of these analogs were evaluated using the fluorescent substrate Gly-Pro--butyl-4-amino-1,8-naphthalimide (GP-BAN). The nitro-substituted analogue exhibited the most potent activity ( = 0.96 M). A structure-activity relationship investigation revealed that 4-hydroxyl and 5-chloro substituents are essential for DPP4 inhibition, while the 3'-nitro substituent improved both DPP4 inhibition and microsomal stability. Furthermore, compound demonstrated good selectivity for DPP4 over other proteases, including dipeptidyl peptidase 9 (DPP9), thrombin, prolyl endopeptidase (PREP), and fibroblast activation protein (FAP). The cytotoxic effect of was evaluated in cancer cell lines HepG-2 and Caco-2 and in somatic RAW264.7 cells and RPTECs. Compound showed no toxicity to normal cells and weak toxicity to cancer cells. In a living cell imaging assay, blocked the dipeptidase activity of DPP4 in both Caco-2 and HepG-2 cells. This compound also dose-dependently suppressed the expression levels of the chemokines tumor necrosis factor- (TNF-), interleukin-6 (IL-6), and interleukin-1 (IL-1).