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

Abstract

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-N-butyl-4-amino-1,8-naphthalimide (GP-BAN). The nitro-substituted analogue 27 exhibited the most potent activity (K i = 0.96 μM). 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 27 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 27 was evaluated in cancer cell lines HepG-2 and Caco-2 and in somatic RAW264.7 cells and RPTECs. Compound 27 showed no toxicity to normal cells and weak toxicity to cancer cells. In a living cell imaging assay, 27 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-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β).

Beneficial effects of food-derived polyphenols on type 2 diabetes: mechanistic insights based on gut microbiota alterations and anti-inflammatory responses

“…Proanthocyanidins from grape seeds could maintain glucose homeostasis by down-regulating the mRNA expression of the DPP-IV gene, thereby inhibiting DPP-IV enzyme activity, or increasing the plasma insulin/glucose ratio [74] . Licochalcone A, derived from Glycyrrhiza uralensis Fisch roots, inhibited DPP-IV activity [75] , showed excellent hypoglycemic effects, and had a protective effect on diabetic nephropathy. The hydroxyl group on 4-position and 5-position chlorine atoms in the structure of licochalcone A were the key structures to exert the DPP-IV inhibitory effect [76] .…”