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

A set of 22 analogs of licochalcone A was designed andsynthesizedto explore their potentials as dipeptidyl peptidase 4 (DPP4) inhibitorswith anti-inflammatory effects. The anti-DPP4 effects of these analogswere evaluated using the fluorescent substrate Gly-Pro-N-butyl-4-amino-1,8-naphthalimide (GP-BAN). The nitro-substitutedanalogue 27 exhibited the most potent activity (K ( i ) = 0.96 & mu;M). A structure-activity relationship investigation revealedthat 4-hydroxyl and 5-chloro substituents are essential for DPP4 inhibition,while the 3 & PRIME;-nitro substituent improved both DPP4 inhibitionand microsomal stability. Furthermore, compound 27 demonstratedgood selectivity for DPP4 over other proteases, including dipeptidylpeptidase 9 (DPP9), thrombin, prolyl endopeptidase (PREP), and fibroblastactivation protein (FAP). The cytotoxic effect of 27 wasevaluated in cancer cell lines HepG-2 and Caco-2 and in somatic RAW264.7cells and RPTECs. Compound 27 showed no toxicity to normalcells and weak toxicity to cancer cells. In a living cell imagingassay, 27 blocked the dipeptidase activity of DPP4 inboth Caco-2 and HepG-2 cells. This compound also dose-dependentlysuppressed the expression levels of the chemokines tumor necrosisfactor-& alpha; (TNF-& alpha;), interleukin-6(IL-6), and interleukin-1 & beta; (IL-1 & beta;).

Automated summary

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 most potent activity was exhibited by the nitro-substituted analogue 27. The structure-activity relationship investigation revealed the importance of 4-hydroxyl and 5-chloro substituents for DPP4 inhibition, while the 3'-nitro substituent improved both DPP4 inhibition and microsomal stability. Furthermore, compound 27 showed good selectivity for DPP4 over other proteases and demonstrated no toxicity to normal cells and weak toxicity to cancer cells.