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).
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