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

被引:2
|
作者
Li, Ci-Qin [1 ]
Shi, Jin-Hui [1 ,2 ,3 ]
Mu, Jie [1 ]
Wang, An-Qi [1 ]
Zou, Li-Wei [1 ,2 ]
Ge, Guang-Bo [1 ,2 ]
机构
[1] Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Shanghai 201203, Peoples R China
[2] Shanghai Univ Tradit Chinese Med, Shanghai Frontiers Sci Ctr TCM Chem Biol, Shanghai 201203, Peoples R China
[3] Kyoto Univ, Grad Sch Biostudies, Lab Single Mol Cell Biol, Kyoto 6068501, Japan
来源
JOURNAL OF NATURAL PRODUCTS | 2023年 / 86卷 / 07期
关键词
KIDNEY INJURY; IV; INFLAMMATION; DISCOVERY; CHALCONE; PATHWAY; DESIGN; POTENT;
D O I
10.1021/acs.jnatprod.3c00355
中图分类号
Q94 [植物学];
学科分类号
071001 ;
摘要
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;).
引用
收藏
页码:1824 / 1831
页数:8
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