2. Academic Validation
  3. Development of a novel nitric oxide (NO) production inhibitor with potential therapeutic effect on chronic inflammation

Development of a novel nitric oxide (NO) production inhibitor with potential therapeutic effect on chronic inflammation

  • Eur J Med Chem. 2020 May 1;193:112216. doi: 10.1016/j.ejmech.2020.112216.
Youzhe Yang 1,  Zhe Wei 2,  Alexander Tobias Teichmann 3,  Frank Heinrich Wieland 3,  Amu Wang 4,  Xiangui Lei 4,  Yue Zhu 4,  Jinxiang Yin 4,  Tiantian Fan 5,  Li Zhou 5,  Chao Wang 5,  Lijuan Chen 6
Affiliations

Affiliations

  • 1 Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, PR China; Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, PR China. Electronic address: [email protected].
  • 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, PR China.
  • 3 Sichuan Provincial Center for Gynaecology and Breast Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, PR China.
  • 4 School of Science, Xihua University, Chengdu, 610039, PR China.
  • 5 Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, PR China.
  • 6 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, PR China. Electronic address: [email protected].
PMID: 32208222 DOI: 10.1016/j.ejmech.2020.112216
Abstract

Inflammation is a complex biological response to stimuli. Activated macrophages induced excessively release of pro-inflammatory cytokines and mediators such as endogenous radical nitric oxide (NO) play a significant role in the progression of multiple inflammatory diseases. Both natural and synthetic Chalcones possess a wide range of bioactivities. In this work, thirty-nine Chalcones and three related compounds, including several novel ones, based on bioactive kava Chalcones were designed, synthesized and their inhibitory effects on NO production in RAW 264.7 cells were evaluated. The novel compound (E)-1-(2'-hydroxy-4',6'-dimethoxyphenyl)-3-(3-methoxy-4-(3-morpholinopropoxy)phenyl)prop-2-en-1-one (53) exhibited a better inhibitory activity (84.0%) on NO production at 10 μM (IC50 = 6.4 μM) with the lowest cytotoxicity (IC50 > 80 μM) among the tested compounds. Besides, western blot analysis indicated that compound 53 was a potent down-regulator of inducible nitric oxide synthase (iNOS) protein. Docking study revealed that compound 53 also can DOCK into the active site of iNOS. Furthermore, at the dose of 10 mg/kg/day, compound 53 could both significantly suppress the progression of inflammation on collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models. In addition, the structure-activity relationship (SAR) of the kava Chalcones based analogs was also depicted.

Keywords

Inducible nitric oxide synthase (iNOS); Inflammation; Kava chalcones; Nitric oxide (NO); Structure-activity relationship (SAR).

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