2. Academic Validation
  3. Novel O-benzylcinnamic acid derivative L26 treats acute lung injury in mice by MD-2

Novel O-benzylcinnamic acid derivative L26 treats acute lung injury in mice by MD-2

  • Eur J Med Chem. 2023 Apr 5;252:115289. doi: 10.1016/j.ejmech.2023.115289.
Xiang Li 1,  Lina Yin 2,  Jing Liao 3,  Jun Yang 3,  Binhao Cai 3,  Yiming Yu 3,  Sijia Su 3,  Zhiteng Du 3,  Xiaobo Li 3,  Ying Zhou 3,  Pan Chen 4,  Won-Jea Cho 5,  Nipon Chattipakorn 6,  Aleksandr V Samorodov 7,  Valentin N Pavlov 7,  Fengzhi Zhang 8,  Guang Liang 9,  Qidong Tang 10
Affiliations

Affiliations

  • 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325024, Zhejiang, China.
  • 2 School of Pharmacy, Hangzhou Medical College, Hangzhou, 311399, Zhejiang, China.
  • 3 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
  • 4 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China; College of Pharmacy, Chonnam National University, Gwangju, 61186, South Korea.
  • 5 College of Pharmacy, Chonnam National University, Gwangju, 61186, South Korea.
  • 6 Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
  • 7 Department of Pharmacology, Bashkir State Medical University, Ufa City, 450005, Russia.
  • 8 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. Electronic address: [email protected].
  • 9 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325024, Zhejiang, China; School of Pharmacy, Hangzhou Medical College, Hangzhou, 311399, Zhejiang, China. Electronic address: [email protected].
  • 10 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325024, Zhejiang, China. Electronic address: [email protected].
PMID: 36963290 DOI: 10.1016/j.ejmech.2023.115289
Abstract

Acute lung injury (ALI) is an inflammation-mediated respiratory disease that is associated with a high mortality rate. In this study, a series of novel O-benzylcinnamic acid derivatives were designed and synthesized using cinnamic acid as the lead compound. We tested the preliminary anti-inflammatory activity of the compounds by evaluating their effect on inhibiting the activity of Alkaline Phosphatase (ALP) in Hek-Blue-TLR4 cells, in which compound L26 showed the best activity and 7-fold more active than CIN. ELISA, immunoprecipitation, and molecular docking indicated that L26 targeted MD-2 protein and competed with LPS to bind to MD-2, which resulted in the inhibition of inflammation. In the LPS-induced mouse model of ALI, L26 was found to decrease ALP activity and inflammatory cytokine TNF-α release to reduce lung injury by inhibiting the NF-κB signaling pathway. Acute toxicity experiments showed that high doses of L26 did not cause adverse reactions in mice, and it was safe in vivo. Also, the preliminary pharmacokinetic parameters of L26 were investigated in SD rats (T1/2 = 4.246 h). In summary, L26 exhibited optimal pharmacodynamic and pharmacokinetic characteristics, which suggested that L26 could serve as a potential agent for the development of ALI treatment.

Keywords

Acute lung injury; Cinnamic acid derivatives; Inflammation; Myeloid differentiation 2.

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