2. Academic Validation
  3. Total synthesis and structural modification of the dibenzylbutane lignan LCA as a potent anti-inflammatory agent against LPS-induced acute lung injury

Total synthesis and structural modification of the dibenzylbutane lignan LCA as a potent anti-inflammatory agent against LPS-induced acute lung injury

  • Eur J Med Chem. 2024 Feb 20:268:116272. doi: 10.1016/j.ejmech.2024.116272.
Juan Zhang 1,  Zhen Wang 1,  Jing Wang 2,  Xiaobin Zhuo 2,  Luyao Yu 3,  Ting Han 3,  Yan Song 4,  Conghao Gai 2,  Yan Zou 2,  Qingguo Meng 5,  Xiaoyun Chai 6,  Qingjie Zhao 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China.
  • 2 Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
  • 3 Department of Pharmacognosy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
  • 4 Navy Medical Center, Second Military Medical University, Shanghai, 200433, China.
  • 5 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China. Electronic address: qinggmeng@163.com.
  • 6 Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China. Electronic address: chaixy1207@163.com.
  • 7 Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China. Electronic address: qjzhao_325@126.com.
PMID: 38402749 DOI: 10.1016/j.ejmech.2024.116272
Abstract

Acute lung injury (ALI) is a serious public health problem associated with high morbidity and mortality. However, few efficacious drugs are clinically available. Inhibition of proinflammatory cytokines is considered to be a promising method for the treatment of inflammatory diseases. Herein, the total synthesis of a dibenzylbutane lignan, 9'-O-di-(E)-feruloyl-meso-5,5'-dimethoxysecoisolariciresinol (LCA), was completed. A series of LCA derivatives were designed and synthesized, and their anti-inflammatory activities were evaluated. Derivative 14r significantly inhibited LPS-induced expression of NO and the proinflammatory cytokines TNF-α, IL-6, and IL-1β in RAW 264.7 cells and inhibited activation of the NF-κB pathway. Compound 14r reduced LPS-induced pulmonary inflammation and ALI in mice. It showed significant protective effects against LPS-induced ALI in mice and significantly reduced levels of proinflammatory cytokines in serum and bronchoalveolar lavage fluid. The ratio of wet weight to dry weight of lung tissue was normalized by compound 14r, which was consistent with suppression of neutrophil infiltration and production of proinflammatory cytokines. Compound 14r reduced the mRNA expression of some proinflammatory cytokines, improved histopathologic changes, and reduced macrophage infiltration in lung tissues. Collectively, these results suggest a new series of LCA derivatives that could be promising anti-inflammatory agents for ALI treatment.

Keywords

Acute lung injury; Dibenzylbutane lignan; Inflammation; Synthesis.

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