2. Academic Validation
  3. Design and synthesis of sirtinol analogs as human neutrophil elastase inhibitors

Design and synthesis of sirtinol analogs as human neutrophil elastase inhibitors

  • Bioorg Med Chem Lett. 2023 Nov 7:97:129544. doi: 10.1016/j.bmcl.2023.129544.
Tsong-Long Hwang 1,  Jing-Yi Lin 2,  Liang-Mou Kuo 3,  Ganesh Kumar Dhandabani 4,  Pei-Wen Hsieh 5
Affiliations

Affiliations

  • 1 Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan; Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan. Electronic address: [email protected].
  • 2 Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address: [email protected].
  • 3 Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan. Electronic address: [email protected].
  • 4 Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address: [email protected].
  • 5 Graduate Institute of Natural Products, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan; Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan. Electronic address: [email protected].
PMID: 37939864 DOI: 10.1016/j.bmcl.2023.129544
Abstract

Human neutrophil Elastase (HNE) overexpression has a crucial role in most acute inflammation and alpha1-antitrypsin deficiency syndromes observed in humans, triggering neutrophil invasion and activation of macrophage inflammatory and proteolytic effects, leading to tissue damage. Manipulating HNE level homeostasis could potentially help treat neutrophilic inflammation. Previous studies have shown that sirtinol (1) has a specific influence on HNE and potently attenuates acute lung injury and hepatic injury mediated by lipopolysaccharide or trauma hemorrhage. Therefore, 1 was chosen as the model structure to obtain more potent anti-HNE agents. In the present study, we synthesized a series of sirtinol analogues and determined their inhibitory effects on HNE. Structure-activity relationship (SAR) studies showed that swapping the imine and methyl groups of the sirtinol scaffold with diazene and carboxyl groups, respectively, enhances the HNE inhibiting potency. Compound 29 exhibited the highest potency in the SAR study and showed dual inhibitory effects on HNE and proteinase 3 with IC50 values of 4.91 and 20.69 µM, respectively. Furthermore, 29 was confirmed to have dual impacts on inhibiting O2•- generation and Elastase release in cell-based assays with IC50 values of 0.90 and 1.86 µM, respectively. These findings suggest that 29 is a promising candidate for developing HNE inhibitors in the treatment of neutrophilic inflammatory diseases.

Keywords

Neutrophilic inflammatory diseases, human neutrophil elastase; Sirtinol analogs; Structure–activity relationship (SAR).

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