2. Academic Validation
  3. Curcumol derivatives exhibit ameliorating effects on lipopolysaccharide-induced acute lung injury: Synthesis, biological evaluation, structure-activity relationship and action mechanism

Curcumol derivatives exhibit ameliorating effects on lipopolysaccharide-induced acute lung injury: Synthesis, biological evaluation, structure-activity relationship and action mechanism

  • Bioorg Chem. 2024 Dec:153:107838. doi: 10.1016/j.bioorg.2024.107838.
Gen Li 1,  Yajing Guo 2,  Anna Ma 2,  Dan Wang 2,  Qi Zhang 2,  Chongyan Zhao 2,  Xuling Peng 2,  Liqin Ding 3,  Xi Chen 4,  Feng Qiu 5
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, PR China; Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, PR China.
  • 2 School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, PR China.
  • 3 Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, PR China.
  • 4 School of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, PR China. Electronic address: andychen0803@sina.com.
  • 5 School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, PR China; Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, PR China. Electronic address: fengqiu20070118@163.com.
PMID: 39353222 DOI: 10.1016/j.bioorg.2024.107838
Abstract

Acute lung injury (ALI) is an intricate clinical disease marked by high mortality and a sudden start. Currently, although there are no specific therapeutics for ALI, the administration of anti-inflammatory drugs is a promising treatment strategy. Curcumol, a terpenoid natural product, has demonstrated significant anti-inflammatory activity. Herein, we designed and synthesised 42 curcumol derivatives using curcumol as the core scaffold. These derivatives underwent in vitro screening for anti-inflammatory activity, and their structure-activity relationship was assessed. Among them, derivative 2 exhibited potent anti-inflammatory potential, inhibiting the expression of inflammatory markers at the nanomolar level. In addition, its water solubility was considerably improved, thereby laying the foundation for enhanced druggability. Derivative 2 also ameliorated lipopolysaccharide (LPS)-induced ALI and reduced pulmonary inflammation at a dose of 5 mg/kg. Proteomics analysis revealed that the anti-inflammatory effect of this compound primarily involved the mTOR signalling pathway. Furthermore, molecular docking and cellular thermal shift assays indicated that GSK3β is a critical target of action of derivative 2, as verified via western blotting. These findings suggest that derivative 2 can be a lead therapeutic compound for ALI, with GSK3β emerging as a promising novel target for the development of specific anti-ALI drugs.

Keywords

Acute lung injury; Anti-inflammatory; Curcumol; GSK3β; Proteomics; mTOR.

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