Design, synthesis and bioactivity evaluation of parthenolide-chalcone hybrids as potential anti-lung cancer agents

  • Bioorg Chem. 2025 Sep:164:108808. doi: 10.1016/j.bioorg.2025.108808.
Yongping Bai  1 ,  Junqi Wang  2 ,  Weinan Li  2 ,  Ning Liu  3 ,  Kun Liu  2 ,  Hui Li  2 ,  Yihao Zhao  2 ,  Xiyan Duan  4 ,  Yahui Ding  5
Affiliations
  • 1. College of Pharmacy, State Key Laboratory of Medicinal Chemical Biology and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China.
  • 2. School of Chemistry & Chemical Engineering, Henan University of Science and Technology, Luoyang 471003, Henan, China.
  • 3. School of Nursing, Henan University of Science and Technology, Luoyang 471003, Henan, People's Republic of China.
  • 4. School of Chemistry & Chemical Engineering, Henan University of Science and Technology, Luoyang 471003, Henan, China. Electronic address: [email protected].
  • 5. College of Pharmacy, State Key Laboratory of Medicinal Chemical Biology and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China; College of Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, People's Republic of China. Electronic address: [email protected].
PMID: 40763598 DOI: 10.1016/j.bioorg.2025.108808
Abstract

Natural products are valuable resources in drug discovery. To improve the activity of parthenolide, 49 parthenolide-chalcone hybrids were designed and synthesized. The activity evaluation suggested compound 10d exhibited the most potent Anticancer activity with an IC₅₀ of 0.11 μM, 40.9-fold improvement compared with parthenolide. Besides that, compound 10d induced Apoptosis, inhibited cell migration and proliferation. The mechanistic studies revealed that 10d may directly bind to Cys416 of ALOX5 (Arachidonate 5-lipoxygenase) and enhance its protein stability, then inhibited β-catenin protein levels and eventually suppressed STAT3 (Signal Transducer and Activator of Transcription 3) signal pathway. Moreover, water-soluble prodrug of 10d significantly inhibited tumor growth in lung Cancer patient-derived xenograft (PDX) model without notable toxicity. These findings suggested that 10d could be considered as a promising ALOX5-targeting Anticancer candidate worthy of further development.

Keywords
ALOX5; Anti-cancer activity; Apoptosis; Chalcone; Parthenolide.
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