2. Academic Validation
  3. Discovery of sinomenine/8-Bis(benzylthio)octanoic acid hybrids as potential anti-leukemia drug candidate via mitochondrial pathway

Discovery of sinomenine/8-Bis(benzylthio)octanoic acid hybrids as potential anti-leukemia drug candidate via mitochondrial pathway

  • Bioorg Med Chem Lett. 2023 Nov 7:97:129545. doi: 10.1016/j.bmcl.2023.129545.
Xiang Gao 1,  Haonan Li 1,  Siyu Wang 1,  Xiaokang Long 2,  Xuehai Guo 3,  Huiming Hua 4,  Dahong Li 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
  • 2 Department of Pharmacy, The First Affiliated Hospital of Jishou University, 26 Century Avenue, Hunan 416000, PR China.
  • 3 Huangshi Food and Drug Inspection and Testing Center, 26 Guangzhou Road, Hubei 435000, PR China.
  • 4 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: huimhua@163.com.
  • 5 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: lidahong0203@163.com.
PMID: 37939862 DOI: 10.1016/j.bmcl.2023.129545
Abstract

Traditional Chinese medicine Qingfengteng primarily acquired from the dried canes of Sinomenium acutum (Thunb.) Rehd. et Wils. var. cinereum Rehd. et Wils. and S. acutum (Thunb.) Rehd. et Wils. For the therapeutic treatment of rheumatism, acute arthritis, and rheumatoid arthritis based on Qingfengteng, sinomenine hydrochloride was recently made the principal active ingredient in various dosage forms. 8-Bis(benzylthio)octanoic acid (CPI-613) was an orphan medicine that the FDA and EMA approved orphan for the treatment of certain resistant malignancies. Its unique mode of action and minimal toxicity toward normal tissues made for an apt pharmacophore. In order to expand the field of sinomenine Anticancer structures, sinomenine/8-Bis(benzylthio)octanoic acid derivatives were designed and synthesized. Among them, target hybrids e4 stood out for having notable cytotoxic effects against Cancer cell lines, especially for K562 cells, with IC50 values of 2.45 μM and high safety. In-depth investigations demonstrated that e4 caused Apoptosis by stopping the cell cycle at G1 phase, and doing so by altering the morphology of the nucleus and causing membrane potential of the in mitochondria to collapse. These results indicated e4 exerted an antiproliferative effect through Apoptosis induction via mitochondrial pathway.

Keywords

Apoptosis; CPI-613; Leukemia; Sinomenine.

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