Identification of a novel 10-hydroxyevodiamine prodrug as a potent topoisomerase inhibitor with improved aqueous solubility for treatment of hepatocellular carcinoma

  • Eur J Med Chem. 2024 Sep 1:279:116807. doi: 10.1016/j.ejmech.2024.116807.
Xiuzhen Wei  1 ,  Xi Zhang  1 ,  Yan Peng  1 ,  Junbo Wu  2 ,  Hanxuan Mo  1 ,  Zhigang An  1 ,  Xinyu Deng  1 ,  Ying Peng  1 ,  Linyi Liu  1 ,  Weifan Jiang  1 ,  Jinjin Chen  1 ,  Zecheng Hu  3 ,  Zhen Wang  4 ,  Linsheng Zhuo  5
Affiliations
  • 1. School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 2. Department of Colorectal Surgery, Hengyang Central Hospital, Hengyang, Hunan, 421001, China.
  • 3. The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: [email protected].
  • 4. The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, 810008, China; National Health Commission Key Laboratory of Birth Defect Research and Prevention Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, 410008, China; MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha, 410000, China. Electronic address: [email protected].
  • 5. The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: [email protected].
PMID: 39243453 DOI: 10.1016/j.ejmech.2024.116807
Abstract

Natural product evodiamine (Evo) and its synthetic derivatives represent an attractive dual Topo 1/2 inhibitors with broad-spectrum antitumor efficacy. However, the clinical applications of these compounds have been impeded by their poor aqueous solubility. Herein, a series of water-soluble 10-substituted-N(14)-phenylevodiamine derivatives were designed and synthesized. The most potent compound 45 featuring a quaternary ammonium salt fragment achieved robust aqueous solubility and nanomolar potency against a panel of human hepatoma cell lines Huh7, HepG2, SK-Hep-1, SMMC-7721, and SMMC-7721/DOX (doxorubicin-resistant cell). Further studies revealed that 45 could inhibit Topo 1 and Topo 2, induce Apoptosis, arrest the cell cycle at the G2/M stage and inhibit the migration and invasion. Compound 45 exhibited potent antitumor activity (TGI = 51.1 %, 10 mg/kg) in the Huh7 xenograft model with acceptable safety profile. In addition, a 21-day long-term dose toxicity study confirmed that the maximum tolerated dose of compound 45 was 20 mg/kg. Overall, this study presented a promising Evo-derived candidate for the treatment of hepatocellular carcinoma.

Keywords
Aqueous solubility; Evodiamine; Quaternary ammonium salt; Topoisomerases.
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