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

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

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: huzecheng@outlook.com.
  • 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: zhenw@usc.edu.cn.
  • 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: lszhuo@usc.edu.cn.
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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