2. Academic Validation
  3. Structure-activity relationship study of novel evodiamine amino acid conjugates with potent anti-colorectal cancer efficacy

Structure-activity relationship study of novel evodiamine amino acid conjugates with potent anti-colorectal cancer efficacy

  • Eur J Med Chem. 2025 Feb 5:283:117132. doi: 10.1016/j.ejmech.2024.117132.
Shuting Chen 1,  Xi Zhang 1,  Hanxuan Mo 1,  Ying Peng 1,  Zhigang An 1,  Junbo Wu 2,  Xiuzhen Wei 1,  Siyi Zhang 1,  Yongxia Xiong 1,  Weifan Jiang 1,  Xue Peng 1,  Linsheng Zhuo 3,  Zhengwen Lei 4,  Zhen Wang 5,  Zecheng Hu 6
Affiliations

Affiliations

  • 1 The First Affiliated Hospital, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 2 Department of Colorectal Surgery, Affiliated Hengyang Hospital of Hunan Normal University & Hengyang Central Hospital, Hengyang, Hunan, 421001, China.
  • 3 The First Affiliated Hospital, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: lszhuo@usc.edu.cn.
  • 4 The First Affiliated Hospital, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: leizhengwen0803@163.com.
  • 5 The First Affiliated Hospital, 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.
  • 6 The First Affiliated Hospital, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: huzecheng@outlook.com.
PMID: 39647421 DOI: 10.1016/j.ejmech.2024.117132
Abstract

Evodiamine has been a promising lead structure with broad-spectrum antitumor activity. Druggability optimization is the most challenging part of evodiamine-based lead-to-candidate campaign. Amino acids as building blocks for conjugates are widely incorporated into approved drug and drug candidates, demonstrating highly attractive druggability. Herein, a series of evodiamine amino acid conjugates were designed and synthesized based on the evodiamine lead compound (±)-8b discovered in our previous work. The structure-activity relationship (SAR) studies culminated in the identification of a promising conjugate (-)-15h featuring a N-Boc-l-glutamine group and a chiral carbon atom (sinister), which exhibited nanomolar antiproliferative activity against LoVo and RKO colorectal Cancer cells. Moreover, (-)-15h could inhibit topoisomerases I, arrest the cell cycle in the G2/M phase, and induce Apoptosis. Importantly, (-)-15h (tumor growth inhibition rate was 82.53 % in 40 mpk) showed better efficacy and tolerability to that of parent compound (-)-8b (tumor growth inhibition rate was 51.22 % in 40 mpk) in LoVo xenograft model. Further, (-)-15h (tumor growth inhibition rate was 70.09 % in 40 mpk) showed comparable efficacy and better tolerability to that of topotecan (tumor growth inhibition rate was 70.67 % in 0.5 mpk) in HT-29 xenograft model. Collectively, this study further provided a strong scientific basis for amino acid-based structural modifications and a drug lead for anti-colorectal Cancer applications.

Keywords

Amino acid derivatives; Anti-colorectal cancer; Evodiamine; Topoisomerases.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168736
    Anti-colorectal Agent