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
  • 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: [email protected].
  • 4. The First Affiliated Hospital, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: [email protected].
  • 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: [email protected].
  • 6. The First Affiliated Hospital, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: [email protected].
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.
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