Novel Carbamate-Based o-aminobenzamide Derivatives as Potent Antigastric Carcinoma Agents via Disrupting NAD+ Salvage Synthesis

  • J Med Chem. 2025 Jun 12;68(11):10738-10756. doi: 10.1021/acs.jmedchem.4c02686.
Siyi Zhang  1 ,  Zhen Li  1 ,  Bo Li  1 ,  Zhiyi Li  1 ,  Huiqian Peng  1 ,  Lixian Shen  1  2 ,  Lejing Zhu  1 ,  Tong Mo  2 ,  Jialiang Peng  2 ,  Linsheng Zhuo  1 ,  Zhen Wang  1  2  3  4 ,  Weifan Jiang  1
Affiliations
  • 1. School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China.
  • 2. School of Basic Medicine, The First Affiliated Hospital, The Second Affiliated Hospital, MOE Key Lab of Rare Pediatric Diseases, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China.
  • 3. Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, Qinghai, China.
  • 4. National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha 410008, Hunan, China.
PMID: 40448666 DOI: 10.1021/acs.jmedchem.4c02686
Abstract

Blocking NAD+ biosynthesis presents an appealing strategy for antitumor therapies. This study developed a series of o-aminobenzamide derivatives with substantial antitumor efficacy against gastric Cancer. Notably, compound 9a demonstrated exceptional antitumor activity against undifferentiated gastric Cancer HGC27 cells (IC50 = 0.049 μM), and significant inhibitory effects on cellular proliferation, self-renewal, invasion, and migration. Mechanistic investigations revealed that 9a could damage mitochondria, arrest the cell cycle, promote Apoptosis, and alter cellular metabolism. Furthermore, the rate-limiting enzyme NAMPT in the NAD+ salvage synthetic pathway was identified as a primary target of 9a. By inhibiting NAMPT, 9a reduced intracellular levels of NAD+ and ATP, while NMN, a natural product of NAMPT, counteracts its antimetabolic and cytotoxic effects. Overall, this study highlights 9a as a promising NAMPT Inhibitor with significant activity against undifferentiated gastric Cancer, laying the groundwork for developing novel antigastric Cancer agents through inhibiting NAD+ biosynthesis.

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