2. Academic Validation
  3. Design, synthesis and biological evaluation of novel o-aminobenzamide derivatives as potential anti-gastric cancer agents in vitro and in vivo

Design, synthesis and biological evaluation of novel o-aminobenzamide derivatives as potential anti-gastric cancer agents in vitro and in vivo

  • Eur J Med Chem. 2022 Jan 5:227:113888. doi: 10.1016/j.ejmech.2021.113888.
Yiyue Feng 1,  Yingmei Lu 1,  Junfang Li 1,  Honghua Zhang 1,  Zhao Li 1,  Hanzhong Feng 2,  Xuemei Deng 1,  Dan Liu 1,  Tao Shi 1,  Weifan Jiang 3,  Yongxing He 4,  Jian Zhang 5,  Zhen Wang 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
  • 2 Ministry of Education, Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China.
  • 3 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 4 Ministry of Education, Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China. Electronic address: heyx@lzu.edu.cn.
  • 5 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China. Electronic address: jian.zhang@sjtu.edu.cn.
  • 6 School of Pharmacy, Lanzhou University, Lanzhou, 730000, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: zhenw@lzu.edu.cn.
PMID: 34628244 DOI: 10.1016/j.ejmech.2021.113888
Abstract

Although gastric Cancer has become a major public health problem, oral agents applied in clinics for gastric Cancer therapy are scarce. Therefore, to explore new oral chemical entities with high efficiency and low toxicity, 41 o-aminobenzamide derivatives based on the scaffolds of MS-275 and SAHA were designed, synthesized, and evaluated for their anti-gastric Cancer abilities in vitro and in vivo. Structure-activity relationships were discussed, leading to the identification of compounds F8 (IC50 = 0.28 μM against HGC-27 cell) and T9 (IC50 = 1.84 μM against HGC-27 cell) with improved cytotoxicity, anti-gastric Cancer proliferation potency, induction of cell Apoptosis and cell cycle arrest ability, inhibition of cell migration and invasion. What is worth mentioning is that compound F8 was more efficient and less toxic than the positive drug capecitabine in vivo on the HGC-27-xenograft model. Meanwhile, compound F8 exhibited suitable pharmacokinetic properties and less acute toxicity (LD50 > 1000 mg/kg). Besides, western blotting analysis, IHC analysis, differentially expressed proteins analysis and ABPP experiment indicated that compound F8 could modulate molecular pathways involved in Apoptosis and cell cycle progression. Consequently, compound F8 is a strong candidate for the development of human gastric Cancer therapy.

Keywords

Cell cycle analysis; Gastric cancer; Migration and invasion; Structure-activity relationship; o-Aminobenzamide derivatives.

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