2. Academic Validation
  3. Development of novel bis-pyrazole derivatives as antitumor agents with potent apoptosis induction effects and DNA damage

Development of novel bis-pyrazole derivatives as antitumor agents with potent apoptosis induction effects and DNA damage

  • Eur J Med Chem. 2018 Jan 1:143:1066-1076. doi: 10.1016/j.ejmech.2017.11.098.
Hong Dai 1,  Shushan Ge 1,  Jing Guo 2,  Shi Chen 2,  Meiling Huang 3,  Jiaying Yang 3,  Siyu Sun 4,  Yong Ling 5,  Yujun Shi 6
Affiliations

Affiliations

  • 1 College of Chemistry and Chemical Engineering, Nantong University, Nantong, 226019, People's Republic of China; School of Pharmacy, Nantong University, Nantong, 226001, People's Republic of China.
  • 2 School of Pharmacy, Nantong University, Nantong, 226001, People's Republic of China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, People's Republic of China.
  • 3 School of Pharmacy, Nantong University, Nantong, 226001, People's Republic of China.
  • 4 College of Chemistry and Chemical Engineering, Nantong University, Nantong, 226019, People's Republic of China.
  • 5 College of Chemistry and Chemical Engineering, Nantong University, Nantong, 226019, People's Republic of China; School of Pharmacy, Nantong University, Nantong, 226001, People's Republic of China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, People's Republic of China. Electronic address: Lyyy111@sina.com.
  • 6 College of Chemistry and Chemical Engineering, Nantong University, Nantong, 226019, People's Republic of China. Electronic address: yjshi2015@163.com.
PMID: 29232583 DOI: 10.1016/j.ejmech.2017.11.098
Abstract

A series of bis-pyrazole derivatives were designed and synthesized, and their antitumor effects in vitro and in vivo were investigated. Several compounds displayed good antiproliferative activity with IC50 values in low-micromolar range against three human Cancer cell lines in vitro, superior to 5-FU. The most potent compound 10M selectively inhibited human hepatocellular carcinoma cells but not non-tumor liver cell proliferation in vitro, and significantly triggered SMMC-7721 cell Apoptosis by cleavage of both PARP and Caspase-3 in a concentration-dependent manner. Further study revealed that the potent activity in the cell growth inhibition and Apoptosis induction effects of 10M were related to DNA damage and activation of the p53 signaling pathway. Moreover, 10M showed low acute toxicity to mice and significant growth inhibition of the hepatoma tumor in vivo.

Keywords

Antitumor agent; Apoptosis; Bis-pyrazole derivatives; DNA damage; Synthesis.

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