2. Academic Validation
  3. Design, synthesis and pharmacological evaluation of new 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives as potential antitumor agents

Design, synthesis and pharmacological evaluation of new 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives as potential antitumor agents

  • Eur J Med Chem. 2018 Sep 5:157:139-150. doi: 10.1016/j.ejmech.2018.07.066.
Wen-Bin Kuang 1,  Ri-Zhen Huang 2,  Jiao-Lan Qin 3,  Xing Lu 3,  Qi-Pin Qin 3,  Bi-Qun Zou 4,  Zhen-Feng Chen 5,  Hong Liang 6,  Ye Zhang 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Guilin Medical University, Guilin 541004, China; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China.
  • 2 Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.
  • 3 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China.
  • 4 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China; Department of Chemistry & Pharmaceutical Science, Guilin Normal College, Xinyi Road 15, Guangxi 541001, China.
  • 5 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China. Electronic address: chenzf@gxnu.edu.cn.
  • 6 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China. Electronic address: hliang@gxnu.edu.cn.
  • 7 School of Pharmacy, Guilin Medical University, Guilin 541004, China; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China; Department of Chemistry & Pharmaceutical Science, Guilin Normal College, Xinyi Road 15, Guangxi 541001, China. Electronic address: zhangye81@126.com.
PMID: 30092368 DOI: 10.1016/j.ejmech.2018.07.066
Abstract

A series of new 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives (5a1-5d6) were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that some compounds exhibited moderate to high inhibitory activity against HepG2, SK-OV-3, NCI-H460 and BEL-7404 tumor cell lines, and most compounds exhibited much lower cytotoxicity against the HL-7702 normal cell line compared to 5-FU and cisplatin. In vivo antitumor assay results demonstrated that 5a3 exhibited effective inhibition on tumor growth in the NCI-H460 xenograft mouse model and that 5d3 displayed excellent antiproliferative activity in the BEL-7402 xenograft model. These results suggested that both 5a3 and 5d3 could be used as Anticancer drug candidates. Mechanistic studies suggested that compounds 5a3 and 5d3 exerted their antitumor activity by up-regulation of Bax, intracellular CA2+ release, ROS generation, downregulation of Bcl-2, activation of caspase-9 and Caspase-3 and subsequent cleavage of PARP, inhibition of CDK activity and activation of the p53 protein.

Keywords

3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives; Action mechanism; Antitumor activity; Synthesis; p53.

Figures