2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel 6-(pyridin-3-yl) quinazolin-4(3H)-one derivatives as potential anticancer agents via PI3K inhibition

Design, synthesis, and biological evaluation of novel 6-(pyridin-3-yl) quinazolin-4(3H)-one derivatives as potential anticancer agents via PI3K inhibition

  • Bioorg Med Chem. 2021 Sep 15:46:116346. doi: 10.1016/j.bmc.2021.116346.
Huarong Yang 1,  Qing Li 2,  Mingzhi Su 2,  Fang Luo 2,  Yahua Liu 3,  Daoping Wang 4,  Yanhua Fan 5
Affiliations

Affiliations

  • 1 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550002, PR China.
  • 2 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, PR China.
  • 3 School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550002, PR China. Electronic address: liuyahu145@gzy.edu.cn.
  • 4 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, PR China. Electronic address: wangdaoping@gzcnp.cn.
  • 5 State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, PR China. Electronic address: yhfan@gzcnp.cn.
PMID: 34403956 DOI: 10.1016/j.bmc.2021.116346
Abstract

Abnormal activation of the PI3K/Akt pathway is demonstrated in most of human malignant tumors via regulation of proliferation, cell cycle, and Apoptosis. Therefore, drug discovery and development of targeting the PI3K/Akt pathway has attracted great interest of researchers in the development of Anticancer drugs. In this study, fifteen 6-(pyridin-3-yl) quinazolin-4(3H)-one derivatives were designed and synthesized. Anticancer activities of the synthetic compounds were evaluated and the potential mechanisms were explored. Several compounds showed certain proliferation inhibitory activity against the tested Cancer cells including human non-small cell lung Cancer (NSCLC) HCC827, human neuroblastoma SH-SY5Y and hepatocellular carcinoma LM3 cells. Among them, compound 7i and 7m showed the best inhibitory activity against all the Cancer cell lines and more active against HCC827 cells with IC50 values of 1.12 μM and 1.20 μM, respectively. In addition, 7i and 7m showed lower inhibitory activity against H7702 cells (human normal liver cells) with IC50 values of 8.66 μM and 10.89 μM, respectively, nearly 8-fold lower than that in HCC827 cells. These results suggested that compounds 7i and 7m had certain selectivity to tumor cells, compared to human normal cells. Further biological studies indicated 7i induced G2/M phase arrests and cell Apoptosis of HCC827 cells via PI3K/Akt and Caspase dependent pathway. Together, these novel 6-(pyridin-3-yl) quinazolin-4(3H)-one derivatives such as compound 7i and 7m might be lead compounds for development of potential anti-cancer drugs.

Keywords

6-(pyridin-3-yl) quinazolin-4(3H)-one derivatives; Cell apoptosis; G2/M phase arrests; PI3K/Akt pathway.

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