2. Academic Validation
  3. 2-Styryl-4-aminoquinazoline derivatives as potent DNA-cleavage, p53-activation and in vivo effective anticancer agents

2-Styryl-4-aminoquinazoline derivatives as potent DNA-cleavage, p53-activation and in vivo effective anticancer agents

  • Eur J Med Chem. 2020 Jan 15;186:111851. doi: 10.1016/j.ejmech.2019.111851.
Xin-Wei Wei 1,  Jing-Mei Yuan 1,  Wan-Yun Huang 2,  Nan-Ying Chen 1,  Xiao-Juan Li 1,  Cheng-Xue Pan 3,  Dong-Liang Mo 4,  Gui-Fa Su 5
Affiliations

Affiliations

  • 1 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China.
  • 2 Department of Pharmacology, Guilin Medical University, Guilin, 541004, PR China.
  • 3 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China. Electronic address: chengxuepan@163.com.
  • 4 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China. Electronic address: moeastlight@gxnu.edu.cn.
  • 5 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China. Electronic address: gfysglgx@163.com.
PMID: 31761381 DOI: 10.1016/j.ejmech.2019.111851
Abstract

Forty-eight analogues of CP-31398, an antitumor agent modulated the mutant p53 gene were synthesized and their cytotoxicities against four Cancer cell lines with different p-53 status including bladder cell T24 (w-p53), gastric cell MGC-803 (m-p53), prostate cell DU145 (m-p53), prostate cell PC-3 (null-p53), lung cell A549 (w-p53) and normal liver cell line HL-7702 (w-p53) were examined. (E)-2-(4-Nitrostyryl)-4-(3-dimethylaminopropyl)-aminoquinazoline (10ah) was identified as the most potent compound in anti-proliferation against MGC-803 cells, with IC50 lowed to 1.73 μM, far potency than that of CP-31398. Molecular mechanism study revealed that 10ah and CP-31398 differ greatly in mechanism to exert their antitumor properties. 10ah could intercalate into DNA and resulted in significant DNA double-strand break. 10ah-treatment in MGC-803 cells increased the expression of p53, phosphorylated p53 (p-p53), CDK4, p21 to cause cell cycle arrest at G2/M phase, significantly up-regulated the levels of pro-apoptosis proteins Bak, Bax, Bim while down-regulated the anti-apoptosis proteins Bcl-2, Bcl-xL and the levels of cyclin B1, fluctuated the intracellular Reactive Oxygen Species (ROS), CA2+ and mitochondrial membrane potential, activated Caspase-9 and Caspase-3 to induce Apoptosis. 10ah also displayed potent Anticancer efficiency against MGC-803 xenograft tumors models, with tumor growth inhibition (TGI) up to 61.8% at 20 mg/kg without obvious toxicity.

Keywords

2-Styryl-4-aminoquinazoline; Anticancer; CP-31398; DNA intercalator; Synthesis.

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