2. Academic Validation
  3. Discovery of novel 2-substituted 2, 3-dihydroquinazolin-4(1H)-one derivatives as tubulin polymerization inhibitors for anticancer therapy: The in vitro and in vivo biological evaluation

Discovery of novel 2-substituted 2, 3-dihydroquinazolin-4(1H)-one derivatives as tubulin polymerization inhibitors for anticancer therapy: The in vitro and in vivo biological evaluation

  • Eur J Med Chem. 2024 Nov 5:277:116766. doi: 10.1016/j.ejmech.2024.116766.
Cai Shi 1,  Boning Yang 2,  Zhaolong He 3,  Jingxiang Yang 4,  Ling Li 3,  Jian Song 1,  Shiqiang Xu 5,  Wei Song 6,  Jian Yang 7
Affiliations

Affiliations

  • 1 Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
  • 2 Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, 430060, China; Institute of Pharmaceutical Process, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China; Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia.
  • 3 Institute of Pharmaceutical Process, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China.
  • 4 Department of Pharmacy, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430016, China.
  • 5 Institute of Pharmaceutical Process, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China. Electronic address: [email protected].
  • 6 Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, 430060, China. Electronic address: [email protected].
  • 7 Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, 430060, China. Electronic address: [email protected].
PMID: 39163776 DOI: 10.1016/j.ejmech.2024.116766
Abstract

A series of novel 2-substituted 2, 3-dihydroquinazolin-4(1H)-one derivatives were designed, synthesized and estimated for their in vitro antiproliferative activities against HepG2, U251, PANC-1, A549 and A375 cell lines. Among them, compound 32 was the most promising candidate, and displayed strong broad-spectrum Anticancer activity. The mechanism studies revealed that compound 32 inhibited tubulin polymerization in vitro, disrupted cell microtubule networks, arrested the cell cycle at G2/M phase, and induced Apoptosis by up-regulating the expression of cleaved PARP-1 and Caspase-3. Furthermore, molecular docking analysis suggested that compound 32 well occupied the binding site of tubulin. In addition, compound 32 exhibited no significant activity against 30 different kinases respectively, indicating considerable selectivity. Moreover, compound 32 significantly inhibited the tumour growth of the HepG2 xenograft in a nude mouse model by oral gavage without apparent toxicity. These results demonstrated that some 2-substituted 2, 3- dihydroquinazolin-4(1H)-one derivatives bearing phenyl, biphenyl, naphthyl or indolyl side chain at C2-position might be potentially novel antitumor agents as tubulin polymerization inhibitors.

Keywords

2; 3-Dihydroquinazolin-4(1H)-one; Anticancer; In vivo studies; Tubulin inhibitor.

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