2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Heterocyclic-Fused Pyrimidine Chemotypes Guided by X-ray Crystal Structure with Potential Antitumor and Anti-multidrug Resistance Efficacy Targeting the Colchicine Binding Site

Design, Synthesis, and Biological Evaluation of Heterocyclic-Fused Pyrimidine Chemotypes Guided by X-ray Crystal Structure with Potential Antitumor and Anti-multidrug Resistance Efficacy Targeting the Colchicine Binding Site

  • J Med Chem. 2023 Feb 21. doi: 10.1021/acs.jmedchem.2c02115.
Lun Tan 1 2 3 4,  Chengyong Wu 1 2 3 4,  Jifa Zhang 1 2 3 4,  Quanwei Yu 1,  Xiye Wang 5,  Lele Zhang 1 2 3,  Meiyi Ge 1 2 3,  Zhijia Wang 1 2 3,  Liang Ouyang 1 2 3,  Yuxi Wang 1 2 3 4
Affiliations

Affiliations

  • 1 Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 2 Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, Sichuan, China.
  • 3 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 4 Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 5 Department of Pharmacy, Western Theater Command Hospital, Chengdu 610083, Sichuan, China.
PMID: 36802449 DOI: 10.1021/acs.jmedchem.2c02115
Abstract

Herein, a series of quinazoline and heterocyclic fused pyrimidine analogues were designed and synthesized based on the X-ray co-crystal structure of lead compound 3a, showing efficacious antitumor activities. Two analogues, 15 and 27a, exhibited favorable antiproliferative activities, which were more potent than lead compound 3a by 10-fold in MCF-7 cells. In addition, 15 and 27a exhibited potent antitumor efficacy and tubulin polymerization inhibition in vitro. 15 reduced the average tumor volume by 80.30% (2 mg/kg) in the MCF-7 xenograft model and 75.36% (4 mg/kg) in the A2780/T xenograft model, respectively. Most importantly, supported by structural optimization and Mulliken charge calculation, X-ray co-crystal structures of compounds 15, 27a, and 27b in complex with tubulin were resolved. In summary, our research provided the rational design strategy of colchicine binding site inhibitors (CBSIs) based on X-ray crystallography with antiproliferation, antiangiogenesis, and anti-multidrug resistance properties.

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