Design, Synthesis and Biological Evaluation of 4-Aryl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one Derivatives as a PI3Kα Inhibitor

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  • Hu Shengquan
    Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bio-engineering, Beijing University of Technology
  • Zhao Zhichang
    Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bio-engineering, Beijing University of Technology
  • Ni Yeming
    Fan Gongxiu Honors College, Beijing University of Technology
  • Xin Hongxing
    Jumpcan Pharmaceutical Group Company Limited
  • Yan Hong
    Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bio-engineering, Beijing University of Technology
  • Song Xiuqing
    Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bio-engineering, Beijing University of Technology

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  • Design, Synthesis and Biological Evaluation of 4-Aryl-5,7-dihydro-6<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-6-one Derivatives as a PI3Kα Inhibitor

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<p>A novel series of 4-aryl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one derivatives were designed as a phosphoinositide 3-kinase α (PI3Kα) inhibitor by scaffold hopping. The target compounds, characterized by 1H-NMR, 13C-NMR and high resolution (HR)-MS, were synthesized from diethyl malonate and ethyl chloroacetate by nucleophilic substitution, ring-closure, chlorination and Suzuki reaction, etc. The biological activities were evaluated with cytotoxic activity in vitro on Uppsala 87 Malignant Glioma (U87MG) and prostate cancer-3 (PC-3) by Cell Counting Kit-8 (CCK-8). The results showed that compound 9c displayed the higher inhibition than the positive control PI-103, and high PI3Kα inhibitory activity with IC50 of 113 ± 9 nM in the same order of magnitude as BEZ235. In addition, the Log Kow values and molecular docking studies were performed to further investigate the drug-like properties of target compounds and interactions between 9c and PI3Kα.</p>

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