Discovery of Nonpeptide, Environmentally Sensitive Fluorescent Probes for Imaging p53-MDM2 Interactions in Living Cell Lines and Tissue Slice

• Published in: Analytical chemistry (Washington) 2020-02, Vol.92 (3), p.2642-2648
• Main Authors: Dong, Gaopan, He, Shipeng, Qin, Xiaojun, Liu, Tingting, Jiang, Yan, Li, Xiang, Chen, Long, Han, Guangxi, Sheng, Chunquan, Li, Minyong
• Format: Article
• Language: English
• Subjects: A549 Cells; Analytical chemistry; Biotechnology; Cell Line, Tumor; Cell lines; Cells (biology); Chemistry; Drug Discovery; Drug screening; Fluorescent Dyes - chemical synthesis; Fluorescent Dyes - chemistry; Fluorescent indicators; Humans; Imaging; MDM2 protein; Molecular Docking Simulation; Molecular Structure; Optical Imaging; Optimization; p53 Protein; Probes; Protein Binding; Protein expression; Protein interaction; Proteins; Proto-Oncogene Proteins c-mdm2 - chemistry; Selectivity; Spectrometry, Fluorescence; Tissues; Toxicity; Tumor Suppressor Protein p53 - chemistry
• ISSN: 0003-2700; 1520-6882
• DOI: 10.1021/acs.analchem.9b04551

Based on structural optimization work, probes 9–11 with practical activity and selectivity in tissue as well as living cell lines are well designed and synthesized. All the probes showed potent inhibitory and acceptable cell toxicity compared with the commercially available p53-MDM2 inhibitor Nutlin-3, and can increase the protein expression level of p53 and MDM2 in the A549 cell line; in particular, probes 10 and 11 can increase the protein expression level of p53 better than Nutlin-3. Moreover, their application in imaging and detecting wild-type p53-MDM2 protein–protein interactions have been well demonstrated in at the cell and tissue levels. Overall, these environmentally sensitive fluorescent turn-on probes are affordable and rapid for imaging, which is expected for applications in target drug screening as well as in pathologic diagnosis.