Design, synthesis and biological evaluation of a novel tubulin inhibitor 7a3 targeting the colchicine binding site
Autor: | Yuqin Yao, Qinhuai Lai, Yuxi Wang, Ruixue Wang, Ruirui Zhang, Shaoxue Zeng, Liangze Tang, Jinliang Yang, Yiran Tao, Lantu Gou, Hao Chen, Luyi Huang, Haotian Xiang, Yu Liu, Weirong Lai |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Models Molecular Protein Data Bank (RCSB PDB) Antineoplastic Agents Crystallography X-Ray 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Nude mouse Cell Movement Tubulin Cell Line Tumor Drug Discovery medicine Colchicine Animals Humans Cell Proliferation Pharmacology Combretastatin A-4 Combretastatin Ovarian Neoplasms Binding Sites biology Organic Chemistry General Medicine Cell cycle biology.organism_classification Tubulin Modulators Mice Inbred C57BL Molecular Docking Simulation 030104 developmental biology Biochemistry chemistry Mechanism of action 030220 oncology & carcinogenesis Drug Design biology.protein Pyrazoles Female medicine.symptom Drug Screening Assays Antitumor |
Zdroj: | European journal of medicinal chemistry. 156 |
ISSN: | 1768-3254 |
Popis: | Tubulin inhibitors that target the colchicine binding site continue to emerge as promising anticancer agents. In this study, based on the anti-proliferative activities, a novel tubulin inhibitor 7a3 targeting the colchicine binding site was designed, synthesized, and optimized from a series of novel cis-restricted pyrazole analogues of combretastatin A-4. The structure-activity relationships (SARs) of these newly synthesized compounds are summarized indicating that the methyl substituent at the N1 position and deamination were significantly important for the anti-proliferative efficacy. The optimized compound 7a3 exhibited the ability to arrest the cell cycle in the G2/M phase, induce cell apoptosis, and inhibit cell migration in tumour cells. The results of the immunofluorescence analysis using confocal microscopy and the tubulin polymerization assay revealed that tubulin assembly was disrupted by 7a3 in vitro. Furthermore, the targeting identification of 7a3 was illuminated by solving the crystal structure of 7a3 in complex with tubulin at a resolution of 3.2 A (PDB code 5Z4U ), which confirmed the result of molecular docking and further demonstrated that 7a3 binds to the site of colchicine. Moreover, the pharmacokinetic analysis in mouse plasma showed that 7a3 rapidly reached a peak concentration at 0.25 h after intraperitoneal administration, and the T1/2, Cmax, and AUC0-inf were 1.67 ± 0.28 h, 882 ± 71 ng mL-1, and 1166 ± 129 h ng·mL-1, respectively, after a single-dose administration analysed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). In addition, the in vivo study indicated that 7a3 significantly inhibited the tumour growth of the SK-OV-3 xenograft in a nude mouse model. In conclusion, our study proved 7a3 to be a potential microtubule-targeting drug for cancer therapy. The SARs and mechanism of action studies of 7a3 based on the X-ray co-crystal structure provided insights into the next-generation tubulin inhibitors for cancer therapy. |
Databáze: | OpenAIRE |
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