Design, synthesis and biological evaluation of a novel tubulin inhibitor 7a3 targeting the colchicine binding site

Qinhuai Lai, Yuxi Wang, Ruixue Wang, Weirong Lai, Liangze Tang, Yiran Tao, Yu Liu, Ruirui Zhang, Luyi Huang, Haotian Xiang, Shaoxue Zeng, Lantu Gou, Hao Chen, Yuqin Yao, Jinliang Yang

Research output: Contribution to journalArticle

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Abstract

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 Å (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.

Original languageEnglish (US)
Pages (from-to)162-179
Number of pages18
JournalEuropean Journal of Medicinal Chemistry
Volume156
DOIs
StatePublished - Aug 5 2018

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Tubulin Modulators
Colchicine
Tubulin
Binding Sites
Tumors
Structure-Activity Relationship
Crystal structure
Cells
Neoplasms
Pharmacokinetics
Confocal microscopy
Liquid chromatography
Heterografts
Antineoplastic Agents
Deamination
Mass spectrometry
G2 Phase
Assays
Tandem Mass Spectrometry
Cell Cycle Checkpoints

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Design, synthesis and biological evaluation of a novel tubulin inhibitor 7a3 targeting the colchicine binding site. / Lai, Qinhuai; Wang, Yuxi; Wang, Ruixue; Lai, Weirong; Tang, Liangze; Tao, Yiran; Liu, Yu; Zhang, Ruirui; Huang, Luyi; Xiang, Haotian; Zeng, Shaoxue; Gou, Lantu; Chen, Hao; Yao, Yuqin; Yang, Jinliang.

In: European Journal of Medicinal Chemistry, Vol. 156, 05.08.2018, p. 162-179.

Research output: Contribution to journalArticle

Lai, Q, Wang, Y, Wang, R, Lai, W, Tang, L, Tao, Y, Liu, Y, Zhang, R, Huang, L, Xiang, H, Zeng, S, Gou, L, Chen, H, Yao, Y & Yang, J 2018, 'Design, synthesis and biological evaluation of a novel tubulin inhibitor 7a3 targeting the colchicine binding site', European Journal of Medicinal Chemistry, vol. 156, pp. 162-179. https://doi.org/10.1016/j.ejmech.2018.05.010
Lai, Qinhuai ; Wang, Yuxi ; Wang, Ruixue ; Lai, Weirong ; Tang, Liangze ; Tao, Yiran ; Liu, Yu ; Zhang, Ruirui ; Huang, Luyi ; Xiang, Haotian ; Zeng, Shaoxue ; Gou, Lantu ; Chen, Hao ; Yao, Yuqin ; Yang, Jinliang. / Design, synthesis and biological evaluation of a novel tubulin inhibitor 7a3 targeting the colchicine binding site. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 156. pp. 162-179.
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AU - Tang, Liangze

AU - Tao, Yiran

AU - Liu, Yu

AU - Zhang, Ruirui

AU - Huang, Luyi

AU - Xiang, Haotian

AU - Zeng, Shaoxue

AU - Gou, Lantu

AU - Chen, Hao

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AU - Yang, Jinliang

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