50606-35-4Relevant articles and documents
Synthesis and antiproliferative activity of 2-aryl-4-(3,4,5-trimethoxybenzoyl)-1,2,3-triazol derivatives as microtubule-destabilizing agents
Feng, Dongjie,Wu, Yue,Wang, Hao,Bai, Zhaoshi,Wang, Defa,Zuo, Daiying,Bao, Kai,Wu, Yingliang,Zhang, Weige
, p. 29103 - 29111 (2017)
A series of 2-aryl-4-(3,4,5-trimethoxybenzoyl)-1,2,3-triazols were designed as analogs of substituted methoxybenzoyl-aryl-thiazole (SMART) under the consideration of geometric features. The target compounds were synthesized via concise and efficient processes including microwave-assisted cyclization, and were evaluated for their antiproliferative activity against three human cancer cell lines. Most compounds exhibited moderate antiproliferative activity with IC50 values in the micromolar to sub-micromolar range. Tubulin polymerization and immunofluorescence studies demonstrated that (Z)-9a was a potent microtubule-destabilizing agent and disrupted the polymerization dynamics. Moreover, (Z)-9a significantly induced accumulation of cells in the G2/M phase and caused microtubule destabilization. Molecular modeling studies showed that (Z)-9a probably binds to the colchicine site of tubulin.
3,5-Diaryl-1H-pyrazolo[3,4-b]pyridines as potent tubulin polymerization inhibitors: Rational design, synthesis and biological evaluation
Zhai, Min'an,Liu, Shiyuan,Gao, Meiqi,Wang, Long,Sun, Jun,Du, Jianan,Guan, Qi,Bao, Kai,Zuo, Daiying,Wu, Yingliang,Zhang, Weige
, p. 426 - 435 (2019/03/05)
A series of novel 3,5-diaryl-1H-pyrazolo[3,4-b]pyridines as tubulin polymerization inhibitors targeting the colchicine site were designed via ring tethering strategy, which was supported by conformational analysis. The general, chemically unstable and rot
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
, p. 162 - 179 (2018/07/13)
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 ? (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.
