兼具荧光自标记和微管蛋白聚合抑制作用的苯并咪唑衍生物合成及生物活性研究

doi:10.6023/cjoc202407044

研究论文

兼具荧光自标记和微管蛋白聚合抑制作用的苯并咪唑衍生物合成及生物活性研究

冬海洋, 蒲佳欣, 李珂珂, 张昊文, 耿晓晴, 梁停停^*, 王建红^*

河南大学天然药物创新与转化重点实验室开封 475004

收稿日期:2024-07-29 修回日期:2024-09-14
基金资助:
基金目:河南省高等学校重点研究项目(No. 24A350001); 河南省科技攻关项目(No. 242102310439).

Synthesis and Bioactivity Evaluation of Benzimidazole Derivatives with Fluorescent Self-labeling and Tubulin Polymerization Inhibition

Dong Haiyang, Pu Jiaxin, Li Keke, Zhang Haowen, Geng Xiaoqing, Liang Tingting^*, Wang Jianhong^*

Henan Key Laboratory of Natural Medicine Innovation and Transformation, Henan University, Kaifeng 475004

Received:2024-07-29 Revised:2024-09-14
Contact: * E-mail: liangting910710@126.com (T. Liang), hdky@henu.edu.cn (J. Wang)

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摘要/Abstract

以天然产物Combretastatin A-4 (CA-4)为先导化合物,采用理性药物设计策略设计合成了一系列新型苯并咪唑衍生物。通过目标化合物对HT-29(人结肠癌细胞)的增殖抑制活性筛选,发现IV-02具有明显生物活性,并在多种肿瘤细胞上测试其抗肿瘤生物活性。实验结果显示,IV-02对A549细胞的增殖抑制IC₅₀为0.18 µmol/L,与阳性对照秋水仙碱(IC₅₀= 0.15 µmol/L)相当。生物活性研究表明,IV-02能够抑制微管蛋白聚合,诱导G2/M期细胞周期阻滞,并导致细胞凋亡。同时,化合物IV-02具有荧光发射效应,能够实时成像标记化合物在细胞内的动态过程。研究结果表明,IV-02是一种具荧光自标记功能的抗肿瘤化合物。

关键词: 苯并咪唑, 微管蛋白, 抗肿瘤作用, 荧光发射

A series of novel Combretastatin A-4-based benzimidazole derivatives were designed and synthesized according to rational drug design strategies. The antiproliferation activities were preliminarily evaluated against cancer cell line HT-29, and compound IV-02 stood out from the target compounds and exhibited significant antiproliferation potency. Further evaluation on multiple cancer cell lines such as HT-1080, HepG2, A549 and A549/Taxol cells, demonstrated that compound IV-02 showed significant cell growth inhibition on A549 cells with IC₅₀ of 0.18 µmol/L, which was comparable to that of positive control Colchicine (IC₅₀= 0.15 µmol/L). Further mechanistic studies demonstrated that IV-02 could inhibit tubulin polymerization in a concentration-dependent manner, cause cell cycle arrest in G2/M phase and induce the cell apoptosis. In addition, IV-02 exhibited fluorescence emission effect, which would be beneficial to label the intracellular dynamic changes of IV-02 in real time. The results indicated that compound IV-02 could serve as an anticancer compound with fluorescent self-labeling properties.

Key words: benzimidazole, tubulin, antitumor effect, fluorescence emission

引用此文

冬海洋, 蒲佳欣, 李珂珂, 张昊文, 耿晓晴, 梁停停, 王建红. 兼具荧光自标记和微管蛋白聚合抑制作用的苯并咪唑衍生物合成及生物活性研究[J]. 有机化学, doi: 10.6023/cjoc202407044.

Dong Haiyang, Pu Jiaxin, Li Keke, Zhang Haowen, Geng Xiaoqing, Liang Tingting, Wang Jianhong. Synthesis and Bioactivity Evaluation of Benzimidazole Derivatives with Fluorescent Self-labeling and Tubulin Polymerization Inhibition[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202407044.

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参考文献

[1] Hamel E.; Lin C.M. Biochem. Pharmacol. 1983, 32, 3864-3867.
[2] Tron G.C.; Pirali T.; Sorba G.; Pagliai F.; Busacca S.; Genazzani A.A.J. Med. Chem. 2006, 49, 3033-3044.
[3] Cui Y.J.; Liu C.; Ma C.C.; Ji Y.T.; Yao Y.L.; Tang L,Q.; Zhang, C.M.; Wu, J.D.; Liu, Z.P. J. Med. Chem. 2020, 63, 14840-14866.
[4] Seddigi Z.S.; Malik M.S.; Saraswati A.P.; Ahmed S.A.; Babalghith A.O.; Lamfon H.A.; Kamal A.MedChemComm. 2017, 8, 1592-1603.
[5] Gaspari R.; Prota A.E.; Bargsten K.; Cavalli A.; Steinmetz M.O.Chem. 2017, 2, 102-113.
[6] Pecnard S.; Hamze A.; Bignon J.; Prost B.; Deroussent A.; Gallego-Yerga, L.; Peláez, R.; Paik, J.Y.; Diederich, M.; Alami, M.; Provot, O. Eur. J. Med. Chem. 2021, 223, 113656.
[7] Bukhari S.N.A.; Kumar, G.B.; Revankar, H.M.; Qin, H.L. Bioorg. Chem. 2017, 72, 130-147.
[8] Shan Y.; Zhang J.; Liu Z.; Wang M.; Dong Y. Curr. Med. Chem. 2011, 18, 523-538.
[9] Gu Y.F.; Wu C.J.; Wang S.Q.; Zhang S.L.; Lu Y.; Si X.X.; Jiang, B.L. Chin. J. Org.Chem. 2024, DOI: 10.6023/cjoc202403049 (in chinese).
(顾一飞, 吴彩菊, 王思琪, 张世琳, 陆远, 司鑫鑫, 蒋佰玲,有机化学, 2024, DOI: 10.6023/cjoc202403049).
[10] Kremmidiotis,G.; Leske,A.F.; Lavranos,T.C.; Beaumont D. Mol.Cancer Ther. 2010, 9, 1562-1573.
[11] Flynn B.L.; Gill G.S.; Grobelny D.W.; Chaplin J.H.; Paul D.; Leske A.F.; Lavranos T.C.; Chalmers D.K.; Charman S.A.; Kostewicz E. J. Med. Chem. 2011, 54, 6014-6027.
[12] Wang Q.H.; Arnst K.E.; Wang Y.X.; Kumar G.; Ma D.J.; White S.W.; Miller D.D.; Li W.M.; Li W. J. Med. Chem.2019, 62, 14, 6734-6750.
[13] Kashyap V.K.; Wang Q.H.; Setua S.; Nagesh P.K.B.; Chauhan, N.; Kumari, S.; Chowdhury, P.; Miller, D.D.; Yallapu, M.M.; Li, W.; Jaggi, M.; Hafeez, B.B.; Chauhan, S.C. J. Exp. Clin. Cancer Res. 2019, 38, 29.
[14] Lai Q.H.; Wang Y.X.; Wang R.X.; Lai W.R.; Tang L.Z.; Tao Y.R.; Liu Y.; Zhang R.R.; Huang L.Y.; Xiang H.T.; Zeng S.X.; Gou L.T.; Chen H.; Yao Y.Q.; Yang, J.L. Eur. J. Med.Chem. 2018, 156, 162-179.
[15] Huo Z.;Liu K.; Zhang X.; Liang Y.; Sun X. Eur.J. Med. Chem. 2022, 235, 114271.
[16] Li G.; Wu J.Q.; Cai X.J.; Guan W.; Zeng Z.J.; Ou Y.H.; Wu X.Y.; Li J.Y.; Fang X.X.; Liu J.L.; Zhang Y.L.; Wang H.M.; Yin C.Q.; Yao, H.L. Eur. J. Med.Chem. 2023, 252, 115284.
[17] Karetnikov G.L.; Vasilyeva L.A.; Babayeva G.; Pokrovsky V.S.; Skvortsov D.A.; Bondarenko, O.B. ACS Pharmacol. Transl.Sci. 2024, 7, 384-394.
[18] Tan Y.C.; Hu H.; Zhu W.J.; Wang T.; Gao T.; Wang H.Q.; Chen J.; Xu J.Y.; Xu S.T.; Zhu, H.J. Eur. J. Med.Chem. 2023, 262, 115881.
[19] Li Y.; Ma H.Q.; Wang, Y.L. Chin. J. Org.Chem. 2008, 28, 210-217 (in chinese)
(李焱, 马会强, 王玉炉, 有机化学, 2008, 8, 210-217.)
[20] Santosh P.C.; Pandeya S.N.; Pathak A.K.International Journal of Research in Ayurveda & Pharmacy. 2001, 2, 1726-1737.
[21] Dong, H.Y. Ph.D. Dissertation, Henan University, Kaifeng, 2024 (in Chinese).
(冬海洋, 博士论文, 河南大学, 开封, 2024).