• 中国精品科技期刊
  • 中国高校百佳科技期刊
  • 中国中文核心期刊
  • 中国科学引文数据库核心期刊
Advanced Search
WU Wenping, LI Sisi, MA Cheng. Design, synthesis and anti-tumor activity of combretastatin A-4 derivatives[J]. Journal of China Pharmaceutical University, 2022, 53(3): 278-285. DOI: 10.11665/j.issn.1000-5048.20220304
Citation: WU Wenping, LI Sisi, MA Cheng. Design, synthesis and anti-tumor activity of combretastatin A-4 derivatives[J]. Journal of China Pharmaceutical University, 2022, 53(3): 278-285. DOI: 10.11665/j.issn.1000-5048.20220304
shu

Design, synthesis and anti-tumor activity of combretastatin A-4 derivatives

  • College of Pharmacy, Xinjiang Medical University, Urumqi 830011, China

Funds: The study was supported by the Natural Science Foundation of Xinjiang Uygur Autonomous Region (No.2019D01C28), and the Project of Xinjiang Key Laboratory of Active Components of Natural Medicine and Drug Release Technology (No.XJDX1713)
More Information
  • Received Date: March 10, 2022
  • Revised Date: April 25, 2022
    Graphical Abstract
    • Abstract
  • Based on the structure of combretastatin A-4 (CA-4), a microtubulin inhibitor, eight novel compounds were designed and synthesized by introducing different substituents into the benzimidazole backbone which substituted B ring of CA-4, and the structures were characterized by NMR and HRMS. Proliferation inhibition of six tumor cells including A549, HepG2, HCT-116, MCF-7, PC-3 and Siha was measured by MTT method.The effect of active compound on cell migration was evaluated by scratch test.Molecular docking technique was applied to investigate the interaction between the most active compound with the tubulin and PI3K kinases respectively.Compound 4e showed prominent inhibition against six strains of tumor cells, especially with the strongest inhibitory effect on Siha cells (IC50 = 12.18 ± 1.17 μmol/L).Moreover, compound 4e could effectively inhibit cell migration, which deserves further study.Molecular docking study showed that the binding energy to the tubulin of compound 4e was stronger than that of CA-4, and the affinity with PI3Ks displayed that the PI3Kδ subtype kinase was the strongest; its binding energy was -37.2 kJ/mol.This study lays a foundation for the development of anti-tumor drug based on PI3K and microtubulin.
    • FullText(HTML)
    • References (26)
  • [1]
    . CA Cancer J Clin，2021，71（3）：209-249.
    [2]
    Figueroa-Magalh?es MC，Jelovac D，Connolly RM，et al. Treatment of HER2-positive breast cancer［J］. Breast，2014，23（2）：128-136.
    [3]
    Sun YT，Jiang LQ，Wen T，et al. Trends in the research into immune checkpoint blockade by anti-PD1/PDL1 antibodies in cancer immunotherapy：a bibliometric study［J］. Front Pharmacol，2021，12：670900.
    [4]
    Cushing TD，Metz DP，Whittington DA，et al. PI3Kδ and PI3Kγ as targets for autoimmune and inflammatory diseases［J］. J Med Chem，2012，55（20）：8559-8581.
    [5]
    Joshi MC，Kumar K，Kumar V. Potent phosphatidylinositol 3-kinase inhibitors and their biology［J］. Curr Drug Discov Technol，2014，11（2）：113-126.
    [6]
    Huang QX，Gao S，Zhao DQ，et al. Review of ginsenosides targeting mitochondrial function to treat multiple disorders：current status and perspectives［J］. J Ginseng Res，2021，45（3）：371-379.
    [7]
    Huang TT，Brill E，Nair JR，et al. Targeting the PI3K/mTOR pathway augments CHK1 inhibitor-induced replication stress and antitumor activity in high-grade serous ovarian cancer［J］. Cancer Res，2020，80（23）：5380-5392.
    [8]
    Zhu SR，Liu XL，Xue M，et al. 20（S）-ginsenoside Rh2 induces caspase-dependent promyelocytic leukemia-retinoic acid receptor A degradation in NB4 cells via Akt/Bax/caspase9 and TNF-α/caspase8 signaling cascades［J］. J Ginseng Res，2021，45（2）：295-304.
    [9]
    Herschbein L，Liesveld JL. Dueling for dual inhibition：means to enhance effectiveness of PI3K/Akt/mTOR inhibitors in AML［J］. Blood Rev，2018，32（3）：235-248.
    [10]
    Vlahos CJ，Matter WF，Hui KY，et al. A specific inhibitor of phosphatidylinositol 3-kinase，2-（4-morpholinyl）-8-phenyl-4H-1-benzopyran-4-one （LY294002）［J］. J Biol Chem，1994，269（7）：5241-5248.
    [11]
    Walker EH，Pacold ME，Perisic O，et al. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin，LY294002，quercetin，myricetin，and staurosporine［J］. Mol Cell，2000，6（4）：909-919.
    [12]
    Bell K，Sunose M，Ellard K，et al. SAR studies around a series of triazolopyridines as potent and selective PI3Kγ inhibitors［J］. Bioorg Med Chem Lett，2012，22（16）：5257-5263.
    [13]
    Lv XY，Zhang YM，Liu L. Research progress of PI3K inhibitors combined with anti-tumor drugs［J］. Food and Drug（食品与药品），2020，22（2）：158-167.
    [14]
    Bohnacker T，Prota AE，Beaufils F，et al. Deconvolution of Buparlisib''s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention［J］. Nat Commun，2017，8：14683.
    [15]
    McKay RR，de Velasco G，Werner L，et al. A phase 1 study of buparlisib and bevacizumab in patients with metastatic renal cell carcinoma progressing on vascular endothelial growth factor-targeted therapies［J］. Cancer，2016，122（15）：2389-2398.
    [16]
    Al-Hamashi AA，Koranne R，Dlamini S，et al. A new class of cytotoxic agents targets tubulin and disrupts microtubule dynamics［J］. Bioorg Chem，2021，116：105297.
    [17]
    Wang Z，Guan Q，Zhang XJ. Advances in combretastatin A-4 analogues of tubulin colchicine binding site inhibitors［J］. J Shenyang Pharm Univ（沈阳药科大学学报），2019，36（9）：844-852.
    [18]
    Liu RL，Huang MX，Zhang S，et al. Design，synthesis and bioevaluation of 6-aryl-1-（3，4，5-trimethoxyphenyl）-1H-benzo［d］imidazoles as tubulin polymerization inhibitors［J］. Eur J Med Chem，2021，226：113826.
    [19]
    Pettit GR，Singh SB，Hamel E，et al. Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4［J］. Experientia，1989，45（2）：209-211.
    [20]
    Hagras M，El Deeb MA，Elzahabi HSA，et al. Discovery of new quinolines as potent colchicine binding site inhibitors：design，synthesis，docking studies，and anti-proliferative evaluation［J］. J Enzyme Inhib Med Chem，2021，36（1）：640-658.
    [21]
    Ren YC，Ruan Y，Cheng BB，et al. Design，synthesis and biological evaluation of novel acridine and quinoline derivatives as tubulin polymerization inhibitors with anticancer activities［J］. Bioorg Med Chem，2021，46：116376.
    [22]
    Fan Y，Luo Y，Ma C. Synthesis and cytotoxic evaluation of combretastatin A-4 analogues of benzo［b］furans［J］. Monatsh Chem，2017，148：1823-1832.
    [23]
    Gao YT，Ma C，Feng XZ，et al. BF12，a novel benzofuran，exhibits antitumor activity by inhibiting microtubules and the PI3K/Akt/mTOR signaling pathway in human cervical cancer cells［J］. Chem Biodivers，2020，17（3）：e1900622.
    [24]
    Xiaohelaiti HMT，Gao YT，Ma C，et al. Design，synthesis and antitumor activity screening of 2-aryl benzimidazoles［J］. Northwest Pharm J（西北药学杂志），2020，35（2）：249-254.
    [25]
    Gilfillan L，Blair A，Morris BJ，et al. Synthesis and biological evaluation of novel 2，3-dihydro-1H-1，5-benzodiazepin-2-ones； potential imaging agents of the metabotropic glutamate 2 receptor［J］. Med Chem Commun，2013，4（7）：1118-1123.
    [26]
    Won DI，Lee JS，Ji JM，et al. Highly robust hybrid photocatalyst for carbon dioxide reduction：tuning and optimization of catalytic activities of dye/TiO2/Re（I） organic-inorganic ternary systems［J］. J Am Chem Soc，2015，137（42）：13679-13690.
    • Related Articles

  • Related Articles

    [1]SHI Min, YONG Qin, HE Yingna, HUANG Shiqin, ZHAO Xuan, YU Xian. Construction and in vivo evaluation of a thermosensitive hydrogel system loading with Pseudomonas aeruginosa DNA vaccine[J]. Journal of China Pharmaceutical University, 2021, 52(2): 186-194. DOI: 10.11665/j.issn.1000-5048.20210207
    [2]CHEN Ye, YIN Jun, YAO Wenbing, GAO Xiangdong. Advances of DNA-based nanomaterials in tumor therapy[J]. Journal of China Pharmaceutical University, 2020, 51(4): 406-417. DOI: 10.11665/j.issn.1000-5048.20200404
    [3]WANG Rui, WANG Yongmei, CAI Mingjun, KE Xuejia, WU Yue, CHONG Jun, CAO Rongyue. Pharmacological effects of anti-melanoma DC vaccine sensitized by fusion proteins of G3G6 and HST1[J]. Journal of China Pharmaceutical University, 2019, 50(2): 238-245. DOI: 10.11665/j.issn.1000-5048.20190216
    [4]HAN Xiu, QI Xiaole, WU Zhenghong. Advances in self-assemblied DNA nanocages as drug delivery systems[J]. Journal of China Pharmaceutical University, 2017, 48(6): 663-669. DOI: 10.11665/j.issn.1000-5048.20170605
    [5]ZHANG Zhiqing, WANG Fang, ZHOU Ting, ZHANG Guodong, WANG Xiufeng, LI Yunze. A DNA polyaptamer system as a targeted antitumor drug delivery[J]. Journal of China Pharmaceutical University, 2015, 46(4). DOI: 10.11665/j.issn.1000-5048.20150408
    [6]Formula optimization and transfection efficiency of polyethyleneimine/DNA complexes[J]. Journal of China Pharmaceutical University, 2010, 41(1): 40-44.
    [7]Study on the Flavonoids from Lonicera confusa DC.[J]. Journal of China Pharmaceutical University, 2004, (4): 9-12.
    [8]Applications of Au Nanoparticles Labeling Method in DNA-detection and the Technology of Genechip[J]. Journal of China Pharmaceutical University, 2003, (2): 88-93.
    [9]The Isoquinolones from Menispermum dauricum DC.[J]. Journal of China Pharmaceutical University, 2001, (2): 16-17.
    [10]Ptotoplast Transformation of Staphylococcal DNA[J]. Journal of China Pharmaceutical University, 1992, (4): 239-242.

  • Cited by

    Periodical cited type(3)

    1. 石敏，雍琴，何颖娜，黄仕琴，赵轩，余娴. 载铜绿假单胞菌DNA疫苗温敏水凝胶系统的构建及体内评价. 中国药科大学学报. 2021(02): 186-194 . 本站查看
    2. 雍琴，岳瀚勋，石敏，黄仕琴，赵轩，余娴. pH响应性PTEN/PLGA-(HE)_(10)-MAP纳米粒的构建及体外评价. 中国药科大学学报. 2021(03): 301-310 . 本站查看
    3. 冯旸，徐霄，莫然. 淋巴靶向药物递送系统在抗肿瘤转移治疗中的研究进展. 中国药科大学学报. 2020(04): 425-432 . 本站查看

    Other cited types(2)

Catalog

    Get Citation
    PDF
    XML
    Article views (196) PDF downloads (350) Cited by(5)
    Turn off MathJax
    Article Contents
    Abstract
    References
    Related Articles

    Copyright © Journal of China Pharmaceutical University苏ICP备12050101号-2

    Address：24 Tongjia Lane, Nanjing City, Jiangsu Province （210009）Tel: 025-83271566E-mail: xuebao@cpu.edu.cn

    Supported by: Beijing Renhe Information Technology Co., Ltd.  Baidu Analytics

    Total visits：292754

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return