考布他汀A-4衍生物的设计、合成及其抗肿瘤活性

吴文平; 李斯思; 马成

doi:10.11665/j.issn.1000-5048.20220304

考布他汀A-4衍生物的设计、合成及其抗肿瘤活性

新疆医科大学药学院，乌鲁木齐 830011

基金项目: 新疆维吾尔自治区自然科学基金资助项目（No.2019D01C208）；新疆天然药物活性组分与释药技术重点实验室资助项目（No.XJDX1713）

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出版历程
- 收稿日期: 2022-03-10
- 修回日期: 2022-04-25
- 刊出日期: 2022-06-24

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)

摘要

摘要: 以微管蛋白抑制剂考布他汀A-4（CA-4）为先导化合物，通过骨架变换，以苯并咪唑环取代CA-4结构中的B环，并引入不同的取代基，设计合成了8个新化合物，结构经NMR，HRMS表征。通过MTT法测定其对A549、HepG2、HCT-116、MCF-7、PC-3以及Siha等6种肿瘤细胞的增殖抑制作用，利用划痕实验评价了化合物对细胞迁移作用的影响，运用分子对接法分析了活性化合物与微管蛋白及PI3K激酶各亚型的作用方式。结果表明，化合物4e对6种肿瘤细胞表现出较好的增殖抑制活性，尤其对宫颈癌细胞Siha的抑制作用最强（IC₅₀ = 12.18 ± 1.17 μmol/L），且能有效抑制细胞迁移，具有进一步研究的价值。分子对接结果表明，化合物4e与微管蛋白的结合能强于CA-4，与PI3Kδ激酶蛋白相互作用最强，结合能为-37.2 kJ/mol。本研究为基于PI3K与微管蛋白的抗肿瘤药物研究提供了一定的理论依据。
- 考布他汀A-4 /
- 微管蛋白 /
- 磷脂酰肌醇-3-激酶 /
- 合成 /
- 抗肿瘤
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.
- combretastatinA-4 /
- tubulin /
- phosphoinositide 3-kinase /
- synthesis /
- anti-tumor

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参考文献(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/Ba_x/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.

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考布他汀A-4衍生物的设计、合成及其抗肿瘤活性

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出版历程

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

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出版历程

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