有机化学 ›› 2017, Vol. 37 ›› Issue (6): 1523-1529.DOI: 10.6023/cjoc201704018 上一篇    下一篇

研究简报

新型靛玉红衍生物的合成及其对急性髓系白血病HL-60细胞增殖、周期和凋亡的影响

张磊a, 刘来a, 郑诚月a, 王杨a, 王京a, 姚其正b   

  1. a. 遵义医学院药学院 遵义 563003;
    b. 中国药科大学药学院 南京 210009
  • 收稿日期:2017-04-12 修回日期:2017-04-28 发布日期:2017-05-10
  • 通讯作者: 张磊,王京 E-mail:lzhang@zmc.edu.cn;wangjing@zmc.edu.cn
  • 基金资助:

    贵州省科技厅(Nos.黔科合LH字[2014]7557,黔科合LH字[2014]7565)、遵义医学院博士科研启动基金(No.F-631)、国家级大学生创新创业(No.201510661009)、遵义医学院大学生创新创业(Nos.院发[2014]5811,遵医科院发[2014]2918)和遵义医学院学科建设(药物化学)资助项目.

Synthesis of Novel Indirubin Derivatives and Their Effects on the Proliferation, Cell Cycle and Apoptosis in Acute Myeloblastic Leukemia HL-60 Cells

Zhang Leia, Liu Laia, Zheng Chengyuea, Wang Yanga, Wang Jinga, Yao Qizhengb   

  1. a. School of Pharmacy, Zunyi Medical University, Zunyi 563003;
    b. School of Pharmacy, China Pharmaceutical University, Nanjing 210009
  • Received:2017-04-12 Revised:2017-04-28 Published:2017-05-10
  • Contact: 10.6023/cjoc201704018 E-mail:lzhang@zmc.edu.cn;wangjing@zmc.edu.cn
  • Supported by:

    Project supported by the Department of Science and Technology of Guizhou Province (Nos.[2014]7557,[2014]7565), the Priming Scientific Research Foundation for Doctoral Program of Zunyi Medical University (No. F-631), the National Undergraduate Training Programs for Innovation and Entrepreneurship (No. 201510661009), the Undergraduate Training Programs for Innovation and Entrepreneurship of Zunyi Medical University (Nos.[2014]5811,[2014]2918) and the Discipline Construction Funding (Medicinal Chemistry) of Zunyi Medical University.

急性髓细胞白血病是一种血液系统的恶性疾病,严重危害人类生命健康,目前尚无低毒、高效的治疗药物.靛玉红是我国传统中药青黛的有效成分,具有一定的抗白血病活性,但其水溶性差及造成的生物利用度较低,严重影响其临床应用.为了提高靛玉红的水溶性,进一步增强其抗白血病功效,在靛玉红结构中引入亲水性的胺基侧链,设计并合成了五个结构新颖的靛玉红衍生物,其结构经HRMS、1H NMR和13C NMR确证.同时,采用CCK-8法测试目标产物对急性髓系白血病HL-60细胞的体外抑制作用.结果表明,四个靛玉红衍生物具有显著的抗HL-60细胞增殖的活性,其中,化合物N1-(2-二甲氨基乙基)靛玉红(5a)的活性最强,其IC50值为(3.564±0.211) μmol/L.流式细胞术和Hoechst 33342染色实验显示,化合物5a能够显著诱导HL-60细胞周期阻滞和凋亡.此外,化合物5a还能影响细胞周期和凋亡相关蛋白的表达.综上研究表明,化合物5a是一个具有深入研究价值的抗白血病先导化合物.

关键词: 靛玉红, 衍生物, 抗肿瘤活性, 细胞周期, 细胞凋亡, HL-60白血病细胞

Acute myelogenous leukemia is a malignant disease of the hemopoietic tissue, which causes great harm to human health, and there is no therapeutic drugs with low toxicity and high efficiency. Indirubin is the active constituent of the traditional chinese medicine qingdai, which has potential anti-leukemia activity. However, poor water solubility and low bioavailability have limited its clinical treatment. To improve the water solubility and anti-leukemia activity of indirubin, hydrophilic amino side chain was linked to the indirubin, and five novel indirubin derivatives were synthesized, which were identified by HRMS, 1H NMR and 13C NMR. Meanwhile, the effects of target molecules on the proliferation of acute myeloblastic leukemia HL-60 cells were evaluated using CCK-8 assay. The results showed that four derivatives displayed potent antiproliferative activity against HL-60 cells. Notably, N1-(2-dimethylaminoethyl)indirubin (5a) exhibited the best anticacner activity with an IC50 value of (3.564±0.211) μmol/L. Flow cytometry and Hoechst 33342 staining indicated that compound 5a could significantly trigger cell cycle arrest and induce apoptosis of HL-60 cells. Finally, compound 5a could regulate the levels of cell cycle arrest-and apoptosis-related proteins. Together, these findings revealed that compound 5a maybe be a promising lead candidate for the treatment of leukemia.

Key words: indirubin, derivatives, anticancer activity, cell cycle, cell apoptosis, HL-60 leukemia cells