Citation: Zhang Lei, Liu Lai, Zheng Chengyue, Wang Yang, Wang Jing, Yao Qizheng. Synthesis of Novel Indirubin Derivatives and Their Effects on the Proliferation, Cell Cycle and Apoptosis in Acute Myeloblastic Leukemia HL-60 Cells[J]. Chinese Journal of Organic Chemistry, ;2017, 37(6): 1523-1529. doi: 10.6023/cjoc201704018 shu

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

Zhang Lei ^a,*,, ,
Liu Lai ^a ,
Zheng Chengyue ^a ,
Wang Yang ^a ,
Wang Jing ^a,*,, ,
Yao Qizheng ^b

a.
School of Pharmacy, Zunyi Medical University, Zunyi 563003
b.
School of Pharmacy, China Pharmaceutical University, Nanjing 210009

Corresponding author: Zhang Lei, lzhang@zmc.edu.cn Wang Jing, wangjing@zmc.edu.cn
Received Date: 12 April 2017
Revised Date: 28 April 2017

Fund Project: the Undergraduate Training Programs for Innovation and Entrepreneurship of Zunyi Medical University [2014]5811the Department of Science and Technology of Guizhou Province [2014]7565the Discipline Construction Funding Medicinal Chemistrythe Undergraduate Training Programs for Innovation and Entrepreneurship of Zunyi Medical University [2014]2918the Department of Science and Technology of Guizhou Province [2014]7557the National Undergraduate Training Programs for Innovation and Entrepreneurship 201510661009the Priming Scientific Research Foundation for Doctoral Program of Zunyi Medical University F-631

Figures(7)

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.
- indirubin,
- derivatives,
- anticancer activity,
- cell cycle,
- cell apoptosis,
- HL-60 leukemia cells
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