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

doi:10.6023/cjoc201704018

Chin. J. Org. Chem. ›› 2017, Vol. 37 ›› Issue (6): 1523-1529.DOI: 10.6023/cjoc201704018 Previous Articles Next Articles

Notes

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

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 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

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.

1. Synthesis of Novel Indirubin Derivatives and Their Effects on the Proliferation, Cell Cycle and Apoptosis in Acute Myeloblastic Leukemia HL-60 Cells.PDF(1344KB)

Abstract

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

Cite this article

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]. Chin. J. Org. Chem., 2017, 37(6): 1523-1529.

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[1] Döhner, H.; Estey, E. H.; Amadori, S.; Appelbaum, F. R.; Büchner, T.; Burnett, A. K.; Dombret, H.; Fenaux, P.; Grimwade, D.; Larson, R. A.; Lo-Coco, F.; Naoe, T.; Niederwieser, D.; Ossenkoppele, G. J.; Sanz, M. A.; Sierra, J.; Tallman, M. S.; Löwenberg, B.; Bloomfield, C. D. Blood 2010, 115, 453.
[2] Ofran, Y.; Rowe J. M. Acta Haematol. 2014, 132, 292.
[3] Choi, T. Y.; Lee, M. S.; Ernst, E. Support. Care Cancer 2015, 23, 1819.
[4] Cai, J.; Damaraju, V. L.; Groulx, N.; Mowles, D.; Peng, Y.; Robins, M. J.; Cass, C. E.; Gros, P. Cancer Res. 2008, 68, 2349.
[5] Xiao, Z.; Hao, Y.; Liu, B.; Qian, L. Leukocyte Lymph. 2002, 43, 1763.
[6] Gaboriaud-Kolar, N.; Vougogiannopoulou, K.; Skaltsounis, A. L. Expert Opin. Ther. Patents 2015, 25, 583.
[7] Ponnusamy, K.; Petchiammal, C.; Mohankumar, R.; Hopper, W. J. Ethnopharmacol. 2010, 132, 349.
[8] Hsieh, W. L.; Lin, Y. K.; Tsai, C. N.; Wang, T. M.; Chen, T. Y.; Pang, J. H. S. J. Dermatol. Sci. 2012, 67, 140.
[9] Mak, N. K.; Leung, C. Y.; Wei, X. Y.; Shen, X. L.; Wong, R. N. S.; Leung, K. N.; Fung, M. C. Biochem. Pharmacol. 2004, 67, 167.
[10] Kunikata, T.; Tatefuji, T.; Aga, H.; Iwaki, K.; Ikeda, M.; Kurimoto, M. Eur. J. Pharmacol. 2000, 410, 93.
[11] Zhang, X.; Song, Y.; Wu, Y.; Dong, Y.; Lai, L.; Zhang, J.; Lu, B.; Dai, F.; He, L.; Liu, M.; Yi, Z. Int. J. Cancer 2011, 129, 2502.
[12] Suzuki, K.; Adachi, R.; Hirayama, A.; Watanabe, H.; Otani, S.; Watanabe, Y.; Kasahara, T. Brit. J. Haematol. 2005, 130, 681.
[13] Gu, Y. C.; Li, G. L.; Yang, Y. P.; Fu, J. P.; Li, C. Z. Acta Pharm. Sinica 1989, 24, 629 (in Chinese).(顾月翠, 李国林, 杨尧平, 付建平, 李成章, 药学学报, 1989, 24, 629.)
[14] Hsuan, S. L.; Chang, S. C.; Wang, S. Y.; Liao, T. L.; Jong, T. T.; Chien, M. S.; Lee, W. C.; Chen, S. S.; Liao, J. W. J. Ethnopharmacol. 2009, 123, 61.
[15] Hoessel, R.; Leclerc, S.; Endicott, J. A.; Nobel, M. E. M.; Lawrie, A.; Tunnah, P.; Leost, M.; Damiens, E.; Marie, D.; Marko, D.; Niederberger, E.; Tang, W.; Eisenbrand, G.; Meijer, L. Nat. Cell Biol. 1999, 1, 60.
[16] Vougogiannopoulou, K.; Ferandin. Y.; Bettayeb, K.; Myrianthopoulos, V.; Lozach, O.; Fan, Y.; Johnson, C. H.; Magiatis, P.; Skaltsounis, A. L.; Mikros, E.; Meijer, L. J. Med. Chem. 2008, 51, 6421.
[17] Song, J. H.; Lee, J. E.; Cho, K. M.; Park, S. H.; Kim, H. J.; Kim, Y. C.; Kim, T. S. Mol. Carcinog. 2016, 55, 611.
[18] Libnow, S.; Methling, K.; Hein, M.; Michalik, D.; Harms, M.; Wende, K.; Flemming, A.; Köckerling, M.; Reinke, H.; Bednarski, P. J.; Lalk, M.; Langer, P. Bioorg. Med. Chem. 2008, 16, 5570.
[19] Cheng, X.; Rasqué, P.; Vatter, S.; Merz, K. H.; Eisenbrand, G. Bioorg. Med. Chem. 2010, 18, 4509.
[20] Wang, T. C.; Wei, J. Z.; Guo, C. S.; Zhang, H. B.; Fan, H. X. Chin. Chem. Lett. 2010, 21, 1407.
[21] Wang, Z. H.; Li, W. Y.; Li, F. L.; Zhang, L.; Hua, W. Y.; Cheng, J. C.; Yao, Q. Z. Chin. Chem. Lett. 2009, 20, 542.
[22] Wang, Z.; Wang, Y.; Feng, M.; Tan, X.; Cheng, J.; Hua, W.; Yao, Q. Chin. J. Org. Chem. 2009, 29, 1606 (in Chinese). (王朝晖, 王越, 冯明声, 谭雪, 程景才, 华维一, 姚其正, 有机化学, 2009, 29, 1606.)
[23] Wang, Z. H.; Dong, Y.; Wang, T.; Shang, M. H.; Hua, W. Y.; Yao, Q. Z. Chin. Chem. Lett. 2010, 21, 297.
[24] Cragg, G. M.; Grothaus, P. G.; Newman, D. J. Chem. Rev. 2009, 109, 3012.
[25] Evan, G. I.; Vousden, K. H. Nature 2001, 411, 342.
[26] Fesik, S. W. Nat. Rev. Cancer 2005, 5, 876.
[27] Klöcka, C.; Jin, X.; Choi, K.; Khosla, C.; Madrid, P. B.; Spencer, S.; Raimundo, B. C.; Boardman, P.; Lanza, G.; Griffin, J. H. Bioorg. Med. Chem. Lett. 2011, 21, 2692.
[28] Zhang, L.; Zhang, Z.; Chen, F.; Chen, Y.; Lin, Y.; Wang, J. Eur. J. Med. Chem. 2016, 123, 226.
[29] Zhang, L.; Liu, L.; Zheng, C.; Wang, Y.; Nie, X.; Shi, D.; Chen, Y.; Wei, G.; Wang, J. Eur. J. Med. Chem. 2017, 131, 81.

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

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

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