Citation: Zhang Yan, Wang Yunyun, Zhao Yuxun, Zhang Chenglong, Gu Wen, Wang Zhonglong, Zhu Yongqiang, Wang Shifa. Camphor-Based Thiosemicarbazone Analogues Induced G2 Cell Cycle Arrest and Apoptosis via Reactive Oxygen Species (ROS)-Mediated Mitochondrial Pathway in Human Breast Cancer Cells[J]. Chinese Journal of Organic Chemistry, ;2020, 40(8): 2374-2386. doi: 10.6023/cjoc202001021 shu

Camphor-Based Thiosemicarbazone Analogues Induced G2 Cell Cycle Arrest and Apoptosis via Reactive Oxygen Species (ROS)-Mediated Mitochondrial Pathway in Human Breast Cancer Cells

a.
Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037
b.
Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd, Nanjing 210033

Corresponding author: Zhu Yongqiang, zhyqscu@163.com Wang Shifa, wangshifa65@163.com
Received Date: 14 January 2020
Revised Date: 22 May 2020
Available Online: 8 June 2020
Fund Project: Natural National Science Foundation of China 31470592Doctorate Fellowship Foundation of Nanjing Forestry University 31470592Key Technology of Green Processing and Efficient Utilization on Oleoresin 2016YFD0600804Project supported by the Doctorate Fellowship Foundation of Nanjing Forestry University, the Natural National Science Foundation of China (No. 31470592), the University Science Research Project of Jiangsu Province (No. 14KJ220001) and the Key Technology of Green Processing and Efficient Utilization on Oleoresin (No. 2016YFD0600804)University Science Research Project of Jiangsu Province 14KJ220001

Figures(7)

22 novel camphor-based thiosemicarbazone derivatives were synthesized using camphor-based thiosemicarbazone as material and their structures were determined by ¹H NMR, ¹³C NMR and HRMS. The crystal structure of 2-(3-(pyridin-4-ylmethylene)-1, 7, 7-trimethylbicyclo[2.2.1]heptan-2-ylidene)hydrazinecarbothioamide (3n) was determined by single crystal X-ray diffraction. The derivatives were screened in vitro for anticancer activities against human breast cancer cell line (MDA-MB-231), human lung adenocarcinoma cell line (A549), human multiple myeloma cell line (RPMI-8226) and toxicity against a normal human cell line (GES-1) by 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS). It was found that majority of the tested analogs showed moderate to significant antitumor activity against selected cancer cell lines. Noticeably, 2-(3-(anthracen-9-ylmethylene)-1, 7, 7-trimethylbicyclo[2.2.1]heptan-2-ylidene)-hydrazinecarbothioamide (3s) exhibited selective anti-tumor activities against MDA-MB-231 cells (IC₅₀=3.90±0.04 μmol·L^-1) and low toxicity to GES-1 cells (IC₅₀>50 μmol·L^-1). In the process of exploring the underlying mechanism of 3s, it was found that compound 3s could cause G2 phase arrest and apoptosis in MDA-MB-231 cells by overproduction of intracellular reactive oxygen species and collapse of mitochondrial membrane potential. The measured results were confirmed by western blot assay.
- camphor-based thiosemicarbazone,
- anti-tumor activity,
- G2 phase arrest,
- reactive oxygen species (ROS),
- mitochondrial apoptosis pathway
1. [1]
  Xu Z., Zhao S. J., Liu Y.Eur. J. Med. Chem., 2019, 183:111700.
2. [2]
  Zhang L., Xu Z.Eur. J. Med. Chem., 2019, 181:111587.
3. [3]
  Magalhaes Moreira D. R., de Oliveira A. D., Teixeira de Moraes Gomes P. A., de Simone C. A., Villela F. S., Ferreira R. S., Leite A. C.Eur. J. Med. Chem., 2014, 75:467.
4. [4]
  De Melos J. L., Torres-Santos E. C., Faioes Vdos S., Del Cistia Cde N., Sant'Anna C. M., Rodrigues-Santos C. E., Echevarria A.Eur. J. Med. Chem., 2015, 103:409.
5. [5]
  Linciano P., Moraes C. B., Alcantara L. M., Franco C. H., Pascoalino B., Freitas-Junior L. H., Costi M. P.Eur. J. Med. Chem., 2018, 146:423.
6. [6]
  El-Sharief M. A., Abbas S. Y., El-Bayouki K. A., El-Gammal E. W.Eur. J. Med. Chem., 2013, 67:263.
7. [7]
  Zhang X., Guo H., Li Z., Song F., Wang W., Dai H., Wang J.Eur. J. Med. Chem., 2015, 101:419.
8. [8]
  Banerjee D., Yogeeswari P., Bhat P., Thomas A., Srividya M., Sriram D.Eur. J. Med. Chem., 2011, 46:106.
9. [9]
  Kesel A. J.Eur. J. Med. Chem., 2011, 46:1656.
10. [10]
  Chavarria G. E., Horsman M. R., Arispe W. M., Kumar G. D., Chen S. E., Strecker T. E., Trawick M. L.Eur. J. Med. Chem., 2012, 58:568.
11. [11]
  Pervez H., Khan N., Zaib S., Yaqub M., Naseer M. M., Tahir M. N., Iqbal J.Bioorg. Med. Chem., 2017, 25:1022.
12. [12]
  Song S., You A., Chen Z., Zhu G., Wen H., Song H., Yi W.Eur. J. Med. Chem., 2017, 139:815.
13. [13]
  De Oliveira J. F., Lima T. S., Vendramini-Costa D. B., de Lacerda Pedrosa S. C. B., Lafayette E. A., da Silva R. M. F., de Lima M.Eur. J. Med. Chem., 2017, 136:305.
14. [14]
  Vandresen F., Falzirolli H., Almeida Batista S. A., da Silva-Giardini A. P., de Oliveira D. N., Catharino R. R., da Silva C. C.Eur. J. Med. Chem., 2014, 79:110.
15. [15]
  Lukmantara A. Y., Kalinowski D. S., Kumar N., Richardson D. R.Bioorg. Med. Chem. Lett., 2013, 23:967.
16. [16]
  Rao V. A., Klein S. R., Agama K. K., Toyoda E., Adachi N., Pommier Y., Shacter E. B.Cancer Res., 2009, 69:948.
17. [17]
  Malarz K., Mrozek-Wilczkiewicz A., Serda M., Rejmund M., Musiol R.Oncotarget, 2018, 9:17689.
18. [18]
  Lovejoy D. B., Richardson D. R.Blood, 2002, 100:666.
19. [19]
  Da Silva A. P., Martini M. V., de Oliveira C. M., Cunha S., de Carvalho J. E., Ruiz A. L., da Silva C. C.Eur. J. Med. Chem., 2010, 45:2987.
20. [20]
  Bao M., Yang Y., Gu W., Xu X., Cao M., Wang S.Chin. J. Org. Chem., 2014, 34:2146(in Chinese).
21. [21]
  Sun N., Wang X., Ding Z., Zhang Q., Xu X., Xu H., Wang S.Chin. J. Org. Chem., 2016, 36:2489(in Chinese).
22. [22]
  Rui J., Cai T., Yang J., Yang Y., Xu X., Wang S.J. Nanjing. For. Univ., 2017, 41:149(in Chinese).
23. [23]
  Ma C., Wang Y., Dong F., Wang Z., Zhao Y., Shan Y., Wang S.Chem. Biol. Drug Des., 2019, 94:1457.
24. [24]
  Wang Y., Wang Z., Kuang H., Zhang Y., Gu W., Zhu Y., Wang S.Chem. Biol. Drug Des., 2019, 94:1281.
25. [25]
  Sokolova A. S., Yarovaya O. C., Korchagina D. V., Zarubaev V. V., Tretiak T. S., Anfimov P. M., Salakhutdinov N. F.Bioorg. Med. Chem., 2017, 127:661.
26. [26]
  Stavrakov G., Valcheva V., Philipova I., Doytchinova I.Eur. J. Med. Chem., 2013, 70:372.
27. [27]
  Sokolova A. S., Yarovaya O. C., Korchagina D. V., Zarubaev V. V., Tretiak T. S., Anfimov P. M., Salakhutdinov N. F.Bioorg. Med. Chem., 2014, 22:2141.
28. [28]
  Kuranov S. O., Tsypysheva I. P., Khvostov M. V., Zainullina L. F., Borisevich S. S., Vakhitova Y. V., Salakhutdinov N. F.Bioorg. Med. Chem., 2018, 26:4402.
29. [29]
  Hossain M., Das U., Dimmock J. R.Eur. J. Med. Chem., 2019, 183:111687.
30. [30]
  Dan W., Dai J.Eur. J. Med. Chem., 2020, 187:111980.
31. [31]
  Zhu M., Wang J., Xie J., Chen L., Wei X., Jiang X., Bao M., Qiu Y., Chen Q., Li W., Jiang C., Zhou X., Jiang L., Qiu P., Wu J.Eur. J. Med. Chem., 2018, 157:1395.
32. [32]
  Liu C., Wen R., He M., Yi X., Ye X., Fang L.Chin. J. Appl. Chem., 2017, 38:900(in Chinese).
33. [33]
  Zhang H., Qian Y., Zhu D., Yang X., Zhu H.Eur. J. Med. Chem., 2011, 46:4702.
34. [34]
  Simon H. U., Haj-Yehia A., Levi-Schaffer F.Apoptosis, 2000, 5:415.
35. [35]
  Circu M. L., Aw T. Y.Free Radical Biol. Med., 2010, 48:749.
36. [36]
  Dharmaraja A. T.J. Med. Chem., 2017, 60:3221.
37. [37]
  Yamada Y., Harashima H.Adv. Drug Delivery Rev., 2008, 60:1439.
38. [38]
  Galluzzi L., Zamzami N., de La Motte Rouge T., Lemaire C., Brenner C., Kroemer G.Apoptosis, 2007, 12:803.
39. [39]
  Jin Z., El-Deiry W. S.Cancer Biol. Ther., 2005, 4:139.
40. [40]
  Martinou J. C., Desagher S., Antonsson B.Nat. Cell Biol., 2005, 2:41.
41. [41]
  Xiong S., Mu T., Wang G., Jiang X.Protein Cell, 2014, 5:737.
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沈阳化工大学材料科学与工程学院沈阳 110142