Citation: Gao Dingding, Bao Keting, Zhang Mingming, Li Yingxia. Design, Synthesis and Biological Evaluation of Small-Molecule Inhibitors of Signal Transducer and Activator of Transcription
3 (STAT3) Signaling Pathway[J]. Chinese Journal of Organic Chemistry, ;2016, 36(8): 1854-1862. doi: 10.6023/cjoc201602030 shu

Design, Synthesis and Biological Evaluation of Small-Molecule Inhibitors of Signal Transducer and Activator of Transcription
3 (STAT3) Signaling Pathway

1.
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203

Corresponding author: Li Yingxia, liyx417@fudan.edu.cn
Received Date: 27 February 2016
Revised Date: 27 March 2016

Fund Project: Project supported by the National Natural Science Foundation of China and the Opening Foundation of Zhejiang Key Course of Chemical Engineering and Technology, Zhejiang University of Technology Nos. 21172197 and 21372201

Figures(1)

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is involved in the occurrence and development of the tumors, and is regarded as an attractive therapeutic target for cancer therapy. Our laboratory discovered some STAT3 inhibitors containing benzothiazole scaffold through virtual screening before. In a continuing effort to develop more potential STAT3 inhibitors, twenty-one target compounds based on our identified hit compound (16v) were rational designed and synthesized. These structures were characterized by ¹H NMR, ¹³C NMR and HRMS. All the target compounds were tested for their inhibitory activity using a STAT3 luciferase reporter system. The results showed that many compounds displayed better activity than lead compound 16v in series I. However, compounds containing thiazolo[5,4-d]pyrimidine scaffold led to the loss of inhibitory activity. This may attributed to the losing of hydrogen bonding to Glu638.
- benzothiazole,
- thiazolo[5,4-d]pyrimidine,
- STAT3 signaling pathway
1. [1]
  Darnell, J. E. Jr. Science 1997, 277, 1630.
2. [2]
  Bromberg, J.; Darnell, J. E. Jr. Oncogene 2000, 19, 2468.
3. [3]
  Yu, H.; Pardoll, D.; Jove, R. Nat. Rev. Cancer 2009, 9, 798.
4. [4]
  Ihle, J. N. Curr. Opin. Cell. Biol. 2001, 13, 211.
5. [5]
  Darnell, J. E., Jr. Nat. Rev. Cancer 2002, 2, 740.
6. [6]
  Yu, H.; Jove, R. Nat. Rev. Cancer 2004, 4, 97.
7. [7]
  Gabriella, M.; Tyvette, S. H.; James, T. Nat. Rev. Drug Discovery 2013, 12, 611.
8. [8]
  Turkson, J. Expert. Opin. Ther. Targets 2004, 8, 409.
9. [9]
  Miklossy, G.; Hilliard, T. S.; Turkson, J. Nat. Rev. Drug Discovery 2013, 12, 611.
10. [10]
  Banerjee, K.; Resat, H. Int. J. Cancer 2016, 138, 2570.
11. [11]
  Tell, R. W.; Horvath, C. M. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 12787.
12. [12]
  Priceman, S. J. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 13079.
13. [13]
  Aggarwal, B. B.; Kunnumakkara, A. B.; Harikumar, K. B.; Gupta, S. R.; Tharakan, S. T.; Koca, C.; Dey, S.; Sung, B. Ann. N. Y. Acad. Sci. 2009, 1171, 59.
14. [14]
  Darnell, J. E. Nat. Med. 2005, 11, 595.
15. [15]
  Masciocchi, D.; Gelain, A.; Meneghetti, F.; Barlocco, D. Future Med. Chem. 2011, 3, 567;
16. [16]
  Haftchenary, S.; Avadisian, M.; Gunning, P. T. Anticancer Drugs 2011, 22, 115.
17. [17]
  Becker, S.; Groner, B.; Muller, C. W. Nature 1998, 394, 145.
18. [18]
  Turkson, J.; Ryan, D.; Kim, J. S.; Zhang, Y.; Chen, Z. Laudano, A.; Jove, R. J. Biol. Chem. 2001, 276, 45443.
19. [19]
  Lin, L.; Hutzen, B.; Li, P. K.; Ball, S.; Zuo, M.; DeAngelis, S.; Foust, E.; Sobo, M.; Friedman, L.; Bhasin, D.; Cen, L.; Li, C.; Lin, J. A. Neoplasia 2010, 12, 39.
20. [20]
  Zhang, X.; Sun, Y.; Pireddu, R.; Yang, H.; Urlam, M. K.; Lawrence, H. R.; Guida, W. C.; Lawrence, N. J.; Sebti, S. Cancer Res. 2013, 73, 1922.
21. [21]
  Ji, P.; Xu, X.; Ma, S.; Fan, J.; Zhou, Q.; Mao, X.; Qiao, C. ACS Med. Chem. Lett. 2015, 6, 1010.
22. [22]
  Lai, M. J.; Lee, H. Y.; Chuang, H. Y.; Chang, L. H.; Tsai, A. C.; Chen, M. C.; Huang, H. L.; Wu, Y. W.; Teng, C. M.; Pan, S. L.; Liu, Y. M.; Mehndiratta, S.; Liou, J. P. J. Med. Chem. 2015, 58, 6549.
23. [23]
  Zhang, M.; Zhu, W.; Li, Y. Eur. J. Med. Chem. 2013, 62, 301.
24. [24]
  Wang, Z.; Shi, X.; Wang, J. Bioorg. Med. Chem. Lett. 2011, 21, 1097.
25. [25]
  Takio, N.; Shoji, I. Pharm. Soc. Jpn. 1968, 16, 745.
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通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

Design, Synthesis and Biological Evaluation of Small-Molecule Inhibitors of Signal Transducer and Activator of Transcription3 (STAT3) Signaling Pathway

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通讯作者: 陈斌, bchen63@163.com

Design, Synthesis and Biological Evaluation of Small-Molecule Inhibitors of Signal Transducer and Activator of Transcription
3 (STAT3) Signaling Pathway