Citation: Ding Yong, Li Qinghan, Zhao Zhigang, Yang Xuejun, Chen Feng. Design, Synthesis and Anti-tumor Activity Evaluation of a Novel Series of Isoxazoles Bearing (1-Bi(4-fluorophenyl)methyl)-piperazine Unit[J]. Chinese Journal of Organic Chemistry, ;2017, 37(12): 3282-3288. doi: 10.6023/cjoc201707001 shu

Design, Synthesis and Anti-tumor Activity Evaluation of a Novel Series of Isoxazoles Bearing (1-Bi(4-fluorophenyl)methyl)-piperazine Unit

College of Chemistry and Environmental Protection Engineering, Southwest Minzu University, Chengdu 610041

Corresponding author: Li Qinghan, lqhchem@163.com
Received Date: 2 July 2017
Revised Date: 19 August 2017
Available Online: 15 December 2017
Fund Project: Project supported by the Sichuan Provincial Department of Science and Technology Support Program (No. 2015NZ0033)the Sichuan Provincial Department of Science and Technology Support Program 2015NZ0033

Figures(1)

Twelve novel isoxazoles containing (1-bi(4-fluorophenyl)methyl)piperazine unit were prepared in two steps starting from propargyl bromide, (1-bi(4-fluorophenyl)methyl)piperazine and hydroxymoyl chlorides with moderate yield (21%~76%). The structures of the new compounds were characterized by IR, MS, ¹H NMR, ¹³C NMR and elemental analysis, and their in vitro anti-tumor activity was screened. The bioactive assay for the newly prepared compounds manifested that ten newly isoxazole derivatives exhibited good to excellent inhibitory activity against CDC25B in 20 μg/mL with inhibition of 64.15%~95.87% and IC₅₀ of 35.62~13.67 μg/mL. Four isoxazoles exhibited good to excellent inhibitory activity against Leukemia cell HL-60 in 40 μmol/L (IC₅₀:36.51~15.25 μg/mL), 2-(2-fluorophenyl)-5-(1-(bi-(4-fluorophenyl)methyl)-piperazine)methylisoxazole (5g) and 2-(4-fluorophenyl)-5-(1-(bi-(4-fluorophenyl)methyl)piperazine)methylisoxazole (5h) exhibited good to excellent inhibitory activity against Lung cancer cell A-549 (IC₅₀ value up to 21.09 and 35.36 μg/mL, respectively).
- 1-[bi(4-fluorophenyl)methyl]piperazine,
- isoxazole,
- organic synthesis,
- anti-tumor activity
1. [1]
  Jemal, A.; Bray, F.; Center, M. M.; Ferlay, J.; Ward, E.; Forman, D. Ca-Cancer J. Clin. 2011, 61, 69. doi: 10.3322/caac.v61:2
2. [2]
  Murray, C. J. L.; Lopez, A. D. Lancet 1997, 349, 1498. doi: 10.1016/S0140-6736(96)07492-2
3. [3]
  Mathers, C. D.; Loncar, D. PLoS Med. 2006, 3, e442. doi: 10.1371/journal.pmed.0030442
4. [4]
  Chen, H.-X.; Cleck, J. N. Nat. Rev. Clin. Oncol. 2009, 6, 465. doi: 10.1038/nrclinonc.2009.94
5. [5]
  Rowley, M.; Broughton, H. B.; Collins, I.; Baker, R.; Emms, F.; Marwood, R.; Patel, S.; Ragan, C. I.; Freedman, S. B.; Leeson, P. D. J. Med. Chem. 1996, 39, 1943. doi: 10.1021/jm960072u
6. [6]
  Frolund, B.; Jorgensen, A. T.; Tagmose, L.; Stensbol, T. B.; Vestergaard, H. T.; Engblom, C.; Kristiansen, U.; Sanchez, C.; Krogsgaard-Larsen, P.; Liljefors, T. J. Med. Chem. 2002, 45, 2454. doi: 10.1021/jm020027o
7. [7]
  Talley, J. J.; Bertenshaw, S. R.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Kellogg, M. S.; Koboldt, C. M.; Yuan, J. H.; Zhang, Y.-Y.; Seibert, K. J. Med. Chem. 2000, 43, 1661. doi: 10.1021/jm000069h
8. [8]
  Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y.-Y.; Zweifel, B. S.; Seibert, K. J. Med. Chem. 2000, 43, 775. doi: 10.1021/jm990577v
9. [9]
  Giovannoni, M. P.; Vergelli, C.; Ghelardini, C.; Galeotti, N.; Bartolini, A.; Dal Piaz, V. J. Med. Chem. 2003, 46, 1055. doi: 10.1021/jm021057u
10. [10]
  Daidone, G.; Raffa, D.; Maggio, B.; Plescia, F.; Cutuli, V. M. C.; Mangano, N. G.; Caruso, A. Arch. Pharm. 1999, 332, 50. doi: 10.1002/(ISSN)1521-4184
11. [11]
  Bhatt, A. H.; Parekh, H. H.; Parikh, A. R. Heterocycl. Commun. 1998, 4, 361.
12. [12]
  Li, W.-T.; Hwang, D.-R.; Chen, C.-P.; Shen, C.-W.; Huang, C.-L.; Chen, T.-W.; Lin, C.-H.; Chang, Y.-L.; Chang, Y.-Y.; Lo, Y.-K.; Tseng, H.-Y.; Lin, C.-C.; Song, J.-S.; Chen, H.-C.; Chen, S.-J.; Wu, S.-H.; Chen, C.-T. J. Med. Chem. 2003, 46, 1706. doi: 10.1021/jm020471r
13. [13]
  Yong, J.-P.; Lu, C.-Z.; Wu, X.-Y. Med. Chem. Commun. 2014, 5, 968. doi: 10.1039/c4md00151f
14. [14]
  Haga, T.; Fujikawa, K.; Koyanag, T.; Nakajima, T.; Hayashi, K. Heterocycles 1984, 22, 117. doi: 10.3987/R-1984-01-0117
15. [15]
  Yoshida, S.; Meyer, O. G. J.; Rosen, T. C.; Haufe, G.; Song, Y.; Sloan, M. J.; Kirk, K. L. J. Med. Chem. 2004, 47, 1796. doi: 10.1021/jm030398k
16. [16]
  Shelke, S. N.; Mhaske, G. R.; Bonifàcio, V. D. B.; Gawande, M. B. Bioorg. Med. Chem. Lett. 2012, 22, 5727. doi: 10.1016/j.bmcl.2012.06.072
17. [17]
  Ge, Z.-M.; Guo, B.-G.; Wang, H.-Y.; Cheng, T.-M.; Li, R.-T. J. Peking Univ. (Heal. Sci.) 2001, 33, 213(in Chinese).
18. [18]
  Ding, Y.; Zhang, Z.; Zhang, G.; Mo, S.; Li, Q.-H.; Zhao, Z.-G. Res. Chem. Intermed. 2016, 42, 3105. doi: 10.1007/s11164-015-2200-5
19. [19]
  Naoki, S.; Fumihiko, A.; Shigeki, K.; Masahiko, K.; Yoshiko, S.; Haruko, Y.; Masanori, S.; Chikara, F. J. Med. Chem. 1994, 37, 1977. doi: 10.1021/jm00039a010
20. [20]
  Naoki, S.; Fumihiko, A.; Shigeki, K.; Masahiko, K.; Yoshiko, S.; Haruko, Y.; Masanori, S.; Chikara, F. S. J. Med. Chem. 1994, 37, 1977. doi: 10.1021/jm00039a010
21. [21]
  Li, Q.-H.; Ding, Y.; Yang, X.-J. Chin. Chem. Lett. 2014, 25, 1296. doi: 10.1016/j.cclet.2014.04.019
22. [22]
  Li, Q.-H.; Ding, Y.; Huang, N.-W. Chin. Chem. Lett. 2014, 25, 1469. doi: 10.1016/j.cclet.2014.05.022
23. [23]
  Li, Q.-H.; Zhang, G.; Ding, Y.; Chen, F.; Zhang, Z.; Mo, S. J. Southwest Univ. Nat. (Nat. Sci. Ed.) 2014, 40, 826(in Chinese).
24. [24]
  Li, Q.-H.; Zhao, Z.-G. Chin. J. Org. Chem. 2009, 29, 119(in Chinese).
25. [25]
  Deng, J.; Li, A.-N.; Li, Q.-H.; Ding, Y.; Yang, X.-J.; Chen, F. Chin. J. Org. Chem. 2016, 36, 2981(in Chinese).
26. [26]
  Li, Q.-H.; Ding, Y.; Zhang, G.; Zhang, Z.; Mong, S. Chin. J. Org. Chem. 2016, 36, 83(in Chinese).
27. [27]
  Mo, S.; Ding, Y.; Zhang, G.; Zhang, Z.; Shao, X.-B.; Li, Q.-H.; Yang, X.-J.; Chen, F. Chin. J. Org. Chem. 2017, 37, 1000(in Chinese).
28. [28]
  Altug, C.; Güneş, H.; Nocentini, A.; Monti, S. M.; Buonanno, M.; Supuran, C. T. Bioorg. Med. Chem. 2017, 25, 1456. doi: 10.1016/j.bmc.2017.01.008
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