SIOC 中文
CJOG
Adv search

Chinese Journal of Organic Chemistry >

2021 , Vol. 41 >Issue 4: 1631 - 1638

DOI: https://doi.org/10.6023/cjoc202007073

ARTICLES

Synthesis and Anti-proliferative Activity of Indole-2-amide Derivatives as Cyclooxygenase-2/5-lipoxygenase (COX-2/5-LOX) Dual Inhibitors

  • Shihu Qian ,
  • Yuanzheng Huang ,
  • Jiaming Li ,
  • Yanchun Zhang ,
  • Bin Zhang ,
  • Fan Jin
Expand
  • a School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230031
    b Department of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei 230031
* Corresponding author. E-mail:

Received date: 2020-07-31

  Revised date: 2020-10-23

  Online published: 2020-12-19

Fold

Abstract

A novel series of indole-2-amide-derived cyclooxygenase-2/5-lipoxygenase (COX-2/5-LOX) dual inhibitors were designed and synthesized, and biologically evaluated as anti-proliferative agents. Among them, (5-chloro-1-(4-fluoro- benzyl)-1H-indol-2-yl)(4-(4-methoxy-benzyl)piperazin-1-yl)methanone (12h) exhibited stronger inhibitory activity against three tumor strains of HCT-116, SGC-7901 and A549 than celecoxib, and (5-chloro-1-(4-methoxybenzyl)-1H-indol-2-yl)(4- (4-methoxybenzyl)piperazin-1-yl)methanone (7b) displayed outstanding anti-proliferative activity against A549 (IC50=6.47 μmol?L –1) and HCT-116 (IC50=13.80 μmol?L –1) cell lines. As the most potent compound in anti-proliferative assay, 7b demonstrated attractive COX-2 (IC50=85.04 nmol?L–1) and 5-LOX (IC50=125.3 nmol?L–1) inhibitory activities. As revealed by the docking analysis, the substituents on the indole ring were beneficial for improving the binding affinity to the enzyme. Further investigation confirmed that 7b could induce the apoptosis of A549 cells in a dose-dependent manner.

Key words： indole; anti-tumor; cyclooxygenase (COX); 5-lipoxygenase (5-LOX); docking

Cite this article

Shihu Qian , Yuanzheng Huang , Jiaming Li , Yanchun Zhang , Bin Zhang , Fan Jin . Synthesis and Anti-proliferative Activity of Indole-2-amide Derivatives as Cyclooxygenase-2/5-lipoxygenase (COX-2/5-LOX) Dual Inhibitors[J]. Chinese Journal of Organic Chemistry, 2021 , 41(4) : 1631 -1638 . DOI: 10.6023/cjoc202007073

References

[1]
Whiteman, D.C.; Wilson, L.F. Cancer Epidemiol. 2016, 44,203.
[2]
Qu, X.L.; Tang, Ying; Hua, S.C.; Front. Immunol. 2018, 9,563.
[3]
Riemann, A; Ihling, A.; Reime, S. Adv. Exp. Med. Biol. 2016, 923,105.
[4]
Zhang, L.; Wang, Z.C.; Li, X.E. J. Med. Chem. 2019, 169,168.
[5]
Marsico, F.; Paolillo, S.; Filardi, P.P. J. Cardiovasc. Med. 2017, 18,40.
[6]
Jacqueline, K.L.; Philip, C.C. Prostaglandins, Leukotrienes Essent. Fatty Acids 2018, 132,41.
[7]
Jacob, P.J.; Manju, S.L.; Ethiraj, K.R. Eur. J. Pharm. Sci. 2018, 121,356.
[8]
Nicholas, S.K.; Joan, R.; Blerina, A.S. Cardiovasc. Res. 2019, 12,12.
[9]
Soumaoro, L.T.; Iida, S.; Uetake, H. World J. Gastroenterol. 2006, 12,6355.
[10]
Cai, H.; Huang, X.J.; Xu, S.T. E. J. Med. Chem. 2016, 108,89.
[11]
Reddy, K.K.; Vidya, R.V. K.; Gupta, A. BMC Res. Notes 2015, 8,1-10.
[12]
Guo, Z.-R. Acta Pharm. Sin. 2005,11.
[13]
Huang, Y.Z.; Zhang, B.; Li, J.M. E. J. Med. Chem. 2019, 180,41.
[14]
Alford, J.S.; Davies, H.M. L. J. Am. Chem. Soc. 2014, 136,10266.
[15]
Huang, W.J.; Wang, Y.J.; Li, J.M. Chem. Biol. Drug Des. 2018, 93,110.
[16]
Bowers, A.A.; West, N.; Newkirk, T.L. Org. Lett. 2009, 11,1301.
[17]
Kurumbail, R.G.; Stevens, A.M.; Gierse, J.K. Nature 1996, 384,644.
[18]
Scott, W.R.; James, R.K.; Jeffery, J.P. J. Biol. Chem. 2003, 278,45763.
Options
Outlines

/

〈 〉