Synthesis and Anti-Tumor Activity Evaluation of Novel 7-Fluoro-4-(1- Piperazinyl) Quinolines

Author(s): Dan Liu* , Aiqi Xue , Zhixin Liu , Yi Zhang , Penghui Peng , Haifeng Wang .

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 6 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Three series of new 7-fluoro-4-(1-piperazinyl) quinolines (I1~I6, II1~II2 and IV1~IV4) were synthesized. Their anti-tumor activity was evaluated in vitro against three human carcinoma cell lines, namely SGC-7901 cells, BEL-7402 cells and A549 cells expressing high levels of EGFR by Methyl Thiazolyl Terazolium (MTT) assay.

Methods: Three series of quinoline derivatives were synthesized, characterized and evaluated for their in vitro anti-tumor activities.

Results and Discussion: Structures of the newly synthesized compounds were confirmed by spectral analysis. The preliminary bioassay indicated that compounds I1, I10 and II1 exhibited better anti-tumor activity than the rest of the target compounds and gefitinib against A549 cell based assay, which demonstrated that compounds I1, I10 and II1 are potential agents for cancer therapy. Results suggested that the substitutes on piperazinyl influenced anti-tumor activities remarkably.

Conclusion: These results are useful for discovering more potent novel anti-tumor compounds and further studies are ongoing.

Keywords: 7-fluoro-4-(1-piperazinyl) quinolines, anti-tumor, tyrosine kinase inhibitors, synthesize, cancer therapy, Methyl Thiazolyl Tetrazolium (MTT), carcinoma cell.

[1]
Zhou, B.Y.; An, C.N.; Pu, X.P. Current status of research and development of new tyrosine kinase inhibitors. Chin. New Drug J., 2011, 20(17), 1661-1666.
[2]
Arora, A.; Scholar, E.M. Role of tyrosine kinase inhibitors in cancer therapy. J. Pharmacol. Exp. Ther., 2005, 315(3), 971-979.
[3]
Jiang, M.; Liu, D.; Lan, S.P. Progressed in quinolines as protein tyrosine kinase inhibitors. Chem. Reagents., 2013, 35(4), 333-336.
[4]
Erlichman, C.; Hidalgo, M.; Boni, J.P.; Martins, P.; Quinn, S.E.; Zacharchuk, C.; Amorusi, P.; Adjei, A.A.; Rowinsky, E.K. Phase I study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors. J. Clin. Oncol., 2006, 24(15), 2252-2260.
[5]
Wang, Y.; Long, Y.Q. Advances in small-molecule inhibitors of protein tyrosine kinases. Chin. J. Org. Chem., 2011, 31(10), 1595-1606.
[6]
Liu, B.; You, Q.D.; Li, Z.Y. Design, synthesis and anti-tumour activity of 6,7-disubstituted 4- (heteroarylamino)quinoline-3-carbonitrile derivatives. Chin. Chem. Lett., 2010, 21, 554-557.
[7]
Boschelli, D.H.; Ye, F.; Wang, Y.D.; Dutia, M.; Johnson, S.L.; Wu, B.Q.; Miller, K.; Powell, D.W.; Yaczko, D.; Young, M.; Tischler, M.; Arndt, K.; Discafani, C.; Etienne, C.; Gibbons, J.; Grod, J.; Lucas, J.; Weber, J.M.; Boschelli, F. Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity. J. Med. Chem., 2001, 44(23), 3965-3977.
[8]
Golas, J.M.; Arndt, K.; Etienne, C.; Lucas, J.; Nardin, D.; Gibbons, J.; Frost, P.; Ye, F.; Boschelli, D.H.; Boschelli, F. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res., 2003, 63(2), 375-381.
[9]
Wissner, A.; Mansour, T.S. The development of HKI-272 and related compounds for the treatment of the cancer. Arch. Pharm. Chem. Life Sci, 2008, 341(8), 465-477.
[10]
Cao, X.; You, Q.D.; Li, Z.Y.; Guo, Q.L.; Shang, J.; Yan, M.; Chem, J.W.; Chen, M. Design and synthesis of 7-alkoxy-4-heteroarylamino-3-quinolinecarbonitriles as dual inhibitors of c-Src kinase and nitric oxide synthase. Bioorg. Med. Chem., 2008, 16(11), 5890-5898.
[11]
Liu, B.Q.; You, Q.D.; Li, Z.Y. Synthesis and biological evaluation of 3-quinolinecarbonitrile-7-amide derivatives. Acta Pharm. Sin., 2009, 44(8), 879-884.
[12]
Liao, J.J. Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. J. Med. Chem., 2007, 50(3), 409-424.
[13]
Zhang, S.L.; Zhao, Y.F.; Liu, Y.J.; Chen, D.; Lan, W.H.; Zhao, Q.L.; Dong, C.C.; Xia, L.; Gong, P. Synthesis and antitumor activities of novel 1,4-disubstituted phthalazine derivatives. Eur. J. Med. Chem., 2010, 45(8), 3504-3510.
[14]
Liu, D.; Luan, T.; Kong, J.; Zhang, Y.; Wang, H.F. Synthesis and anti-tumor activities of 4-anilino-quinoline derivatives. Molecules, 2016, 21, 21.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 6
Year: 2019
Page: [663 - 669]
Pages: 7
DOI: 10.2174/1570180815666180820131036
Price: $58

Article Metrics

PDF: 39
HTML: 3
EPUB: 1
PRC: 1