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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Cytotoxicity and Molecular Targeting Study of Novel 2-Chloro-3- substituted Quinoline Derivatives as Antitumor Agents

Author(s): Mohammed A.M. Massoud*, Magda A. El-Sayed, Waleed A. Bayoumi and Basem Mansour

Volume 16 , Issue 3 , 2019

Page: [273 - 283] Pages: 11

DOI: 10.2174/1570180815666180604090924

Price: $65


Background: Quinoline scaffold acts as “privileged structure” for anticancer drug design. Certain derivatives showed good results through different mechanisms as topoisomerase 1 and kinase inhibition.

Methods: A new series of 2-chloro-3-(2-amino-3-cyano-4H-chromene, 4H-pyranyl and fused 1- cyclohexen-4-yl)quinoline structures (3-5, 6 and 7) were designed, synthesized, and evaluated for their in vitro antitumor activity. All compounds were tested by MTT assay against a panel of four different human tumor cell lines. The inhibitory activity of selected compounds was assessed on topoisomerase 1 and epidermal growth factor receptor tyrosine kinase via ELISA. In addition, compounds 7b and 3a were docked into the X-ray crystal structure of Topo 1 and EGFR enzymes, respectively to explain the molecular basis of the potent activity.

Results: Compounds 3a, 3b and 7b showed characteristic efficacy profile. 7b showed the best cytotoxic activity on all types of tested cell lines with IC50 range (15.8±1.30 to 28.2±3.37 µM), relative to 5-fluoruracil of IC50 range (40.7±2.46 to 63.8±2.69 µM). Via ELISA, 7b and 3a showed characteristic inhibition profile on Topo 1 and EGFR-TK respectively. In addition, 7b has scored binding energy (101.61 kcal/mol) and six hydrogen bonds with amino acids conserved residues in the enzyme pocket.

Conclusion: Analysis of results revealed that compounds 7a and 7b mainly were Topo 1 inhibitors while 3a was mainly EGFR inhibitor. This property may be exploited to design future quinoline derivatives as antitumor agents with enhanced selectivity towards either of the two molecular targets.

Keywords: Antitumor, cell lines, docking, EGFR, ELISA, MTT assay, topo 1, quinoline.

Graphical Abstract
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