1,4,5,6,7,8-Hexahydroquinolines and 5,6,7,8-tetrahydronaphthalenes: A new class of antitumor agents targeting the colchicine binding site of tubulin.

New series of 2-amino-1,4,5,6,7,8-hexahydroquinoline-3-carbonitriles 3a,b and 2-amino-5,6,7,8-tetrahydronaphthalene-1,3-dicarbonitriles 4a-h were synthesized and evaluated for their antitumor activity. In vitro antitumor screening of the new members against HepG2, HCT-116 and MCF-7 cancer cells showed that the tetrahydronaphthalene-1,3-dicarbonitrile 4c has the highest potency against the three tested cancer cells (IC ₅₀  = 6.02, 8.45 and 6.28 µM, respectively). In addition, 4c displayed low cytotoxicity against WI38 and WISH normal cells (IC ₅₀  = 51.78 and 42.36 µM, respectively), and it might be utilized as a potent and selective antitumor agent. Compound 4c was further studied for its effect on tubulin polymerization, different phases of cell cycle, apoptosis and caspases 3/9 levels. Results revealed that analog 4c has good tubulin polymerization inhibitory activity (IC ₅₀ = 3.64 μM). Additionally, it induced significant accumulation of the tested cancer cells in G2/M phase, and induced cell death primarily via apoptosis. Besides, it showed evident increase in caspase-3 level in HepG2 and HCT-116 cells, and caspase-9 level in MCF-7 cells. Further, docking studies proved the exact fit of 4c into the colchicine binding site of tubulin.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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