[EZ-Cytox] Discovery of a 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amine derivative as a novel DNA intercalating topoisomerase IIα poison

2022.01.28 09:16 442 1



∙Thirty 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amines were synthesized.

∙4-Trifluoromethylphenyl substituents displayed strong topo IIα inhibition.

∙Compound 19 was determined to be a DNA intercalative topo IIα poison inhibitor.

∙Molecular docking of compound 19 showed selectivity for topo IIα than topo IIβ.


Several anticancer agents have been developed and innovative approaches have been made toward cancer type-specific medicines for cancer treatment. As a continuous effort to develop potential chemotherapeutic agents, a novel series of 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amines containing amino groups, hydroxyphenyl and fluorine functionalities were designed and synthesized. The compounds were evaluated for topo IIα inhibitory and cytotoxicity against HCT15, and HeLa human cancer cell lines. Among synthesized thirty compounds, the majority exhibited strong topo IIα inhibition and anti-proliferation against HCT15 colorectal adenocarcinoma cell line. The structure-activity relationship study revealed that compounds with –CF3 and –OCF3 substituents at 4- position and 3′ or 4′-hydroxyphenyl at 2-position attached to the central pyridine ring displayed potent topo IIα and anti-proliferative activity in colorectal and cervix cancer cell line. In vitro studies provided the evidence that compounds 161922, and 28 possess excellent topo IIα inhibition and antiproliferative activity. For a better understanding, topo IIα cleavage complex, EtBr displacement, KI quenching assays and molecular docking of compound 19 was performed and the results revealed the mode of action as a DNA intercalative topo IIα poison inhibitor. The results obtained from this study provide insight into the DNA binding mechanism of 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amines and alteration in topo IIα inhibitory and antiproliferative activity with modifications in the rigid structure.

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