Several anticancer agents have been developed and innovative approaches are still ongoing toward cancer type-specific medicines for chemotherapy. 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 using the one-pot microwave synthesis method. The compounds were evaluated for topo their topo IIa inhibitory and cytotoxicity against HCT15, and HeLa human cancer cell lines. Among synthesized thirty compounds, the majority exhibited strong topo IIa inhibition and anti-proliferation against the 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 IIa and antiproliferative activity in colorectal and cervix cancer cell line. In vitro studies provided evidence that compounds 16, 19, 22, and 28 possess excellent topo IIa inhibition and antiproliferative activity. For a better understanding, topo IIa cleavage complex, EtBr displacement, KI quenching assays, and molecular docking of compound 19 were performed and the results revealed the mode of action as a DNA intercalative topo IIa 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 IIa inhibitory and antiproliferative activity with modifications in the rigid structure.

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

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.