Hydroxylated 2,4-diphenyl indenopyridine derivatives as a selective non-intercalative topoisomerase IIα catalytic inhibitor

• 2,4-Diphenyl indenopyridines were prepared for topo I and II inhibition, and antiproliferative activity.
• Most indenopyridines showed selective and strong topo IIα inhibition as well as antiproliferative activity.
• Positive correlation between topo IIα inhibition and antiproliferative activity was observed.
• Increased number of hydroxyl moiety is important for selectivity of topo IIα inhibition.
• Compound 16 was a non-intercalative topo IIα catalytic inhibitor.

For the development of novel anticancer agents, we designed and synthesized hydroxylated 2,4-diphenyl indenopyridines, and evaluated their topoisomerase inhibitory activity as well as their antiproliferative activities against several human cancer cell lines. The structure–activity relationship study showed that indenopyridines with hydroxyl group at meta or para positions of 2- or 4-phenyl ring displayed selective and significant topoisomerase IIα (topo IIα) inhibitory activity and potent antiproliferative activity. Positive correlation between topo IIα inhibition and antiproliferative activity was observed for compounds 15, 16, 18–20, 22, 23, 25 and 26. The mode of action of compound 16 was further evaluated to be a non-intercalative topo IIα catalytic inhibitor.

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