Synthesis, antitumor activity, and structure–activity relationship study of trihydroxylated 2,4,6-triphenyl pyridines as potent and selective topoisomerase II inhibitors

• Eighteen trihydroxylated 2,4,6-triphenyl pyridines were systematically designed and synthesized as selective topo II inhibitors.
• Evaluated for topo I and II inhibitory activity, and cytotoxicity.
• Most of the compounds exhibited stronger topo II inhibitory activity than that of etoposide and significant cytotoxicity in low micromolar range.
• Positive correlation between topo II inhibitory activity and cytotoxicity was observed for most compounds.
• Molecular docking study shows qualitatively consistent with the results of biological assays.

A series of eighteen trihydroxylated 2,4,6-triphenyl pyridines were designed and synthesized which contain hydroxyl groups at ortho, meta or para position of each phenyl rings attached to the central pyridine. They were evaluated for topoisomerase I and II inhibitory activity, and cytotoxicity against several human cancer cell lines for the development of novel anticancer agents. Most of the compounds exhibited strong and selective topoisomerase II inhibitory activity compared to the positive control, etoposide, and also displayed significant cytotoxicity in low micromolar range. Trihydroxylated 2,4,6-triphenyl pyridines were more potent than mono- and di-hydroxylated 2,4,6-triphenyl pyridines, which have been previously studied in our research group. Positive correlation between topoisomerase II inhibitory activity and cytotoxicity was observed for the most compounds. Molecular docking study shows qualitatively consistent with the results of biological assays.

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