Dihydroxylated 2,4,6-triphenyl pyridines: Synthesis, topoisomerase I and II inhibitory activity, cytotoxicity, and structure–activity relationship study

Twelve dihydroxylated 2,4,6-triphenyl pyridines were designed and synthesized which contain hydroxyl groups at ortho, meta or para position of 2- and 6-phenyl, or 2- and 4-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. Generally, dihydroxylated 2,4,6-triphenyl pyridines exhibited stronger topoisomerase II inhibitory activity, and cytotoxicity compared to those of monohydroxylated 2,4,6-triphenyl pyridines. The concrete structure–activity relationship was observed that dihydroxylated 2,4,6-triphenyl pyridines with hydroxyl group at meta or para position of 2-phenyl ring displayed significant topoisomerase II inhibitory activity as well as cytotoxicity. Positive correlation between topoisomerase II inhibitory activity and cytotoxicity was observed for compounds 10, 12, 13, 17–20 and 22.

Twelve dihydroxylated 2,4,6-triphenyl pyridines were synthesized and evaluated for topo I and II inhibitory activity, and cytotoxicity, which displayed strong topo II inhibition. Concrete SAR was observed for topo II inhibitory activity, and cytotoxicity.Figure optionsDownload as PowerPoint slideHighlights
► Twelve dihydroxylated 2,4,6-triphenyl pyridines were synthesized.
► Prepared compounds were evaluated for topo I and II inhibitory activity, and cytotoxicity.
► Most of the compounds displayed stronger topo II inhibition than etoposide.
► Concrete SAR was observed for topo II inhibitory activity, and cytotoxicity.
► Positive correlation between topo II inhibition and cytotoxicity observed for most compounds.