Synthesis, topoisomerase I and II inhibitory activity, cytotoxicity, and structure–activity relationship study of 2-phenyl- or hydroxylated 2-phenyl-4-aryl-5H-indeno[1,2-b]pyridines

Novel twenty-eight 2-phenyl- or hydroxylated 2-phenyl-4-aryl-5H-indeno[1,2-b]pyridines were designed, synthesized, and evaluated for topo I and II inhibitory activity, and cytotoxicity. [Display omitted] A series of novel twenty-eight rigid 2-phenyl- or hydroxylated 2-phenyl-4-aryl-5H-indeno[1,2-b]pyridines were synthesized and evaluated for their topoisomerase inhibitory activity as well as their cytotoxicity against several human cancer cell lines. Generally, hydroxylated compounds (16–18, 22–25, and 29–31) containing furyl or thienyl moiety at 4-position of central pyridine exhibited strong topoisomerase I and II inhibitory activity compared to positive control, camptothecin and etoposide, respectively, in low micromolar range. Structure–activity relationship study revealed that indenopyridine compounds with hydroxyl group at 2-phenyl ring in combination with furyl or thienyl moiety at 4-position are important for topoisomerase inhibition. Compounds (22–25) which contain hydroxyl group at meta position of the 2-phenyl ring at 2-position and furanyl or thienyl substitution at 4-position of indenopyridine, showed concrete correlations between topo I and II inhibitory activity, and cytotoxicity against evaluated human cancer cell lines.