A new phenolic series of indenopyridinone as topoisomerase inhibitors: Design, synthesis, and structure-activity relationships

DNA Topoisomerase II alpha (topo II alpha) is one of the most effective therapeutic targets to control cancer. In an effort to develop novel and effective topo II alpha targeting anti-proliferative agent, a phenolic series of indenopyridinone and indenopyridinol were designed and prepared using efficient multi-component one pot synthetic method. Total twenty-two synthesized compounds were assessed for topo I and II alpha inhibition, and anti-proliferation in three different human cancer cell lines. Overall structure-activity relationship study explored the significance of meta-phenolic group at 4-position and para-phenolic group at 2- and/or 4-position of indenopyridinone skeleton for strong topo II alpha-selective inhibition and anti-proliferative activity against human cervix (HeLa) and colorectal (HCT15) cell lines. Compound 12 with excellent topo II alpha inhibition (93.7%) was confirmed as a DNA intercalator that could be a new promising lead to develop effective topo II alpha-targeted anticancer agents.