Synthesis, Biological Evaluation, and Theoretical Study of Indenoquinolinylphosphine Oxide Derivatives as Topoisomerase 1 Inhibitors and Antiproliferative Agents

Abstract

The topoisomerase 1 (TOP1) enzymatic inhibition and antiproliferative activity of phosphorated indenoquinoline derivatives were investigated. First, the preparation of new hybrid quinoline and tetrahydroquinoline structures with a phosphine oxide group was performed by a two-step Povarov type [4 + 2]-cycloaddition reaction between the corresponding phosphorated aldimines with indene in the presence of BF₃·Et₂O, affording corresponding 1,2,3,4-tetrahydroindeno[2,1-c]quinolinylphosphine oxides 9, 7H-indeno[2,1-c]quinolinylphosphine oxides 10 and 7-oxoindeno[2,1-c]quinolinylphosphine oxides 11 with good yields. The synthesized derivatives were evaluated as TOP1 inhibitors, showing that some derivatives (9f, 9g, 9l, and 11m) show better or similar activity to the reference compound (CPT) at 1 min. The synthesized derivatives were screened for their antiproliferative activity in different cancerous cell lines, and all of them present a higher selective cytotoxicity in the human lung adenocarcinoma cell line (A549), than in the others. In contrast, almost none of the synthesized phosphorated compounds exhibited antiproliferative activity toward nonmalignant lung fibroblasts MCR5. These results suggest that phosphine oxide-substituted quinoline derivatives have important properties as TOP1 inhibitors and show an interesting cytotoxicity against six different cancerous cell lines.