Novel topoisomerase I inhibitors. Syntheses and biological evaluation of phosphorus substituted quinoline derivates with antiproliferative activity

Abstract

This work describes the synthesis of 1,2,3,4-tetrahydroquinolinylphosphine oxides, phosphanes and phosphine sulfides as well as that of quinolinylphosphine oxides and phosphine sulfides, which were synthesized in good to high overall yield. The synthetic route involves a multicomponent reaction of (2-phosphine-oxide)-, 2-phosphine- or (2-phosphine-sulfide)-aniline, aldehydes and olefins and allows the selective generation of two stereogenic centres in a short, efficient and reliable synthesis. The selective dehydrogenation of 1,2,3,4-tetrahydroquinolinylphosphine oxides and phosphine sulfides leads to the formation of corresponding phosphorus substituted quinolines. Some of the products which were prepared showed excellent activity as topoisomerase I (Top1) inhibitors. In addition, prolonged effect of the most potent compounds is maintained with the same intensity even after 3 min of the beginning of the enzymatic reaction. The cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549), human ovarian carcinoma (SKOV03) and human embryonic kidney (HEK293) was also screened. 1,2,3,4-Tetrahydroquinolinylphosphine oxide 6g with an IC50 value of 0.25 ± 0.03 μM showed excellent activity against the A549 cell line in vitro, while 1,2,3,4-tetrahydroquinolinylphosphane 9c with an IC50 value of 0.08 ± 0.01 μM and 1,2,3,4-tetrahydroquinolinylphosphine sulfide derivative 10f with an IC50 value of 0.03 ± 0.04 μM are more active against the A549 cell line. Moreover, selectivity towards cancer cell (A549) over non-malignant cells (MRC5) has been observed. According to their structure, they may be excellent antiproliferative candidates.