Targeting topoisomerase II with trypthantrin derivatives: Discovery of 7-((2-(dimethylamino)ethyl)amino)indolo[2,1-b]quinazoline-6,12-dione as an antiproliferative agent and to treat cancer

Drugs targeting human topoisomerase II (topoll) are used in clinical practice since decades. Nevertheless, there is an urgent need for new and safer topoll inhibitors due to the emergence of secondary malignancies and the appearance of resistance mechanisms upon treatment with topoll-targeted anticancer drugs. In the present investigation, we report the discovery of a new topoll inhibitor, whose design was based on the structure of the natural product trypthantrin, a natural alkaloid containing a basic indoloquinazoline moiety. This new topoll inhibitor, here numbered compound 5, is found to inhibit topoll with an IC50 of 26.6 +/- 4.7 mu M. Notably, compound 5 is more potent than the template compound trypthantrin, and even than the widely used topoll-targeted clinical drug etoposide. In addition, compound 5 also exhibits high water solubility, and a promising antiproliferative activity on different tumor cell lines such as acute leukemia, colon, and breast cancer. In light of these results, compound 5 represents a promising lead for developing new topoll inhibitors as anti-cancer therapeutic agents. (C) 2020 Elsevier Masson SAS. All rights reserved.