A Dual Topoisomerase Inhibitor of Intense Pro‐Apoptotic and Antileukemic Nature for Cancer Treatment

Abstract

Classic cytotoxic drugs remain indispensable instruments in antitumor therapy due to their effectiveness and a more prevalent insensitivity toward tumor resistance mechanisms. Herein we describe the favorable properties of 6-(N,N-dimethyl-2-aminoethoxy)-11-(3,4,5-trimethoxyphenyl)pyrido[3,4-c][1,9]phenanthroline (P8-D6), a powerful inducer of apoptosis caused by an equipotent inhibition of human topoisomerase I and II activities. A broad-spectrum effect against human tumor cell lines at nanomolar concentrations, as well as strong antileukemic effects, were shown to be superior to those of marketed topoisomerase-targeting drugs and dual topoisomerase inhibitors in clinical trials. The facile four-step synthesis, advantageous drugability properties, and initial in vivo data encourage the application of P8-D6 in appropriate animal tumor models and further drug development.

The Aza-Analogous Benzo[c]phenanthridine P8-D6 Acts as a Dual Topoisomerase I and II Poison, thus Exhibiting Potent Genotoxic Properties

“…Previously, we documented the dual inhibitory potential of P8-D6 against Topo I and II under cell-free conditions, as well as its strong cytotoxic effects on multiple cell lines [5]. However, the mechanism of action was not fully elucidated, leaving open research questions to be addressed.…”

“…The in vivo toxicity study on athymic nude mice indicated reversible toxic effects at a concentration of 5 mg P8-D6 kg −1 body weight [5]. Adverse hepatotoxic effects are currently being investigated in vitro.…”

“…Naturally occurring substances of this drug class, such as fagaronine, have been described to inhibit topoisomerase I and II by stabilizing the covalent DNA-enzyme intermediate [3]. Due to poor yields and toxicological problems, synthesis of azo-analogous benzo[c]phenanthridines was previously optimized into a four step process [4,5]. The synthetic products were improved to enhance physicochemical properties and cytotoxicity.…”

“…In order to predict effects and side effects of drugs, detailed knowledge about their mechanisms of action is of great importance. We recently described P8-D6 to exert strong cytotoxic, pro-apoptotic, and anti-leukemic effects due to its ability to inhibit human topoisomerase (Topo) isoforms I and II, thus acting as a so-called "dual Topo inhibitor" [5].…”

“…We recently demonstrated the high capability of P8-D6 to induce apoptosis and cell death in various cancer cell lines [5]. In the NCI-60 DTP Human Tumor Cell Line screening, the average growth inhibition to 50% (GI 50 ) over all 60 human tumor cell lines was 49 nM, and P8-D6 was thus found to be more active than the natural alkaloids fagaronin and nitidine.…”