Piperazinyl fragment improves anticancer activity of Triapine

Abstract

A new class of TSCs containing piperazine (piperazinylogs) of Triapine, was designed to fulfill the di-substitution pattern at the TSCs N4 position, which is a crucial prerequisite for the high activity of the previously obtained TSC compounds±DpC and Dp44mT. We tested the important physicochemical characteristics of the novel compounds L1-L12. The studied ligands are neutral at physiological pH, which allows them to permeate cell membranes and bind cellular Fe pools more readily than less lipid-soluble ligands, e.g. DFO. The selectivity and anti-cancer activity of the novel TSCs were examined in a variety of cancer cell types. In general, the novel compounds demonstrated the greatest promise as anti-cancer agents with both a potent and selective anti-proliferative activity. We investigated the mechanism of action more deeply, and revealed that studied compounds inhibit the cell cycle (G1/S phase). Additionally we detected apoptosis, which is dependent on cell line's specific genetic profile. Accordingly, structure-activity relationship studies suggest that the combination of the piperazine ring with Triapine allows potent and selective anticancer chelators that warrant further in vivo examination to be identified. Significantly, this study proved the importance of the di-substitution pattern of the amine N4 function.