A novel class of piperidones exhibit potent, selective and pro-apoptotic anti-leukemia properties

In the present pre-clinical study, a series of 1-[3-(2-methoxyethylthio)-propionyl]-3,5- bis(benzylidene)-4 piperidones and structurally-related compounds were observed to be cytotoxic in vitro to three human leukemia cell lines, namely Nalm-6, CEM and Jurkat. The 50% cytotoxic concentration (CC₅₀) values of the three cell lines ranged between 0.9-126.4 µM and 0.3-11.7 µM at 24 and 48 h subsequent to exposure, respectively. The two lead compounds with sub-micromolar CC₅₀ concentrations, 1-(2-methoxyethylthio-propionyl)-3,5-bis(benzylidene)-4 piperidone (2a) and 3,5-bis(4-fluorobenzylidene)-1-[3-(2-methoxyethyl sulfinyl)-propionyl]-4-piperidone (3e), were selected for additional analyses. Several strategies were undertaken to determine whether the above piperidones caused cell death via apoptosis or necrosis on T-lymphocyte leukemia Jurkat cells. The results revealed that the two piperidones caused phosphatidylserine externalization, mitochondrial depolarization and activation of caspase-3, which are all biochemical hallmarks of apoptosis. In addition, the selected piperidones displayed selective cytotoxicity towards leukemia cells, and were less toxic in non-cancerous control cells. Therefore, the findings of the present study revealed that the novel piperidones 2a and 3e exert a selective cytotoxic effect on lymphocyte leukemia cells by favoring the activation of the intrinsic/mitochondrial apoptotic pathway.