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

Abstract

Abstract. 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 (CC 50 ) 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 CC 50 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.

Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones

“…Previously, we reported the development of several new cancer drugs and screening methods [29, 30]. We found, among others, that compounds containing the piperidone structure are highly cytotoxic, and that the P2 piperidone compound exhibits a potent anti-neoplastic activity against breast cancer cells [30, 31].…”

A Computational Study of Structure and Reactivity of N-Substitued-4-Piperidones Curcumin Analogues and Their Radical Anions

“…Additionally, this feature has been also associated to the generation of reactive oxygen species (ROS), which are involved in several mechanisms of cellular apoptosis [11,12]. Among other possibilities, Among these compounds, those whose central linker is a 4-piperidone scaffold have shown a high potential as anti-inflammatory and anticancer agents [13,15]. These kinds of compounds have a preferential affinity for thiols, in contrast to amino or hydroxyl groups [16].…”

“…In particular, the effect of aromatic ring substituents on the geometrical and molecular orbital properties, as well as their capability to attach an extra electron, are investigated. Among these compounds, those whose central linker is a 4-piperidone scaffold have shown a high potential as anti-inflammatory and anticancer agents [13,15]. These kinds of compounds have a preferential affinity for thiols, in contrast to amino or hydroxyl groups [16].…”

“…Apparently, the central heterocyclic ring fits a primary binding site, being this interaction influenced by the nature of the substituents at the nitrogen atom [17]. The presence of 4-piperidone alkylated at the nitrogen atom, along with phenyl rings bearing a great variety of substituents, constitutes the key features of a series of monocarbonyl analogues of curcumin, whose anti-inflammatory and anti-cancer activities have been recently reported [14,15]. Moreover, dimers linked by the nitrogen atoms, have also shown potent cytotoxicity against cancer cells [18].…”

“…β-diketone moiety by a carbonyl group conjugated by the two sides ( Figure 1) has emerged as a new promising alternative [13,14]. Among these compounds, those whose central linker is a 4-piperidone scaffold have shown a high potential as anti-inflammatory and anticancer agents [13,15]. These kinds of compounds have a preferential affinity for thiols, in contrast to amino or hydroxyl groups [16].…”