Inspired by the well-established clinical evidence about the interplay between apoptotic
TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) mechanism and reactive
oxygen species (ROS)-mediated oxidative stress, a set of novel ONC201 hybrids containing
the impiridone core and one or two differently positioned ferrocenylalkyl groups were
synthesised in our present work. These two types of residues have been implicated
in the aforementioned mechanisms associated with cytotoxic activity. A straightforward,
primary amine-based synthetic approach was used allowing the introduction of a variety
of N-substituents into the two opposite regions of the heterocyclic skeleton. Reference
model compounds with benzyl and halogenated benzyl groups were also synthesised and
tested. The in vitro assays of the novel impiridones on five malignant cell lines
disclosed characteristic structure-activity relationship (SAR) featuring significant
substituent-dependent activity and cell-selectivity. A possible contribution of ROS-mechanism
to the cytotoxicity of the novel metallocenes was suggested by density functional
theory (DFT) studies on simplified models. Accordingly, unlike the mono-ferrocenylalkyl-substituted
products, the compounds containing two ferrocenylalkyl substituents in the opposite
regions of the impiridone core display a much more pronounced long-term cytotoxic
effect against A-2058 cell line than do the organic impiridones including ONC201 and
ONC212. Furthermore, the prepared bis-metallocene derivatives also present substantial
activity against COLO-205-and EBC-1 cell lines.
