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Molecules 2018, 23(9), 2248; https://doi.org/10.3390/molecules23092248

Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships

1
Institute of Chemistry, Eötvös Loránd University (ELTE), Budapest, H-1117 Budapest, Hungary
2
MTA-ELTE Research Group of Peptide Chemistry, Budapest Pázmány P. sétány 1/A, H-1117 Budapest, Hungary
3
Department of Genetics, Cell and Immunobiology, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
*
Author to whom correspondence should be addressed.
Received: 17 August 2018 / Revised: 29 August 2018 / Accepted: 30 August 2018 / Published: 3 September 2018
(This article belongs to the Special Issue Ferrocene and Ferrocene-Containing Compounds)
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Abstract

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. View Full-Text
Keywords: ferrocene; organic synthesis; NMR spectroscopy; DFT calculations; bioorganometallic chemistry; cytotoxic activity; structure–activity relationships ferrocene; organic synthesis; NMR spectroscopy; DFT calculations; bioorganometallic chemistry; cytotoxic activity; structure–activity relationships
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Bárány, P.; Oláh, R.S.; Kovács, I.; Czuczi, T.; Szabó, C.L.; Takács, A.; Lajkó, E.; Láng, O.; Kőhidai, L.; Schlosser, G.; Bősze, S.; Mező, G.; Hudecz, F.; Csámpai, A. Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships. Molecules 2018, 23, 2248.

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