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

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...

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Autores principales: Bárány, Péter, Oláh, Rita Szabó, Kovács, Imre, Czuczi, Tamás, Szabó, Csenge Lilla, Takács, Angéla, Lajkó, Eszter, Láng, Orsolya, Kőhidai, László, Schlosser, Gitta, Bősze, Szilvia, Mező, Gábor, Hudecz, Ferenc, Csámpai, Antal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225426/
https://www.ncbi.nlm.nih.gov/pubmed/30177664
http://dx.doi.org/10.3390/molecules23092248
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author Bárány, Péter
Oláh, Rita Szabó
Kovács, Imre
Czuczi, Tamás
Szabó, Csenge Lilla
Takács, Angéla
Lajkó, Eszter
Láng, Orsolya
Kőhidai, László
Schlosser, Gitta
Bősze, Szilvia
Mező, Gábor
Hudecz, Ferenc
Csámpai, Antal
author_facet Bárány, Péter
Oláh, Rita Szabó
Kovács, Imre
Czuczi, Tamás
Szabó, Csenge Lilla
Takács, Angéla
Lajkó, Eszter
Láng, Orsolya
Kőhidai, László
Schlosser, Gitta
Bősze, Szilvia
Mező, Gábor
Hudecz, Ferenc
Csámpai, Antal
author_sort Bárány, Péter
collection PubMed
description 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.
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spelling pubmed-62254262018-11-13 Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships Bárány, Péter Oláh, Rita Szabó Kovács, Imre Czuczi, Tamás Szabó, Csenge Lilla Takács, Angéla Lajkó, Eszter Láng, Orsolya Kőhidai, László Schlosser, Gitta Bősze, Szilvia Mező, Gábor Hudecz, Ferenc Csámpai, Antal Molecules Article 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. MDPI 2018-09-03 /pmc/articles/PMC6225426/ /pubmed/30177664 http://dx.doi.org/10.3390/molecules23092248 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bárány, Péter
Oláh, Rita Szabó
Kovács, Imre
Czuczi, Tamás
Szabó, Csenge Lilla
Takács, Angéla
Lajkó, Eszter
Láng, Orsolya
Kőhidai, László
Schlosser, Gitta
Bősze, Szilvia
Mező, Gábor
Hudecz, Ferenc
Csámpai, Antal
Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships
title Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships
title_full Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships
title_fullStr Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships
title_full_unstemmed Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships
title_short Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships
title_sort ferrocene-containing impiridone (onc201) hybrids: synthesis, dft modelling, in vitro evaluation, and structure–activity relationships
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225426/
https://www.ncbi.nlm.nih.gov/pubmed/30177664
http://dx.doi.org/10.3390/molecules23092248
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