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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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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. |
format | Online Article Text |
id | pubmed-6225426 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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