Cargando…
Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling
Hybrid compounds combine fragments with complementary targets to achieve a common pharmacological goal. This approach represents an increasingly popular strategy for drug discovery. In this work, we aimed to design antitumor hybrid compounds based on an inhibitor of ataxia-telangiectasia and Rad3-re...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346169/ https://www.ncbi.nlm.nih.gov/pubmed/32545536 http://dx.doi.org/10.3390/antiox9060519 |
_version_ | 1783556349713448960 |
---|---|
author | Latif, Ahmed Dhahir Jernei, Tamás Podolski-Renić, Ana Kuo, Ching-Ying Vágvölgyi, Máté Girst, Gábor Zupkó, István Develi, Sedef Ulukaya, Engin Wang, Hui-Chun Pešić, Milica Csámpai, Antal Hunyadi, Attila |
author_facet | Latif, Ahmed Dhahir Jernei, Tamás Podolski-Renić, Ana Kuo, Ching-Ying Vágvölgyi, Máté Girst, Gábor Zupkó, István Develi, Sedef Ulukaya, Engin Wang, Hui-Chun Pešić, Milica Csámpai, Antal Hunyadi, Attila |
author_sort | Latif, Ahmed Dhahir |
collection | PubMed |
description | Hybrid compounds combine fragments with complementary targets to achieve a common pharmacological goal. This approach represents an increasingly popular strategy for drug discovery. In this work, we aimed to design antitumor hybrid compounds based on an inhibitor of ataxia-telangiectasia and Rad3-related protein (ATR)-dependent signaling, protoapigenone, and a pro-oxidant ferrocene or chalcone fragment. Four new triazole-coupled hybrids were prepared. The compounds were cytotoxic against human breast cancer cell lines in vitro, showing IC(50) values in the sub-micromolar range. The nature of interactions between relevant fragments of the hybrids was evaluated by the Chou–Talalay method. Experimental combination treatment with the fragments showed additive effects or slight/moderate synergism, while strong synergism was observed when the fragments were virtually combined into their hybrids, suggesting a relevant pharmacological benefit of the coupling. All hybrids were strong inhibitors of the ATR-mediated activation of Chk1, and they interfered with the redox balance of the cells leading to mitochondrial membrane depolarization. Additionally, they induced late apoptosis and primary necrosis in MDA-MB-231 and MCF-7 breast cancer cells, respectively. Our results demonstrate that coupling the ATR-dependent signaling inhibitor protoflavone with a pro-oxidant chalcone dramatically increases the antitumor activity compared with either fragment alone. Such compounds may offer an attractive novel strategy for the treatment of various cancers. |
format | Online Article Text |
id | pubmed-7346169 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-73461692020-07-14 Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling Latif, Ahmed Dhahir Jernei, Tamás Podolski-Renić, Ana Kuo, Ching-Ying Vágvölgyi, Máté Girst, Gábor Zupkó, István Develi, Sedef Ulukaya, Engin Wang, Hui-Chun Pešić, Milica Csámpai, Antal Hunyadi, Attila Antioxidants (Basel) Article Hybrid compounds combine fragments with complementary targets to achieve a common pharmacological goal. This approach represents an increasingly popular strategy for drug discovery. In this work, we aimed to design antitumor hybrid compounds based on an inhibitor of ataxia-telangiectasia and Rad3-related protein (ATR)-dependent signaling, protoapigenone, and a pro-oxidant ferrocene or chalcone fragment. Four new triazole-coupled hybrids were prepared. The compounds were cytotoxic against human breast cancer cell lines in vitro, showing IC(50) values in the sub-micromolar range. The nature of interactions between relevant fragments of the hybrids was evaluated by the Chou–Talalay method. Experimental combination treatment with the fragments showed additive effects or slight/moderate synergism, while strong synergism was observed when the fragments were virtually combined into their hybrids, suggesting a relevant pharmacological benefit of the coupling. All hybrids were strong inhibitors of the ATR-mediated activation of Chk1, and they interfered with the redox balance of the cells leading to mitochondrial membrane depolarization. Additionally, they induced late apoptosis and primary necrosis in MDA-MB-231 and MCF-7 breast cancer cells, respectively. Our results demonstrate that coupling the ATR-dependent signaling inhibitor protoflavone with a pro-oxidant chalcone dramatically increases the antitumor activity compared with either fragment alone. Such compounds may offer an attractive novel strategy for the treatment of various cancers. MDPI 2020-06-12 /pmc/articles/PMC7346169/ /pubmed/32545536 http://dx.doi.org/10.3390/antiox9060519 Text en © 2020 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 Latif, Ahmed Dhahir Jernei, Tamás Podolski-Renić, Ana Kuo, Ching-Ying Vágvölgyi, Máté Girst, Gábor Zupkó, István Develi, Sedef Ulukaya, Engin Wang, Hui-Chun Pešić, Milica Csámpai, Antal Hunyadi, Attila Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling |
title | Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling |
title_full | Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling |
title_fullStr | Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling |
title_full_unstemmed | Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling |
title_short | Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling |
title_sort | protoflavone-chalcone hybrids exhibit enhanced antitumor action through modulating redox balance, depolarizing the mitochondrial membrane, and inhibiting atr-dependent signaling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346169/ https://www.ncbi.nlm.nih.gov/pubmed/32545536 http://dx.doi.org/10.3390/antiox9060519 |
work_keys_str_mv | AT latifahmeddhahir protoflavonechalconehybridsexhibitenhancedantitumoractionthroughmodulatingredoxbalancedepolarizingthemitochondrialmembraneandinhibitingatrdependentsignaling AT jerneitamas protoflavonechalconehybridsexhibitenhancedantitumoractionthroughmodulatingredoxbalancedepolarizingthemitochondrialmembraneandinhibitingatrdependentsignaling AT podolskirenicana protoflavonechalconehybridsexhibitenhancedantitumoractionthroughmodulatingredoxbalancedepolarizingthemitochondrialmembraneandinhibitingatrdependentsignaling AT kuochingying protoflavonechalconehybridsexhibitenhancedantitumoractionthroughmodulatingredoxbalancedepolarizingthemitochondrialmembraneandinhibitingatrdependentsignaling AT vagvolgyimate protoflavonechalconehybridsexhibitenhancedantitumoractionthroughmodulatingredoxbalancedepolarizingthemitochondrialmembraneandinhibitingatrdependentsignaling AT girstgabor protoflavonechalconehybridsexhibitenhancedantitumoractionthroughmodulatingredoxbalancedepolarizingthemitochondrialmembraneandinhibitingatrdependentsignaling AT zupkoistvan protoflavonechalconehybridsexhibitenhancedantitumoractionthroughmodulatingredoxbalancedepolarizingthemitochondrialmembraneandinhibitingatrdependentsignaling AT develisedef protoflavonechalconehybridsexhibitenhancedantitumoractionthroughmodulatingredoxbalancedepolarizingthemitochondrialmembraneandinhibitingatrdependentsignaling AT ulukayaengin protoflavonechalconehybridsexhibitenhancedantitumoractionthroughmodulatingredoxbalancedepolarizingthemitochondrialmembraneandinhibitingatrdependentsignaling AT wanghuichun protoflavonechalconehybridsexhibitenhancedantitumoractionthroughmodulatingredoxbalancedepolarizingthemitochondrialmembraneandinhibitingatrdependentsignaling AT pesicmilica protoflavonechalconehybridsexhibitenhancedantitumoractionthroughmodulatingredoxbalancedepolarizingthemitochondrialmembraneandinhibitingatrdependentsignaling AT csampaiantal protoflavonechalconehybridsexhibitenhancedantitumoractionthroughmodulatingredoxbalancedepolarizingthemitochondrialmembraneandinhibitingatrdependentsignaling AT hunyadiattila protoflavonechalconehybridsexhibitenhancedantitumoractionthroughmodulatingredoxbalancedepolarizingthemitochondrialmembraneandinhibitingatrdependentsignaling |