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Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs

Targeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes in dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes...

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Autores principales: Braun, Sebastian, Jelača, Sanja, Laube, Markus, George, Sven, Hofmann, Bettina, Lönnecke, Peter, Steinhilber, Dieter, Pietzsch, Jens, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Hey-Hawkins, Evamarie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10254233/
https://www.ncbi.nlm.nih.gov/pubmed/37299023
http://dx.doi.org/10.3390/molecules28114547
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author Braun, Sebastian
Jelača, Sanja
Laube, Markus
George, Sven
Hofmann, Bettina
Lönnecke, Peter
Steinhilber, Dieter
Pietzsch, Jens
Mijatović, Sanja
Maksimović-Ivanić, Danijela
Hey-Hawkins, Evamarie
author_facet Braun, Sebastian
Jelača, Sanja
Laube, Markus
George, Sven
Hofmann, Bettina
Lönnecke, Peter
Steinhilber, Dieter
Pietzsch, Jens
Mijatović, Sanja
Maksimović-Ivanić, Danijela
Hey-Hawkins, Evamarie
author_sort Braun, Sebastian
collection PubMed
description Targeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes in dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids is a promising approach. The di-tert-butylphenol derivatives R-830, S-2474, KME-4, and E-5110 represent potent dual COX-2/5-LO inhibitors. The incorporation of p-carborane and further substitution of the p-position resulted in four carborane-based di-tert-butylphenol analogs that showed no or weak COX inhibition but high 5-LO inhibitory activities in vitro. Cell viability studies on five human cancer cell lines revealed that the p-carborane analogs R-830-Cb, S-2474-Cb, KME-4-Cb, and E-5110-Cb exhibited lower anticancer activity compared to the related di-tert-butylphenols. Interestingly, R-830-Cb did not affect the viability of primary cells and suppressed HCT116 cell proliferation more potently than its carbon-based R-830 counterpart. Considering all the advantages of boron cluster incorporation for enhancement of drug biostability, selectivity, and availability of drugs, R-830-Cb can be tested in further mechanistic and in vivo studies.
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spelling pubmed-102542332023-06-10 Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs Braun, Sebastian Jelača, Sanja Laube, Markus George, Sven Hofmann, Bettina Lönnecke, Peter Steinhilber, Dieter Pietzsch, Jens Mijatović, Sanja Maksimović-Ivanić, Danijela Hey-Hawkins, Evamarie Molecules Article Targeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes in dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids is a promising approach. The di-tert-butylphenol derivatives R-830, S-2474, KME-4, and E-5110 represent potent dual COX-2/5-LO inhibitors. The incorporation of p-carborane and further substitution of the p-position resulted in four carborane-based di-tert-butylphenol analogs that showed no or weak COX inhibition but high 5-LO inhibitory activities in vitro. Cell viability studies on five human cancer cell lines revealed that the p-carborane analogs R-830-Cb, S-2474-Cb, KME-4-Cb, and E-5110-Cb exhibited lower anticancer activity compared to the related di-tert-butylphenols. Interestingly, R-830-Cb did not affect the viability of primary cells and suppressed HCT116 cell proliferation more potently than its carbon-based R-830 counterpart. Considering all the advantages of boron cluster incorporation for enhancement of drug biostability, selectivity, and availability of drugs, R-830-Cb can be tested in further mechanistic and in vivo studies. MDPI 2023-06-04 /pmc/articles/PMC10254233/ /pubmed/37299023 http://dx.doi.org/10.3390/molecules28114547 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Braun, Sebastian
Jelača, Sanja
Laube, Markus
George, Sven
Hofmann, Bettina
Lönnecke, Peter
Steinhilber, Dieter
Pietzsch, Jens
Mijatović, Sanja
Maksimović-Ivanić, Danijela
Hey-Hawkins, Evamarie
Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs
title Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs
title_full Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs
title_fullStr Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs
title_full_unstemmed Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs
title_short Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs
title_sort synthesis and in vitro biological evaluation of p-carborane-based di-tert-butylphenol analogs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10254233/
https://www.ncbi.nlm.nih.gov/pubmed/37299023
http://dx.doi.org/10.3390/molecules28114547
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