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Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors

Due to its role in lipid biosynthesis, choline kinase α1 (CKα1) is an interesting target for the development of new antitumor agents. In this work, we present a series of 41 compounds designed based on the well-known and successful strategy of introducing thienopyridine and pyrimidine as bioisostere...

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Autores principales: Luque-Navarro, Pilar María, Mariotto, Elena, Ballarotto, Marco, Rubbini, Gianluca, Aguilar-Troyano, Francisco José, Fasiolo, Alberto, Torretta, Archimede, Parisini, Emilio, Macchiarulo, Antonio, Laso, Alejandro, Marco, Carmen, Viola, Giampietro, Carrasco-Jimenez, María Paz, López-Cara, Luisa Carlota
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9032693/
https://www.ncbi.nlm.nih.gov/pubmed/35456549
http://dx.doi.org/10.3390/pharmaceutics14040715
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author Luque-Navarro, Pilar María
Mariotto, Elena
Ballarotto, Marco
Rubbini, Gianluca
Aguilar-Troyano, Francisco José
Fasiolo, Alberto
Torretta, Archimede
Parisini, Emilio
Macchiarulo, Antonio
Laso, Alejandro
Marco, Carmen
Viola, Giampietro
Carrasco-Jimenez, María Paz
López-Cara, Luisa Carlota
author_facet Luque-Navarro, Pilar María
Mariotto, Elena
Ballarotto, Marco
Rubbini, Gianluca
Aguilar-Troyano, Francisco José
Fasiolo, Alberto
Torretta, Archimede
Parisini, Emilio
Macchiarulo, Antonio
Laso, Alejandro
Marco, Carmen
Viola, Giampietro
Carrasco-Jimenez, María Paz
López-Cara, Luisa Carlota
author_sort Luque-Navarro, Pilar María
collection PubMed
description Due to its role in lipid biosynthesis, choline kinase α1 (CKα1) is an interesting target for the development of new antitumor agents. In this work, we present a series of 41 compounds designed based on the well-known and successful strategy of introducing thienopyridine and pyrimidine as bioisosteres of other heterocycles in active antitumor compounds. Notwithstanding the fact that some of these compounds do not show significant enzymatic inhibition, others, in contrast, feature substantially improved enzymatic and antiproliferative inhibition values. This is also confirmed by docking analysis, whereby compounds with longer linkers and thienopyrimidine cationic head have been identified as the most compelling. Among the best compounds is Ff-35, which inhibits the growth of different tumor cells at submicromolar concentrations. Moreover, Ff-35 is more potent in inhibiting CKα1 than other previous biscationic derivatives. Treatment of A549, Hela, and MDA-MB-231 cells with Ff-35 results in their arrest at the G1 phase of the cell cycle. Furthermore, the compound induces cellular apoptosis in a concentration-dependent manner. Altogether, these findings indicate that Ff-35 is a promising new chemotherapeutic agent with encouraging preclinical potential.
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spelling pubmed-90326932022-04-23 Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors Luque-Navarro, Pilar María Mariotto, Elena Ballarotto, Marco Rubbini, Gianluca Aguilar-Troyano, Francisco José Fasiolo, Alberto Torretta, Archimede Parisini, Emilio Macchiarulo, Antonio Laso, Alejandro Marco, Carmen Viola, Giampietro Carrasco-Jimenez, María Paz López-Cara, Luisa Carlota Pharmaceutics Article Due to its role in lipid biosynthesis, choline kinase α1 (CKα1) is an interesting target for the development of new antitumor agents. In this work, we present a series of 41 compounds designed based on the well-known and successful strategy of introducing thienopyridine and pyrimidine as bioisosteres of other heterocycles in active antitumor compounds. Notwithstanding the fact that some of these compounds do not show significant enzymatic inhibition, others, in contrast, feature substantially improved enzymatic and antiproliferative inhibition values. This is also confirmed by docking analysis, whereby compounds with longer linkers and thienopyrimidine cationic head have been identified as the most compelling. Among the best compounds is Ff-35, which inhibits the growth of different tumor cells at submicromolar concentrations. Moreover, Ff-35 is more potent in inhibiting CKα1 than other previous biscationic derivatives. Treatment of A549, Hela, and MDA-MB-231 cells with Ff-35 results in their arrest at the G1 phase of the cell cycle. Furthermore, the compound induces cellular apoptosis in a concentration-dependent manner. Altogether, these findings indicate that Ff-35 is a promising new chemotherapeutic agent with encouraging preclinical potential. MDPI 2022-03-27 /pmc/articles/PMC9032693/ /pubmed/35456549 http://dx.doi.org/10.3390/pharmaceutics14040715 Text en © 2022 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
Luque-Navarro, Pilar María
Mariotto, Elena
Ballarotto, Marco
Rubbini, Gianluca
Aguilar-Troyano, Francisco José
Fasiolo, Alberto
Torretta, Archimede
Parisini, Emilio
Macchiarulo, Antonio
Laso, Alejandro
Marco, Carmen
Viola, Giampietro
Carrasco-Jimenez, María Paz
López-Cara, Luisa Carlota
Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors
title Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors
title_full Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors
title_fullStr Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors
title_full_unstemmed Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors
title_short Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors
title_sort biological evaluation of new thienopyridinium and thienopyrimidinium derivatives as human choline kinase inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9032693/
https://www.ncbi.nlm.nih.gov/pubmed/35456549
http://dx.doi.org/10.3390/pharmaceutics14040715
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