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Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors

Choline kinase inhibitors are an outstanding class of cytotoxic compounds useful for the treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic cells. Here, we present the most in-depth structure-activity relationship studies of an interesting series of n...

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Autores principales: Schiaffino-Ortega, Santiago, Mariotto, Elena, Luque-Navarro, Pilar María, Kimatrai-Salvador, María, Rios-Marco, Pablo, Hurtado-Guerrero, Ramon, Marco, Carmen, Carrasco-Jimenez, María Paz, Viola, Giampietro, López-Cara, Luisa Carlota
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464809/
https://www.ncbi.nlm.nih.gov/pubmed/34575436
http://dx.doi.org/10.3390/pharmaceutics13091360
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author Schiaffino-Ortega, Santiago
Mariotto, Elena
Luque-Navarro, Pilar María
Kimatrai-Salvador, María
Rios-Marco, Pablo
Hurtado-Guerrero, Ramon
Marco, Carmen
Carrasco-Jimenez, María Paz
Viola, Giampietro
López-Cara, Luisa Carlota
author_facet Schiaffino-Ortega, Santiago
Mariotto, Elena
Luque-Navarro, Pilar María
Kimatrai-Salvador, María
Rios-Marco, Pablo
Hurtado-Guerrero, Ramon
Marco, Carmen
Carrasco-Jimenez, María Paz
Viola, Giampietro
López-Cara, Luisa Carlota
author_sort Schiaffino-Ortega, Santiago
collection PubMed
description Choline kinase inhibitors are an outstanding class of cytotoxic compounds useful for the treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic cells. Here, we present the most in-depth structure-activity relationship studies of an interesting series of non-symmetric choline kinase inhibitors previously reported by our group: 3a–h and 4a–h. They are characterized by cationic heads of 3-aminophenol bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium through several linkers. These derivatives were evaluated both for their inhibitory activity on the enzyme and their antiproliferative activity in a panel of six human tumor cell lines. The compounds with the N-atom connected to the linker (4a–h) show the best inhibitory results, in the manner of results supported by docking studies. On the contrary, the best antiproliferative compounds were those with the O-atom bounded to the linker (3a–h). On the other hand, as was predictable in both families, the inhibitory effect on the enzyme is better the shorter the length of the linker. However, in tumor cells, lipophilicity and choline uptake inhibition could play a decisive role. Interestingly, compounds 3c and 4f, selected for both their ability to inhibit the enzyme and good antiproliferative activity, are endowed with low toxicity in non-tumoral cells (e.g., human peripheral lymphocytes) concerning cancer cells. These compounds were also able to induce apoptosis in Jurkat leukemic cells without causing significant variations of the cell cycle. It is worth mentioning that these derivatives, besides their inhibitory effect on choline kinase, displayed a modest ability to inhibit choline uptake thus suggesting that this mechanism may also contribute to the observed cytotoxicity.
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spelling pubmed-84648092021-09-27 Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors Schiaffino-Ortega, Santiago Mariotto, Elena Luque-Navarro, Pilar María Kimatrai-Salvador, María Rios-Marco, Pablo Hurtado-Guerrero, Ramon Marco, Carmen Carrasco-Jimenez, María Paz Viola, Giampietro López-Cara, Luisa Carlota Pharmaceutics Article Choline kinase inhibitors are an outstanding class of cytotoxic compounds useful for the treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic cells. Here, we present the most in-depth structure-activity relationship studies of an interesting series of non-symmetric choline kinase inhibitors previously reported by our group: 3a–h and 4a–h. They are characterized by cationic heads of 3-aminophenol bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium through several linkers. These derivatives were evaluated both for their inhibitory activity on the enzyme and their antiproliferative activity in a panel of six human tumor cell lines. The compounds with the N-atom connected to the linker (4a–h) show the best inhibitory results, in the manner of results supported by docking studies. On the contrary, the best antiproliferative compounds were those with the O-atom bounded to the linker (3a–h). On the other hand, as was predictable in both families, the inhibitory effect on the enzyme is better the shorter the length of the linker. However, in tumor cells, lipophilicity and choline uptake inhibition could play a decisive role. Interestingly, compounds 3c and 4f, selected for both their ability to inhibit the enzyme and good antiproliferative activity, are endowed with low toxicity in non-tumoral cells (e.g., human peripheral lymphocytes) concerning cancer cells. These compounds were also able to induce apoptosis in Jurkat leukemic cells without causing significant variations of the cell cycle. It is worth mentioning that these derivatives, besides their inhibitory effect on choline kinase, displayed a modest ability to inhibit choline uptake thus suggesting that this mechanism may also contribute to the observed cytotoxicity. MDPI 2021-08-29 /pmc/articles/PMC8464809/ /pubmed/34575436 http://dx.doi.org/10.3390/pharmaceutics13091360 Text en © 2021 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
Schiaffino-Ortega, Santiago
Mariotto, Elena
Luque-Navarro, Pilar María
Kimatrai-Salvador, María
Rios-Marco, Pablo
Hurtado-Guerrero, Ramon
Marco, Carmen
Carrasco-Jimenez, María Paz
Viola, Giampietro
López-Cara, Luisa Carlota
Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors
title Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors
title_full Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors
title_fullStr Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors
title_full_unstemmed Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors
title_short Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors
title_sort anticancer and structure activity relationship of non-symmetrical choline kinase inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464809/
https://www.ncbi.nlm.nih.gov/pubmed/34575436
http://dx.doi.org/10.3390/pharmaceutics13091360
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