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Synthesis and Cytotoxic Activity Evaluation of New Cu(I) Complexes of Bis(pyrazol-1-yl) Acetate Ligands Functionalized with an NMDA Receptor Antagonist
In the present article, copper(I) complexes of bis(pyrazol-1-yl) carboxylic acid (LH), bis(3,5-dimethylpyrazol-1-yl) carboxylic acid (L(2)H), and bis(pyrazol-1-yl) acetates conjugated with an N-methyl-d-aspartate (NMDA) receptor antagonist (L(NMDA) or L(2NMDA)) and phosphane ligands (triphenylphosph...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178194/ https://www.ncbi.nlm.nih.gov/pubmed/32283777 http://dx.doi.org/10.3390/ijms21072616 |
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author | Pellei, Maura Bagnarelli, Luca Luciani, Lorenzo Del Bello, Fabio Giorgioni, Gianfabio Piergentili, Alessandro Quaglia, Wilma De Franco, Michele Gandin, Valentina Marzano, Cristina Santini, Carlo |
author_facet | Pellei, Maura Bagnarelli, Luca Luciani, Lorenzo Del Bello, Fabio Giorgioni, Gianfabio Piergentili, Alessandro Quaglia, Wilma De Franco, Michele Gandin, Valentina Marzano, Cristina Santini, Carlo |
author_sort | Pellei, Maura |
collection | PubMed |
description | In the present article, copper(I) complexes of bis(pyrazol-1-yl) carboxylic acid (LH), bis(3,5-dimethylpyrazol-1-yl) carboxylic acid (L(2)H), and bis(pyrazol-1-yl) acetates conjugated with an N-methyl-d-aspartate (NMDA) receptor antagonist (L(NMDA) or L(2NMDA)) and phosphane ligands (triphenylphosphine or 1,3,5-triaza-7-phosphaadamantane) were synthesized. The selection of an NMDA antagonist for the coupling with LH and L(2)H was suggested by the observation that NMDA receptors are expressed and play a role in different types of cancer models. All the new complexes showed a significant antitumor activity on a panel of human tumor cell lines of different histology, with cisplatin-sensitive, cisplatin-resistant, or multi-drug-resistant phenotype. Their half maximal inhibitory concentration (IC(50)) values were in the low- and sub-micromolar range and, in general, significantly lower than that of cisplatin. Interestingly, the fact that all the complexes proved to be significantly more active than cisplatin even in three-dimensional (3D) spheroids of H157 and BxPC3 cancer cells increased the relevance of the in vitro results. Finally, morphological analysis revealed that the most representative complex 8 induced a massive swelling of the endoplasmic reticulum (ER) membrane, which is a clear sign of ER stress. |
format | Online Article Text |
id | pubmed-7178194 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-71781942020-04-28 Synthesis and Cytotoxic Activity Evaluation of New Cu(I) Complexes of Bis(pyrazol-1-yl) Acetate Ligands Functionalized with an NMDA Receptor Antagonist Pellei, Maura Bagnarelli, Luca Luciani, Lorenzo Del Bello, Fabio Giorgioni, Gianfabio Piergentili, Alessandro Quaglia, Wilma De Franco, Michele Gandin, Valentina Marzano, Cristina Santini, Carlo Int J Mol Sci Article In the present article, copper(I) complexes of bis(pyrazol-1-yl) carboxylic acid (LH), bis(3,5-dimethylpyrazol-1-yl) carboxylic acid (L(2)H), and bis(pyrazol-1-yl) acetates conjugated with an N-methyl-d-aspartate (NMDA) receptor antagonist (L(NMDA) or L(2NMDA)) and phosphane ligands (triphenylphosphine or 1,3,5-triaza-7-phosphaadamantane) were synthesized. The selection of an NMDA antagonist for the coupling with LH and L(2)H was suggested by the observation that NMDA receptors are expressed and play a role in different types of cancer models. All the new complexes showed a significant antitumor activity on a panel of human tumor cell lines of different histology, with cisplatin-sensitive, cisplatin-resistant, or multi-drug-resistant phenotype. Their half maximal inhibitory concentration (IC(50)) values were in the low- and sub-micromolar range and, in general, significantly lower than that of cisplatin. Interestingly, the fact that all the complexes proved to be significantly more active than cisplatin even in three-dimensional (3D) spheroids of H157 and BxPC3 cancer cells increased the relevance of the in vitro results. Finally, morphological analysis revealed that the most representative complex 8 induced a massive swelling of the endoplasmic reticulum (ER) membrane, which is a clear sign of ER stress. MDPI 2020-04-09 /pmc/articles/PMC7178194/ /pubmed/32283777 http://dx.doi.org/10.3390/ijms21072616 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 Pellei, Maura Bagnarelli, Luca Luciani, Lorenzo Del Bello, Fabio Giorgioni, Gianfabio Piergentili, Alessandro Quaglia, Wilma De Franco, Michele Gandin, Valentina Marzano, Cristina Santini, Carlo Synthesis and Cytotoxic Activity Evaluation of New Cu(I) Complexes of Bis(pyrazol-1-yl) Acetate Ligands Functionalized with an NMDA Receptor Antagonist |
title | Synthesis and Cytotoxic Activity Evaluation of New Cu(I) Complexes of Bis(pyrazol-1-yl) Acetate Ligands Functionalized with an NMDA Receptor Antagonist |
title_full | Synthesis and Cytotoxic Activity Evaluation of New Cu(I) Complexes of Bis(pyrazol-1-yl) Acetate Ligands Functionalized with an NMDA Receptor Antagonist |
title_fullStr | Synthesis and Cytotoxic Activity Evaluation of New Cu(I) Complexes of Bis(pyrazol-1-yl) Acetate Ligands Functionalized with an NMDA Receptor Antagonist |
title_full_unstemmed | Synthesis and Cytotoxic Activity Evaluation of New Cu(I) Complexes of Bis(pyrazol-1-yl) Acetate Ligands Functionalized with an NMDA Receptor Antagonist |
title_short | Synthesis and Cytotoxic Activity Evaluation of New Cu(I) Complexes of Bis(pyrazol-1-yl) Acetate Ligands Functionalized with an NMDA Receptor Antagonist |
title_sort | synthesis and cytotoxic activity evaluation of new cu(i) complexes of bis(pyrazol-1-yl) acetate ligands functionalized with an nmda receptor antagonist |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178194/ https://www.ncbi.nlm.nih.gov/pubmed/32283777 http://dx.doi.org/10.3390/ijms21072616 |
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