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Antiproliferative Homoleptic and Heteroleptic Phosphino Silver(I) Complexes: Effect of Ligand Combination on Their Biological Mechanism of Action

A series of neutral mixed-ligand [HB(pz)(3)]Ag(PR(3)) silver(I) complexes (PR(3) = tertiary phosphine, [HB(pz)(3)](−) = tris(pyrazolyl)borate anion), and the corresponding homoleptic [Ag(PR(3))(4)]BF(4) compounds have been synthesized and fully characterized. Silver compounds were screened for their...

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Autores principales: Dammak, Khouloud, Porchia, Marina, De Franco, Michele, Zancato, Mirella, Naïli, Houcine, Gandin, Valentina, Marzano, Cristina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700221/
https://www.ncbi.nlm.nih.gov/pubmed/33238608
http://dx.doi.org/10.3390/molecules25225484
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author Dammak, Khouloud
Porchia, Marina
De Franco, Michele
Zancato, Mirella
Naïli, Houcine
Gandin, Valentina
Marzano, Cristina
author_facet Dammak, Khouloud
Porchia, Marina
De Franco, Michele
Zancato, Mirella
Naïli, Houcine
Gandin, Valentina
Marzano, Cristina
author_sort Dammak, Khouloud
collection PubMed
description A series of neutral mixed-ligand [HB(pz)(3)]Ag(PR(3)) silver(I) complexes (PR(3) = tertiary phosphine, [HB(pz)(3)](−) = tris(pyrazolyl)borate anion), and the corresponding homoleptic [Ag(PR(3))(4)]BF(4) compounds have been synthesized and fully characterized. Silver compounds were screened for their antiproliferative activities against a wide panel of human cancer cells derived from solid tumors and endowed with different platinum drug sensitivity. Mixed-ligand complexes were generally more effective than the corresponding homoleptic derivatives, but the most active compounds were [HB(pz)(3)]Ag(PPh(3)) (5) and [Ag(PPh(3))(4)]BF(4) (10), both comprising the lipophilic PPh(3) phosphine ligand. Detailed mechanistic studies revealed that both homoleptic and heteroleptic silver complexes strongly and selectively inhibit the selenoenzyme thioredoxin reductase both as isolated enzyme and in human ovarian cancer cells (half inhibition concentration values in the nanomolar range) causing the disruption of cellular thiol-redox homeostasis, and leading to apoptotic cell death. Moreover, for heteroleptic Ag(I) derivatives, an additional ability to damage nuclear DNA has been detected. These results confirm the importance of the type of silver ion coordinating ligands in affecting the biological behavior of the overall corresponding silver complexes, besides in terms of hydrophilic–lipophilic balance, also in terms of biological mechanism of action, such as interaction with DNA and/or thioredoxin reductase.
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spelling pubmed-77002212020-11-30 Antiproliferative Homoleptic and Heteroleptic Phosphino Silver(I) Complexes: Effect of Ligand Combination on Their Biological Mechanism of Action Dammak, Khouloud Porchia, Marina De Franco, Michele Zancato, Mirella Naïli, Houcine Gandin, Valentina Marzano, Cristina Molecules Article A series of neutral mixed-ligand [HB(pz)(3)]Ag(PR(3)) silver(I) complexes (PR(3) = tertiary phosphine, [HB(pz)(3)](−) = tris(pyrazolyl)borate anion), and the corresponding homoleptic [Ag(PR(3))(4)]BF(4) compounds have been synthesized and fully characterized. Silver compounds were screened for their antiproliferative activities against a wide panel of human cancer cells derived from solid tumors and endowed with different platinum drug sensitivity. Mixed-ligand complexes were generally more effective than the corresponding homoleptic derivatives, but the most active compounds were [HB(pz)(3)]Ag(PPh(3)) (5) and [Ag(PPh(3))(4)]BF(4) (10), both comprising the lipophilic PPh(3) phosphine ligand. Detailed mechanistic studies revealed that both homoleptic and heteroleptic silver complexes strongly and selectively inhibit the selenoenzyme thioredoxin reductase both as isolated enzyme and in human ovarian cancer cells (half inhibition concentration values in the nanomolar range) causing the disruption of cellular thiol-redox homeostasis, and leading to apoptotic cell death. Moreover, for heteroleptic Ag(I) derivatives, an additional ability to damage nuclear DNA has been detected. These results confirm the importance of the type of silver ion coordinating ligands in affecting the biological behavior of the overall corresponding silver complexes, besides in terms of hydrophilic–lipophilic balance, also in terms of biological mechanism of action, such as interaction with DNA and/or thioredoxin reductase. MDPI 2020-11-23 /pmc/articles/PMC7700221/ /pubmed/33238608 http://dx.doi.org/10.3390/molecules25225484 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
Dammak, Khouloud
Porchia, Marina
De Franco, Michele
Zancato, Mirella
Naïli, Houcine
Gandin, Valentina
Marzano, Cristina
Antiproliferative Homoleptic and Heteroleptic Phosphino Silver(I) Complexes: Effect of Ligand Combination on Their Biological Mechanism of Action
title Antiproliferative Homoleptic and Heteroleptic Phosphino Silver(I) Complexes: Effect of Ligand Combination on Their Biological Mechanism of Action
title_full Antiproliferative Homoleptic and Heteroleptic Phosphino Silver(I) Complexes: Effect of Ligand Combination on Their Biological Mechanism of Action
title_fullStr Antiproliferative Homoleptic and Heteroleptic Phosphino Silver(I) Complexes: Effect of Ligand Combination on Their Biological Mechanism of Action
title_full_unstemmed Antiproliferative Homoleptic and Heteroleptic Phosphino Silver(I) Complexes: Effect of Ligand Combination on Their Biological Mechanism of Action
title_short Antiproliferative Homoleptic and Heteroleptic Phosphino Silver(I) Complexes: Effect of Ligand Combination on Their Biological Mechanism of Action
title_sort antiproliferative homoleptic and heteroleptic phosphino silver(i) complexes: effect of ligand combination on their biological mechanism of action
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700221/
https://www.ncbi.nlm.nih.gov/pubmed/33238608
http://dx.doi.org/10.3390/molecules25225484
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