Cargando…
First-Row Transition Metal Complexes Incorporating the 2-(2′-pyridyl)quinoxaline Ligand (pqx), as Potent Inflammatory Mediators: Cytotoxic Properties and Biological Activities against the Platelet-Activating Factor (PAF) and Thrombin
Inflammatory mediators constitute a recently coined term in the field of metal-based complexes with antiplatelet activities. Our strategy targets Platelet-Activating Factor (PAF) and its receptor, which is the most potent lipid mediator of inflammation. Thus, the antiplatelet (anti-PAF) potency of a...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10574351/ https://www.ncbi.nlm.nih.gov/pubmed/37836742 http://dx.doi.org/10.3390/molecules28196899 |
_version_ | 1785120674153496576 |
---|---|
author | Margariti, Antigoni Papakonstantinou, Vasiliki D. Stamatakis, George M. Demopoulos, Constantinos A. Machalia, Christina Emmanouilidou, Evangelia Schnakenburg, Gregor Nika, Maria-Christina Thomaidis, Nikolaos S. Philippopoulos, Athanassios I. |
author_facet | Margariti, Antigoni Papakonstantinou, Vasiliki D. Stamatakis, George M. Demopoulos, Constantinos A. Machalia, Christina Emmanouilidou, Evangelia Schnakenburg, Gregor Nika, Maria-Christina Thomaidis, Nikolaos S. Philippopoulos, Athanassios I. |
author_sort | Margariti, Antigoni |
collection | PubMed |
description | Inflammatory mediators constitute a recently coined term in the field of metal-based complexes with antiplatelet activities. Our strategy targets Platelet-Activating Factor (PAF) and its receptor, which is the most potent lipid mediator of inflammation. Thus, the antiplatelet (anti-PAF) potency of any substance could be exerted by inhibiting the PAF-induced aggregation in washed rabbit platelets (WRPs), which internationally is a well-accepted methodology. Herein, a series of mononuclear (mer-[Cr(pqx)Cl(3)(H(2)O]) (1), [Co(pqx)Cl(2)(DMF)] (2) (DMF = N,N′-dimethyl formamide), [Cu(pqx)Cl(2)(DMSO)] (3) (DMSO = dimethyl sulfoxide), [Zn(pqx)Cl(2)] (4)) and dinuclear complexes ([Mn(pqx)(H(2)O)(2)Cl(2)](2) (5), [Fe(pqx)Cl(2)](2) (6) and [Ni(pqx)Cl(2)](2) (7)) incorporating the 2-(2′-pyridyl)quinoxaline ligand (pqx), were biologically evaluated as inhibitors of the PAF- and thrombin-induced aggregation in washed rabbit platelets (WRPs). The molecular structure of the five-co-ordinate analog (3) has been elucidated by single-crystal X-ray diffraction revealing a trigonal bipyramidal geometry. All complexes are potent inhibitors of the PAF-induced aggregation in WRPs in the micromolar range. Complex (6) displayed a remarkable in vitro dual inhibition against PAF and thrombin, with IC(50) values of 1.79 μM and 0.46 μM, respectively. Within the series, complex (5) was less effective (IC(50) = 39 μM) while complex (1) was almost 12-fold more potent against PAF, as opposed to thrombin-induced aggregation. The biological behavior of complexes 1, 6 and 7 on PAF’s basic metabolic enzymatic pathways reveals that they affect key biosynthetic and catabolic enzymes of PAF underlying the anti-inflammatory properties of the relevant complexes. The in vitro cytotoxic activities of all complexes in HEK293T (human embryonic kidney cells) and HeLa cells (cervical cancer cells) are described via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The results reveal that complex 3 is the most potent within the series. |
format | Online Article Text |
id | pubmed-10574351 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-105743512023-10-14 First-Row Transition Metal Complexes Incorporating the 2-(2′-pyridyl)quinoxaline Ligand (pqx), as Potent Inflammatory Mediators: Cytotoxic Properties and Biological Activities against the Platelet-Activating Factor (PAF) and Thrombin Margariti, Antigoni Papakonstantinou, Vasiliki D. Stamatakis, George M. Demopoulos, Constantinos A. Machalia, Christina Emmanouilidou, Evangelia Schnakenburg, Gregor Nika, Maria-Christina Thomaidis, Nikolaos S. Philippopoulos, Athanassios I. Molecules Article Inflammatory mediators constitute a recently coined term in the field of metal-based complexes with antiplatelet activities. Our strategy targets Platelet-Activating Factor (PAF) and its receptor, which is the most potent lipid mediator of inflammation. Thus, the antiplatelet (anti-PAF) potency of any substance could be exerted by inhibiting the PAF-induced aggregation in washed rabbit platelets (WRPs), which internationally is a well-accepted methodology. Herein, a series of mononuclear (mer-[Cr(pqx)Cl(3)(H(2)O]) (1), [Co(pqx)Cl(2)(DMF)] (2) (DMF = N,N′-dimethyl formamide), [Cu(pqx)Cl(2)(DMSO)] (3) (DMSO = dimethyl sulfoxide), [Zn(pqx)Cl(2)] (4)) and dinuclear complexes ([Mn(pqx)(H(2)O)(2)Cl(2)](2) (5), [Fe(pqx)Cl(2)](2) (6) and [Ni(pqx)Cl(2)](2) (7)) incorporating the 2-(2′-pyridyl)quinoxaline ligand (pqx), were biologically evaluated as inhibitors of the PAF- and thrombin-induced aggregation in washed rabbit platelets (WRPs). The molecular structure of the five-co-ordinate analog (3) has been elucidated by single-crystal X-ray diffraction revealing a trigonal bipyramidal geometry. All complexes are potent inhibitors of the PAF-induced aggregation in WRPs in the micromolar range. Complex (6) displayed a remarkable in vitro dual inhibition against PAF and thrombin, with IC(50) values of 1.79 μM and 0.46 μM, respectively. Within the series, complex (5) was less effective (IC(50) = 39 μM) while complex (1) was almost 12-fold more potent against PAF, as opposed to thrombin-induced aggregation. The biological behavior of complexes 1, 6 and 7 on PAF’s basic metabolic enzymatic pathways reveals that they affect key biosynthetic and catabolic enzymes of PAF underlying the anti-inflammatory properties of the relevant complexes. The in vitro cytotoxic activities of all complexes in HEK293T (human embryonic kidney cells) and HeLa cells (cervical cancer cells) are described via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The results reveal that complex 3 is the most potent within the series. MDPI 2023-10-01 /pmc/articles/PMC10574351/ /pubmed/37836742 http://dx.doi.org/10.3390/molecules28196899 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 Margariti, Antigoni Papakonstantinou, Vasiliki D. Stamatakis, George M. Demopoulos, Constantinos A. Machalia, Christina Emmanouilidou, Evangelia Schnakenburg, Gregor Nika, Maria-Christina Thomaidis, Nikolaos S. Philippopoulos, Athanassios I. First-Row Transition Metal Complexes Incorporating the 2-(2′-pyridyl)quinoxaline Ligand (pqx), as Potent Inflammatory Mediators: Cytotoxic Properties and Biological Activities against the Platelet-Activating Factor (PAF) and Thrombin |
title | First-Row Transition Metal Complexes Incorporating the 2-(2′-pyridyl)quinoxaline Ligand (pqx), as Potent Inflammatory Mediators: Cytotoxic Properties and Biological Activities against the Platelet-Activating Factor (PAF) and Thrombin |
title_full | First-Row Transition Metal Complexes Incorporating the 2-(2′-pyridyl)quinoxaline Ligand (pqx), as Potent Inflammatory Mediators: Cytotoxic Properties and Biological Activities against the Platelet-Activating Factor (PAF) and Thrombin |
title_fullStr | First-Row Transition Metal Complexes Incorporating the 2-(2′-pyridyl)quinoxaline Ligand (pqx), as Potent Inflammatory Mediators: Cytotoxic Properties and Biological Activities against the Platelet-Activating Factor (PAF) and Thrombin |
title_full_unstemmed | First-Row Transition Metal Complexes Incorporating the 2-(2′-pyridyl)quinoxaline Ligand (pqx), as Potent Inflammatory Mediators: Cytotoxic Properties and Biological Activities against the Platelet-Activating Factor (PAF) and Thrombin |
title_short | First-Row Transition Metal Complexes Incorporating the 2-(2′-pyridyl)quinoxaline Ligand (pqx), as Potent Inflammatory Mediators: Cytotoxic Properties and Biological Activities against the Platelet-Activating Factor (PAF) and Thrombin |
title_sort | first-row transition metal complexes incorporating the 2-(2′-pyridyl)quinoxaline ligand (pqx), as potent inflammatory mediators: cytotoxic properties and biological activities against the platelet-activating factor (paf) and thrombin |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10574351/ https://www.ncbi.nlm.nih.gov/pubmed/37836742 http://dx.doi.org/10.3390/molecules28196899 |
work_keys_str_mv | AT margaritiantigoni firstrowtransitionmetalcomplexesincorporatingthe22pyridylquinoxalineligandpqxaspotentinflammatorymediatorscytotoxicpropertiesandbiologicalactivitiesagainsttheplateletactivatingfactorpafandthrombin AT papakonstantinouvasilikid firstrowtransitionmetalcomplexesincorporatingthe22pyridylquinoxalineligandpqxaspotentinflammatorymediatorscytotoxicpropertiesandbiologicalactivitiesagainsttheplateletactivatingfactorpafandthrombin AT stamatakisgeorgem firstrowtransitionmetalcomplexesincorporatingthe22pyridylquinoxalineligandpqxaspotentinflammatorymediatorscytotoxicpropertiesandbiologicalactivitiesagainsttheplateletactivatingfactorpafandthrombin AT demopoulosconstantinosa firstrowtransitionmetalcomplexesincorporatingthe22pyridylquinoxalineligandpqxaspotentinflammatorymediatorscytotoxicpropertiesandbiologicalactivitiesagainsttheplateletactivatingfactorpafandthrombin AT machaliachristina firstrowtransitionmetalcomplexesincorporatingthe22pyridylquinoxalineligandpqxaspotentinflammatorymediatorscytotoxicpropertiesandbiologicalactivitiesagainsttheplateletactivatingfactorpafandthrombin AT emmanouilidouevangelia firstrowtransitionmetalcomplexesincorporatingthe22pyridylquinoxalineligandpqxaspotentinflammatorymediatorscytotoxicpropertiesandbiologicalactivitiesagainsttheplateletactivatingfactorpafandthrombin AT schnakenburggregor firstrowtransitionmetalcomplexesincorporatingthe22pyridylquinoxalineligandpqxaspotentinflammatorymediatorscytotoxicpropertiesandbiologicalactivitiesagainsttheplateletactivatingfactorpafandthrombin AT nikamariachristina firstrowtransitionmetalcomplexesincorporatingthe22pyridylquinoxalineligandpqxaspotentinflammatorymediatorscytotoxicpropertiesandbiologicalactivitiesagainsttheplateletactivatingfactorpafandthrombin AT thomaidisnikolaoss firstrowtransitionmetalcomplexesincorporatingthe22pyridylquinoxalineligandpqxaspotentinflammatorymediatorscytotoxicpropertiesandbiologicalactivitiesagainsttheplateletactivatingfactorpafandthrombin AT philippopoulosathanassiosi firstrowtransitionmetalcomplexesincorporatingthe22pyridylquinoxalineligandpqxaspotentinflammatorymediatorscytotoxicpropertiesandbiologicalactivitiesagainsttheplateletactivatingfactorpafandthrombin |