The regulation of transmembrane chloride transport is a fundamental process involved in many metabolic pathways and its imbalance leads to serious genetic diseases like cystic fibrosis. In Nature, chloride transport is regulated by complex membrane proteins but there are also a few examples of small molecules which act as anion carriers. Chloride transporters have shown interesting biologic activity (e.g. anticancer, antibiotic) and it has been proposed that they could be used in channel replacement therapy for cystic fibrosis patients. In this context, the ability to develop simple molecules able to efficiently promote chloride transport in biological membranes appears really promising. Several examples of artificial chloride carriers are present in literature, usually based on (thio)ureas. On the contrary despite the fact that ion recognition and transport is a typical supramolecular process, there are only a few examples of the use of coordination complexes as anion transporters. Recently our research group reported that a simple bis-phosphine palladium complex, dpppPdCl2, is able to promote chloride transport in liposomes with a carrier mechanism. This represents a completely new class of ionophores and the research project of this Thesis focus on the design and study of the ionophoric activity of Pd(II) based metal complexes. Knowing from literature studies that the lipophilicity of the carrier and its affinity for the anion are the two main properties affecting the transport efficiency, a structure activity relationship study was done on dppp based Pd(II) complexes. The lipophilicity of the Pd(II) complexes was tuned inserting alkyl substituents on the ligands, while the effect of the chloride association constant of the complexes was evaluated by introducing electron-withdrawing and electron-donor substituents on the phenyl rings of the ligand. Moreover, we took into consideration the bite angle of the ligand, which is an important parameter that determines the reactivity of bis-phosphine metal complexes. The ionophoric activity of the compounds was studied with liposomes-based assays. The results indicate that the main factor affecting the ion transport efficiency is lipophilicity. On the other hand, the effects of the bite angle and of the association constant resulted to be more elusive. Moreover, it was possible to gain information on the mechanism of transport promoted by this new class of ionophores, which was confirmed to be an electrogenic or non-electrogenic carrier type mechanism depending on the experimental conditions. The scope of the study was expanded to other transition metals, like copper, nickel and platinum, among which Cu(I) showed the best activity, although lower than palladium. This proved the general validity of the approach and opened the way to further studies on different type of ligands and metal complexes. A second part of the work was focused on the study of the biological properties of this new class of ionophores. In collaboration with dr. M. Benincasa, their antimicrobial activity was tested on Gram-positive and negative bacterias, showing low micromolar efficacy against S. Aureus. With the aim of obtaining information on the mechanism of interaction of the metal-based anionophores with cells, fluorescent ionophores based on naphthalimide or acenaphthene complexes with Cu(I) and Pd(II) were developed. The fluorescence emission of the complexes will be used to localize the complexes inside living cells. Parallel to the development of metal complex based anion carriers, during the course of the Ph.D. period, I have contributed in the study of the ionophoric activity of new synthetic peptoids prepared by professor F. De Riccardis and professor I. Izzo research groups. I have also participated in the development of new electrochromic materials based on naphthalimide phosphine oxides in collaboration with professor J. Parola of the Universidade Nova de Lisboa.

La regolazione del trasporto del cloruro attraverso le membrane biologiche è un processo fondamentale coinvolto in molte vie metaboliche, il cui squilibrio porta a gravi malattie genetiche come la fibrosi cistica. In Natura, il trasporto del cloruro è regolato da complesse proteine di membrana, tuttavia esistono anche alcuni esempi di piccole molecole che fungono da trasportatori di anioni. I trasportatori di cloruro hanno mostrato attività biologiche interessanti (ad esempio antitumorale ed antibiotica) e ne è stato proposto l’utilizzo nella terapia di sostituzione dei canali del cloruro per i pazienti affetti da fibrosi cistica. Quindi, la capacità di sviluppare molecole semplici che siano in grado di promuovere il trasporto del cloruro in membrane biologiche appare molto promettente. In letteratura sono presenti numerosi esempi di trasportatori di cloruro, che generalmente utilizzano (tio)uree come elementi di riconoscimento per l’anione. Al contrario, nonostante sia il riconoscimento che il trasporto di ioni siano tipici processi supramolecolari, ci sono pochi esempi dell'uso di complessi di coordinazione come trasportatori di anioni. Recentemente il nostro gruppo di ricerca ha dimostrato che il complesso di palladio dpppPdCl2 è in grado di promuovere il trasporto di cloruro in liposomi e il progetto di ricerca di questa tesi intende approfondire lo studio dell'attività ionoforica di questi complessi. Le due proprietà principali che influenzano l'efficienza del trasporto sono la lipofilicità dei trasportatori e la loro affinità per gli anioni. E’ stato quindi condotto uno studio di relazione struttura-attività riguardante questi due parametri sui complessi Pd(II) dppp. La lipofilicità dei complessi di Pd(II) è stata modificata inserendo sostituenti alchilici, mentre l'effetto dell’affinità per il cloruro è stato valutato introducendo gruppi elettron-attrattori e donatori. Inoltre, è stato preso in considerazione il bite angle del legante, un parametro importante che influisce sulla reattività dei complessi di coordinazione. L'attività ionoforica dei complessi è stata studiata utilizzando liposomi come modelli di membrane. I risultati ottenuti indicano che il fattore principale che influenza l'efficienza di trasporto degli ioni è la lipofilicità. Invece, per quanto riguarda il bite angle e la costante di affinità, i loro effetti si sono rivelati più complessi da analizzare. Inoltre, è stato possibile ottenere informazioni sul meccanismo di trasporto promosso da questi ionofori, che è stato confermato essere di tipo carrier elettrogenico o non elettrogenico, a seconda del saggio di trasporto. Lo studio dell’attività ionoforica è stato esteso ad altri metalli, come rame, nichel e platino. Tra questi complessi, quello di Cu(I) si è dimostrato il più efficiente, seppure inferiore a quello di palladio. Ciò ha dimostrato la validità generale dell'approccio aprendo la strada a ulteriori studi. Una seconda parte della tesi si è concentrata sullo studio delle proprietà biologiche di questa nuova classe di ionofori. In collaborazione con la dr.ssa M. Benincasa, la loro attività antimicrobica è stata studiata su batteri Gram-positivi e negativi, mostrando efficacia antibatterica a concentrazioni micromolari contro S. Aureus. Per investigare il meccanismo di interazione degli ionofori con le cellule, sono stati sviluppati ionofori fluorescenti basati su complessi di naftalimmidi o acenaftene con Cu(I) e Pd(II), la cui emissione di fluorescenza sarà utilizzata per avere informazioni circa la loro localizzazione nelle cellule. Durante il dottorato ho contribuito allo studio dell'attività ionoforica di nuovi peptoidi sintetici preparati dai gruppi di ricerca del prof. F. De Riccardis e la prof.ssa I. Izzo ed ho partecipato allo sviluppo di nuovi materiali elettrocromici basati su naftalimmidi in collaborazione con il prof. J. Parola, dell’Universidade Nova de Lisboa.

Transition Metal Complexes as Anion Carriers / Tosolini, Massimo. - (2019 Mar 08).

Transition Metal Complexes as Anion Carriers

TOSOLINI, MASSIMO
2019-03-08

Abstract

The regulation of transmembrane chloride transport is a fundamental process involved in many metabolic pathways and its imbalance leads to serious genetic diseases like cystic fibrosis. In Nature, chloride transport is regulated by complex membrane proteins but there are also a few examples of small molecules which act as anion carriers. Chloride transporters have shown interesting biologic activity (e.g. anticancer, antibiotic) and it has been proposed that they could be used in channel replacement therapy for cystic fibrosis patients. In this context, the ability to develop simple molecules able to efficiently promote chloride transport in biological membranes appears really promising. Several examples of artificial chloride carriers are present in literature, usually based on (thio)ureas. On the contrary despite the fact that ion recognition and transport is a typical supramolecular process, there are only a few examples of the use of coordination complexes as anion transporters. Recently our research group reported that a simple bis-phosphine palladium complex, dpppPdCl2, is able to promote chloride transport in liposomes with a carrier mechanism. This represents a completely new class of ionophores and the research project of this Thesis focus on the design and study of the ionophoric activity of Pd(II) based metal complexes. Knowing from literature studies that the lipophilicity of the carrier and its affinity for the anion are the two main properties affecting the transport efficiency, a structure activity relationship study was done on dppp based Pd(II) complexes. The lipophilicity of the Pd(II) complexes was tuned inserting alkyl substituents on the ligands, while the effect of the chloride association constant of the complexes was evaluated by introducing electron-withdrawing and electron-donor substituents on the phenyl rings of the ligand. Moreover, we took into consideration the bite angle of the ligand, which is an important parameter that determines the reactivity of bis-phosphine metal complexes. The ionophoric activity of the compounds was studied with liposomes-based assays. The results indicate that the main factor affecting the ion transport efficiency is lipophilicity. On the other hand, the effects of the bite angle and of the association constant resulted to be more elusive. Moreover, it was possible to gain information on the mechanism of transport promoted by this new class of ionophores, which was confirmed to be an electrogenic or non-electrogenic carrier type mechanism depending on the experimental conditions. The scope of the study was expanded to other transition metals, like copper, nickel and platinum, among which Cu(I) showed the best activity, although lower than palladium. This proved the general validity of the approach and opened the way to further studies on different type of ligands and metal complexes. A second part of the work was focused on the study of the biological properties of this new class of ionophores. In collaboration with dr. M. Benincasa, their antimicrobial activity was tested on Gram-positive and negative bacterias, showing low micromolar efficacy against S. Aureus. With the aim of obtaining information on the mechanism of interaction of the metal-based anionophores with cells, fluorescent ionophores based on naphthalimide or acenaphthene complexes with Cu(I) and Pd(II) were developed. The fluorescence emission of the complexes will be used to localize the complexes inside living cells. Parallel to the development of metal complex based anion carriers, during the course of the Ph.D. period, I have contributed in the study of the ionophoric activity of new synthetic peptoids prepared by professor F. De Riccardis and professor I. Izzo research groups. I have also participated in the development of new electrochromic materials based on naphthalimide phosphine oxides in collaboration with professor J. Parola of the Universidade Nova de Lisboa.
8-mar-2019
TECILLA, PAOLO
31
2017/2018
Settore CHIM/06 - Chimica Organica
Università degli Studi di Trieste
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2962375
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