Dipartimento di Chimica e Tecnologie Chimiche - Tesi di Dottorato

Permanent URI for this collectionhttps://lisa.unical.it/handle/10955/32

Questa collezione raccoglie le Tesi di Dottorato afferenti al Dipartimento di Chimica e Tecnologie Chimiche dell'Università della Calabria.

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Author: search.filters.author.Sicilia, Emilia

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    Anticancer drugs: a detailed computational analysis of "non classical" compounds mechanism of action
    (Università della Calabria, 2020-02-05) Ponte, Fortuna; Andò, Sebastiano; Sicilia, Emilia
    Metal containing drugs have attracted an enormous deal of interest for their use in cancer therapy. Transition metal compounds’ richness offers extraordinary opportunities for the design of anticancer compounds, possessing pharmacokinetic properties inaccessible to purely organic compounds. The most successful and evident proof of their pivotal role is represented by cisplatin that, together with its carboplatin and oxaliplatin derivatives, continues to be routinely used worldwide in clinical practice. However, it is well known that the use of such drugs for fighting cancer is accompanied by severe side effects and intrinsic or acquired resistance that drastically limit their successful action. Therefore, decades of research efforts have been devoted to the search and the synthesis of safer and more effective and selective agents, either containing platinum or alternative metals, acting with similar or different mechanisms. In order to accomplish this aim is of decisive importance the elucidation of the mechanism of action of the drugs. Molecular simulations, or in silico experiments, are able to provide detailed information at atomistic resolution, rarely accessible to experiments, that can complement laboratory experiments. The increasing accuracy of computational approaches and the growing performance of computer performance, allow to properly describe reaction paths and involved molecular orbitals, calculate electronic properties, simulate spectra without any limitation except those connected with the adopted level of theory and compuatational protocol. The main aim of the present work was the detailed investigation, in the framework of the Density Functional Theory, of the mechanism of action of “non classical” platinum and transition metal non-platinum compounds, for some of them in collaboration with experimentalists, and the rationalization of their behaviors. In the next paragraphs all the studied systems will be shortly described together with the motivations that have prompted us to study such systems. Both “non classical” platinum(IV) prodrugs, non-platinum drugs and photoactivatable Pt(II) and Pt(IV) complexes have been examined. In the development of new platinum-based anticancer drugs, is of great interest the emerging class of "dual action" Pt(IV) prodrugs that, undergoing a reductive elimination process, which is the key step for their activation, are able to release the active Pt(II) complexes and bioactive axial ligands that together lead to cell death. Indeed, the two axial ligands, in turn, can be chosen to possess physico-chemical and biopharmaceutical properties or even facilitate the incorporation into a drug delivery system. According to the research lines mentioned above, the use of drug delivery systems has also grown, and many different strategies have been examined to encapsulate platinum drugs within macromolecules, including macrocyclic species, which are responsible for creating supramolecular host-guest structures. The encapsulation slows down and prevents the drug degradation by proteins and peptides. One of the most widely studied class of synthetic supramolecular macrocycles are Calix[n]arenes (CX), whose property, as molecular hosts and delivery systems, are of increasing interest. Photodynamic Therapy (PDT) is a non-toxic therapeutic technique, clinically approved and minimally invasive, used for the treatment of several types of cancers based on the generation of reactive oxygen species (ROS), that acts as cytotoxic agents. In PDT applications three components are required: a photosensitizer (PS), a light of a specific wavelength and tissue oxygen. A promising approach to increase the effectiveness of anticancer therapy is the combination of multimodal treatment methods into a single system. Recently, a strategy has been proposed providing the possibility to combine the classical Pt-based chemotherapy with photodynamic therapy (PDT) treatment. This approach involves the functionalization of a photosensitizer (PS) with a therapeutic drug such as cisplatin-like compounds.
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    A computational mechanistic study of potentially evolving platinum based anticancer drugs
    (Università della Calabria, 2021) Dabbish, Eslam; Andò, Sebastiano; Sicilia, Emilia
    Metals are known to play a fundamental physiological role inside human body affecting many of the biological functions. Analogously, metal based drugs can also have a similar impact. Cisplatin, a simple platinum complex, is well known to be a cytotoxic agent and the first approved and most widely used metal based drug for fighting cancer. Currently, used platinum containing anticancer agents namely cisplatin, carboplatin and oxaliplatin suffer from serious toxic side effects as well as acquired and inherent drug resistance against many types of cancer. Consequently, new platinum anticancer drug families evolved to overcome the current limitations of traditional platinum drugs. Monofunctional platinum complexes, Pt(IV) complexes, platinum complexes targeting mitochondria, platinum idodio derivatives and photoactivated platinum compounds are examples of some of such newly developed platinum based cytotoxic families. Computational chemistry has strongly grown over the past years with both the increase in computers capabilities and the development of new theories and efficient algorithms that can allow to handle bigger models in a reasonable time. Molecular modelling can give a wealth of information about the studied systems in terms of energies, electronic properties, geometries, conformations, structure/activity relationships, reaction mechanisms and many others. By using quantum mechanical methods like Density Functional Theory (DFT) and its time-dependant formulation TD-DFT and molecular dynamics (MD) computational tools, the mechanism of action of some selected examples of non-traditional platinum anticancer drug families have been studied in this thesis. Phenanthriplatin is the most effective member of a new class of platinum anticancer agents (7-40 times more active than cisplatin) known as monofunctional platinum anticancer drugs. In addition, it has started its clinical trials phase. Our computational mechanistic study of phenanthriplatin highlighted the importance of the role played by its unique chemical structure in the drug activation, interaction with DNA and transcription blockage. Targeting of mitochondrial DNA by means of platinum drugs can lead to mitochondrial dysfunction in cancer cells that causes tumour cells growth inhibition and apoptosis. We have undertaken a comparative study between three different isomers of a recently prepared triphenyl phosphonium modified monofunctional platinum complexes for their mechanism of action. Pt(IV) complexes are prodrugs that are reduced inside the body by means of abundant biological reducing agents like ascorbic acid to release the equivalent cytotoxic Pt(II) complexes. This reduction step is considered to be the limiting step for the activity of such class of drugs. In a series of studies, we have carried out a detailed mechanistic study to understand the relation between the nature of Pt(IV) complexes axial and equatorial ligands and the extent and mechanism of reduction by means of ascorbic acid at physiological pH. We highlighted the particular importance and impact of the nature of axial ligands on the reduction process. Photoactivated chemotherapy (PACT) technique allows the localized activation of drugs by means of specific wavelength light. A recently synthesized complex named platicur is a cis-diammineplatinum(II) complex of curcumin in which the Pt(II) centre is bound to a curcumin molecule as the leaving ligand. Upon light irradiation curcumin molecule is released together with the doubly aquated Pt(II) complex that can exert the required cytotoxic effect. In our study, we have provided a deep insight in the photoactivated excited states and their role in the photocleavage mechanism with the release of curcumin.
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    Transition metal-based complexes as chemitherapeutic agents. Theoretical investigation of MoA, interaction with biological molecules and environmental conditions
    (2017-05-05) Ritacco, Ida; Andò, Sebastiano; Sicilia, Emilia
    Molti metalli e, conseguentemente, molti complessi metallici svolgono ruoli importanti all’interno di sistemi biologici e biochimici. Oggigiorno, è risaputo che essi rappresentano ingredienti molto importanti per la vita altrettanto quanto i composti organici. Per esempio, i complessi di ferro svolgono un ruolo fondamentale nel trasporto di O2 nel sangue, i complessi di calcio sono alla base delle ossa, lo zinco è presente nell’ insulina che regola la quantità di zucchero nel nostro corpo. Questo è possibile perché i metalli possiedono particolari proprietà chimiche. Infatti, tendono facilmente a perdere elettroni, diventando specie elettron-deficienti più reattive nei confronti di diverse molecole biologiche e più solubili in soluzioni acquose. I metalli non solo sono elementi vitali in molti fenomeni biologici, ma possono anche essere sfruttati per il trattamento di diverse malattie. L'esempio più importante di questa categoria di composti è il complesso organometallico cisplatino [Pt(Cl)2(NH3)2], il chemioterapico più potente disponibile sul mercato. Scoperto nel 1969 da Rosenberg, esso svolge un ruolo chiave nell’ inibizione della divisione cellulare, causando la morte delle cellule tumorali. Dopo la scoperta della sua attività citotossica, l'applicazione di farmaci metallici nelle varie terapie ha registrato una crescita enorme e la continua ricerca dell'uso di metalli in medicina, in particolare per la cura del cancro, è diventata una disciplina, indicata come Medicinal Inorganic Chemistry. Dopo la scoperta del cisplatino, altri due farmaci antitumorali a base di platino, derivati del cisplatino, sono stati scoperti: carboplatino e ossaliplatino. Questi complessi esercitano la loro azione citotossica coordinando il DNA e bloccando la divisione cellulare. Tuttavia, anche se questi complessi, di formula generale [Pt(X)2(L)2], sono ancora tra i farmaci più frequentemente utilizzati, risultano essere tossici a causa della loro reattività e instabilità. In questi anni, per superare i problemi relativi all’uso di complessi di Pt(II), l’ attenzione è stata concentrata sullo sviluppo di nuovi complessi, generando due diverse categorie di farmaci antitumorali: i complessi di Pt(IV), considerati "profarmaci" e ottenuti per ossidazione dai complessi di Pt(II), e i "farmaci che non contengono platino", come i complessi di iridio, rodio, osmio o rutenio. Le caratteristiche di questi farmaci dovrebbero renderli più inerti, quindi più efficaci dei complessi di Pt(II), e provocare una differenziazione nel meccanismo di azione. Lo studio teorico dei sistemi biologici ha ormai raggiunto la maturità necessaria per fornire informazioni complementari rispetto a quelle ottenibili sperimentalmente nello studio di molte proprietà e fenomeni. Infatti, l’impressionante sviluppo sia delle metodologie teoriche, sia della tecnologia informatica ha consentito di fornire un importante supporto di studi teorici alle bioscienze. Inoltre, l’uso della teoria del funzionale della densità (DFT), che rappresenta un ottimo compromesso tra accuratezza e costi computazionali, è particolarmente adatto allo studio dei sistemi biologici come dimostrato dal fatto che negli ultimi anni sono stati completati con successo molti studi DFT e sono state affrontate questioni fondamentali nelle simulazioni biologiche. Scopo di questa tesi è lo studio teorico di farmaci antitumorali contenenti metalli, in particolare complessi di Pt(IV) e Ir(III), delle principali reazioni del farmaco che avvengono dal momento della sua iniezione o somministrazione orale al raggiungimento del suo bersaglio biologico e investigazione del meccanismo di azione che può essere sia quello classico, già proposto per il cisplatino e, quindi, associato all’accumulo cellulare e al legame con il DNA, sia un meccanismo di diversa natura. In alcuni casi, la teoria del funzionale della densità è stata utilizzata come approccio computazionale supportato da calcoli eseguiti a livello Coupled Cluster post Hartree-Fock nella sua versione CCSD(T).
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    Studio Teorico dei Dettagli Meccanicistici di Reazioni Organiche Catalizzate da Oro
    (2014-03-31) Mazzone, Gloria; Russo, Nino; Sicilia, Emilia
    The catalytic chemistry of gold has had a relatively belated development with respect to other late transition metals, and this has been attributed to the preconception that gold is expensive and unreactive. The interest in gold has grown over the last thirty years, because both of these conceptions have been proven false, and successful applications of gold catalysis have emerged in chemical processing, pollution control, fuel cells design, and many others fields. These evidences have sparked a veritable “gold rush” in the field of catalysis, both homogeneous and heterogeneous. We investigated the role of gold in both homogeneous and heterogeneous catalytic processes. In fact, the theoretical study of mechanistic details for reactions, that involves and underline the characteristics of gold, have been the subjects of this thesis. Density functional theory (DFT) is the method of choice in this kind of studies. Regarding heterogeneous catalysis the synthesis of vinylacetate is the reaction on which we have focused our attention. In particular, a bimetallic catalyst containing low Pd coverage on Au surface (100 and 111) has been selected to outline the reaction mechanism of VAM formation. We have studied in detail both mechanisms proposed in literature, in order to selected the more active surface and the more likely mechanism. The homogeneous catalytic process that has been selected to point out the catalytic activity of gold is the hydration of 1,2-diphenylacetylene to yield benzyl phenyl ketone, catalyzed by a complex of Au(I) with triphenylposphine. This cationic complex coordinates to the alkyne in the first step of the catalytic cycle, thus rendering it more susceptible for a nucleophilic attack. That reaction is a relatively new synthetic strategy that have recently studied experimentally. Our aim is to elucidate the mechanism of the whole reaction.