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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Item Anticancer drugs: a detailed computational analysis of "non classical" compounds mechanism of action(Università della Calabria, 2020-02-05) Ponte, Fortuna; Andò, Sebastiano; Sicilia, EmiliaMetal 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.Item A computational mechanistic study of potentially evolving platinum based anticancer drugs(Università della Calabria, 2021) Dabbish, Eslam; Andò, Sebastiano; Sicilia, EmiliaMetals 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.