The main objective of this doctoral thesis was to identify new small molecules with therapeutic efficacy towards uveal melanoma, an intraocular tumor as rare as aggressive. The work was conducted at the Department of Drug and Health Sciences (University of Catania), at the Department of Organic Chemistry (University of Zaragoza, Spain) and at Vera Salus s.r.l (Viagrande, Catania) In particular, the project envisages the development of new synthetic compounds capable of both antagonize the σ1 receptor and to inhibit HDAC for the treatment of Uveal Melanoma. As reported in the literature, σ receptors are present at the uveal level (iris and rabbit ciliary body) and, as we reported in recent preliminary studies, some dual-target/dual-function ligands (σ1 and HDAC inhibitors) show both antiangiogenic and antiproliferative properties. Moreover, treatment with appropriate σ ligands induces apoptosis and autophagy in human uveal melanoma cells. At the same time, recent studies have shown that some mutations inactivating histone H2A ubiquitin-hydrolase (BAP1) are closely related to the metastatic forms of uveal melanoma. The HDAC inhibitors, as valproic acid (VPA), LBH-589 and others, are capable of reversing the effects of loss of functionality of BAP1 inducing melanocytic differentiation, cell cycle cessation and inhibition of tumour growth. Finally, VPA underwent phase II clinical trials (NCT02068586) for treatment of uveal melanoma. On these grounds, after a careful initial analysis concerning the multitarget strategy and based on the different structural types of multiple-action ligands, several multi-ligands have been designed. The dual-target/dual-function approach involving the design and the synthesis of new molecules capable of having a double antiangiogenic and antiproliferative effect; acting on both σ receptors, as a new molecular target, that on HDAC as inhibitors (HDACi are already widely validated as anticancer).
L’obiettivo principale di questa tesi di dottorato è stato quello di identificare nuove molecole di sintesi con efficacia terapeutica nei confronti del melanoma uveale, un tumore intraoculare tanto raro quanto aggressivo. Il lavoro è stato condotto presso il Dipartimento di Scienze del Farmaco e della Salute (Università degli Studi di Catania), presso il Departamento de Quimica Organica (Universidad de Zaragoza, España) e presso la Vera Salus s.r.l (Viagrande, Catania). In particolare, il progetto persegue lo sviluppo di nuovi composti sintetici in grado sia di antagonizzare il recettore σ che di inibire alcune isoforme dell’enzima istone deacetilasi (HDAC), come potenziali target per il trattamento del melanoma uveale. Come riportato in letteratura, i recettori σ sono presenti a livello uveale (iride e corpo ciliare) e, come abbiamo riportato in recenti studi preliminari, alcuni ligandi dual-target/dual-function (σ1 e HDAC) mostrano sia proprietà antiangiogeniche che antiproliferative. Inoltre, il trattamento con opportuni ligandi σ induce apoptosi e autofagia nelle cellule umane di melanoma uveale. Allo stesso tempo, studi recenti hanno dimostrato che alcune mutazioni che disattivano l'istone H2A ubiquitina-idrolasi (BAP1) sono strettamente correlate alle forme metastatiche del melanoma uveale. Gli inibitori dell’ HDAC, tra i quali acido valproico (VPA), LBH-589 e altri, sono in grado di invertire gli effetti della perdita di funzionalità del BAP1 inducendo la differenziazione dei melanociti, la cessazione del ciclo cellulare e l’inibizione della crescita tumorale. In particolare, VPA è attualmente in fase clinica II (NCT02068586) per il trattamento del melanoma uveale. Sulla base di queste considerazioni, dopo un'attenta analisi iniziale riguardante la strategia multitarget basata sui diversi tipi strutturali di ligandi ad azione multipla, sono stati progettati diversi ligandi multipli. L'approccio dual-target/dual-function coinvolge la progettazione e la sintesi di nuove molecole in grado di avere un doppio effetto anti angiogenico ed antiproliferativo; agendo sia sui recettori σ, come nuovo bersaglio molecolare, che sull’HDAC come inibitori (l’uso di alcuni HDACi è già ampiamente convalidato come antitumorali).
Ligandi ibridi Sigma-HDAC come potenziale trattamento terapeutico per il melanoma uveale: design, sintesi e valutazione biologica / Barbaraci, Carla. - (2021 Jun 14).
Ligandi ibridi Sigma-HDAC come potenziale trattamento terapeutico per il melanoma uveale: design, sintesi e valutazione biologica
BARBARACI, CARLA
2021-06-14
Abstract
The main objective of this doctoral thesis was to identify new small molecules with therapeutic efficacy towards uveal melanoma, an intraocular tumor as rare as aggressive. The work was conducted at the Department of Drug and Health Sciences (University of Catania), at the Department of Organic Chemistry (University of Zaragoza, Spain) and at Vera Salus s.r.l (Viagrande, Catania) In particular, the project envisages the development of new synthetic compounds capable of both antagonize the σ1 receptor and to inhibit HDAC for the treatment of Uveal Melanoma. As reported in the literature, σ receptors are present at the uveal level (iris and rabbit ciliary body) and, as we reported in recent preliminary studies, some dual-target/dual-function ligands (σ1 and HDAC inhibitors) show both antiangiogenic and antiproliferative properties. Moreover, treatment with appropriate σ ligands induces apoptosis and autophagy in human uveal melanoma cells. At the same time, recent studies have shown that some mutations inactivating histone H2A ubiquitin-hydrolase (BAP1) are closely related to the metastatic forms of uveal melanoma. The HDAC inhibitors, as valproic acid (VPA), LBH-589 and others, are capable of reversing the effects of loss of functionality of BAP1 inducing melanocytic differentiation, cell cycle cessation and inhibition of tumour growth. Finally, VPA underwent phase II clinical trials (NCT02068586) for treatment of uveal melanoma. On these grounds, after a careful initial analysis concerning the multitarget strategy and based on the different structural types of multiple-action ligands, several multi-ligands have been designed. The dual-target/dual-function approach involving the design and the synthesis of new molecules capable of having a double antiangiogenic and antiproliferative effect; acting on both σ receptors, as a new molecular target, that on HDAC as inhibitors (HDACi are already widely validated as anticancer).File | Dimensione | Formato | |
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