Carla Barbaraci

Ciclo: XXXIII

Data inizio: 31/10/2017

Curriculum: Farmaceutiche

Borsa: MIUR PON R&I

Titolo tesi: Sigma-HDACi hybrid ligands as potential therapeutic treatment for uveal melanoma: design, synthesis and biological evaluation

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).

Tutor: Marrazzo

Data Conseguimento Titolo: 14/06/2021

Linkedin: Indicate il link

Email: carlabarbaraci@rocketmail.com

Periodi all'estero- Sede e data: Universidad de Zaragoza (Gennaio-Giugno 2019)

Esperienze post-Dottorato ed attuale occupazione: Post-doc presso “Universitat de Barcelona”, Barcellona (Spagna)