Maria Dichiara

Ciclo: XXXIII

Data inizio: 31/10/2017

Curriculum: Farmaceutiche

Borsa: UniCT

Titolo tesi: Synthesis and preclinical evaluation of sigma receptor ligands for cancer treatment and analgesia

Abstract: The objectives of the present PhD thesis have been pursued with the defined interest in identifying new small molecules for therapeutic purposes. The work was conducted at the Department of Drug and Health Sciences (University of Catania), and at the Department of Chemistry and Applied Biosciences (ETH Zürich).

The main approach was the establishment of new series of ligands able to bind sigma receptors (σRs), a class of receptor proteins accepted as valuable target for the management of different pathological states including neurological disorders, pain, and cancer. The first two series of compounds have been developed by combining selective σR ligands endowed with specific functional profile, together with chemical donors able to release therapeutic concentrations of hydrogen sulfide (H2S) or nitric oxide (NO), two gaseous entities known for their pharmacological capabilities. The goal was to obtain a synergistic effect when compared to the relative single entities. The compounds have been synthetized and evaluated for affinity and selectivity with competitive radioligand binding assays. Further pharmacological characterization let to dig up the precise mechanism of action and efficacy in disease models.

A third series of compounds was developed in order to identify novel pure σR ligands for their use thereof. This chemical matter has been developed according to structure-affinity relationships approach consisting in the following steps: (i) design of new candidate ligands; (ii) in vitro radioligand binding assays; (iii) iterative compounds design based on affinity and selectivity; (iv) synthesis of the new compounds for further pharmacological evaluation.

For chemical entities that ground their therapeutic value on the effect in the central nervous system (CNS), such as in the case of tumors or central analgesia, an important issue is their ability to cross the blood-brain barrier (BBB). This diffusion barrier between the blood and the CNS represents a sophisticated protection system against pathogens and toxic compounds. In this context, a useful statistical tool supporting the identification of parameters for BBB crossing has been developed allowing defining a set of rules that would prospectively be used to tune the properties of in-house synthetized ligands.

The last stage of this PhD thesis was addressed to find out high affinity small molecules targeting the human tyrosinases TYR and TYRP1, two closely-related enzymes selectively expressed in neoplastic skin lesions. The methodologies employed included the use of DNA-encoded chemical library technology, beside to improve already known binders reported in literature.

Tutor: Amata

Data Conseguimento Titolo: 29/03/2021

Linkedin: https://www.linkedin.com/in/maria-dichiara-02584710b

Email: maria.dichiara@unisi.it

Periodi all'estero- Sede e data: ETH Zurigo – 1/09/2018-15/03//2019

Esperienze post-Dottorato ed attuale occupazione: RTDA presso Università di Siena