Giordano, Flavia (2021) Design and synthesis of molecular hybrids between drugs for psoriasis treatment and H2S donors. [Tesi di dottorato]

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Abstract

Psoriasis is a chronic and relapsing immune-mediated inflammatory skin disease, characterized by uncontrolled keratinocyte proliferation and dysfunctional differentiation, that affects 2-4% of people worldwide. Glucocorticoids and retinoids are commonly used in the treatment of psoriasis. More recently, H2S has been described to exert positive effect on this disease. Bearing in mind that an improved pharmacological activity and a reduced toxicity can be obtained through hybridization of different molecules, the project has been principally focused on design, synthesis and characterization of molecular hybrids containing a portion pharmacologically active in the treatment of psoriasis and an H2S-releasing moiety, with the aim to develop novel compounds able to modulate multiple targets in antipsoriatic therapy. The molecular hybrids have been evaluated in vitro for their H2S releasing properties via amperometric assay, as well as for their cytoprotective activity and anti-inflammatory power. Antipsoriatic activity has been evaluated in vivo by performing skin tests on animal models of imiquimod-induced psoriasis, determining the ability of the compounds to reduce inflammation and itching. Finally, the study has been extended to the evaluation of the antiasthmatic properties for the obtained derivatives, testing the H2S releasing profile in the cytosol of bronchial smooth muscle cells (BSMC), the inhibitory effect on mast cell degranulation and the ability to induce cell membrane hyperpolarization in BSMC. The second unit of the thesis is focused to the experience held at the Department of Biosciences - University of Salzburg and referred to the synthesis and characterization of three types of peptides: phosphopeptides to investigate the effect of serine phosphorylation on the conformation, peptide models to investigate π-cation interactions, and fluorogenic peptides to investigate the activity of proteases by FRET measurements. In the third unit of the thesis the design of potential formulations for the synthesized compounds that have shown more promising results is described, as well as the studies finalized to the evaluation of physicochemical stability for the active substances and formulations, and to the characterization of their in vitro performances. These activities have been performed at the Genetic s.p.a. in Fisciano (Italy).

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