The Carbonic Anhydrases (CAs, EC 4.2.1.1) are ubiquitous metalloenzymes expressed in almost all living organisms. Being one of the main actors in pH regulation and in the maintenance of proper concentrations of CO2, the dysruption of the activity of such enzymes, by means of adequate modulators, is a validated strategy for the treatment of human affecting pathologies and for the eradication of etiological agents (i.e. pathogenic bacteria, fungi and protozoa). In addition, CA-based biotechnological applications (i.e. CO2 capture) may benefit from modulation of the enzymatic activity. CA Inhibitors (CAIs) have been extensively investigated over the time, and have been validated for the management of hypertensive glaucoma, systemic hypertension, epilepsy, obesity related diseases and recently neuropathic pain, inflammation and hypoxic tumors. Although CA activators (CAA) traditionally lacked interests, currently a repurposing of such compounds is underway with promising results as potential agents for the management of memory deficits related to neurodegenerative diseases. In this Thesis work, an introductive overview on CAs as the main biological targets (Chapter 1) and three distinctive projets (Chapters 2-4) are reported ranging from synthetic chemistry to enzyme biology and spctrophotometry. The first one (Chapter 2) concerns the synthesis and evaluation of new CAIs with Carbon Monoxide (CO) releasing properties for the management of RA. The reported compounds have been fully characterized, their CA inhibitory properties along with the CO releasing effect were assessed. In particular, a spectrophotometric assay was properly set with slight modifications of the protocols reported in the literature. This allowed to obtain a precise and quantitative evaluation of CO released over time from our compounds. The pain refief effect of the designed CAI-CORMs was also evaluated in a rat model of RA with very promising results. The second project (Chapter 3) was aimed to synthetize a small series of CAI-AZT hybrids and to evaluate them as Telomerase Inhibitors, thus with possible antitumoral applications. The compounds synthetized have been profiled in vitro on seven CA isoforms (i.e. I, II, Va, VB, VII, IX and XII). The effects of our compounds on Telomerase Activity have been also determined showing a low-medium inhibition potency. Two promising derivatives have been identified with good IC50 and IC90 values. Co-crystallyzation of selected compounds in adduct with hCA II has been performed and their binding modes were determined. The third project (Chapter 4) was entirely carried out during my six-months visiting student experience at the University of Poitiers in France, and it concerns the synthesis in Superacid medium of new mono and di-fluorinated diamines as CAIs. Insertion of one or more C-F bonds is a validated strategy in Medicinal Chemistry. Fluorine insertion can modulate pharmacokinetic and pharmacodynamic properties of the compounds, thus being an attractive tool in the design of bioactive compounds. Another unrelated project included in this Chapter, is the synthesis of enantiopure fluorinated tricyclic scaffolds obtained by means of a diastereoselective approach.

Carbonic Anhydrase Inhibitors: Versatile Agents for the Treatment of Human Diseases / Emanuela Berrino, Claudiu Supuran, Alessandro Mugelli, Fabrizio Carta. - (2020).

Carbonic Anhydrase Inhibitors: Versatile Agents for the Treatment of Human Diseases

Emanuela Berrino
;
Alessandro Mugelli;Fabrizio Carta
2020

Abstract

The Carbonic Anhydrases (CAs, EC 4.2.1.1) are ubiquitous metalloenzymes expressed in almost all living organisms. Being one of the main actors in pH regulation and in the maintenance of proper concentrations of CO2, the dysruption of the activity of such enzymes, by means of adequate modulators, is a validated strategy for the treatment of human affecting pathologies and for the eradication of etiological agents (i.e. pathogenic bacteria, fungi and protozoa). In addition, CA-based biotechnological applications (i.e. CO2 capture) may benefit from modulation of the enzymatic activity. CA Inhibitors (CAIs) have been extensively investigated over the time, and have been validated for the management of hypertensive glaucoma, systemic hypertension, epilepsy, obesity related diseases and recently neuropathic pain, inflammation and hypoxic tumors. Although CA activators (CAA) traditionally lacked interests, currently a repurposing of such compounds is underway with promising results as potential agents for the management of memory deficits related to neurodegenerative diseases. In this Thesis work, an introductive overview on CAs as the main biological targets (Chapter 1) and three distinctive projets (Chapters 2-4) are reported ranging from synthetic chemistry to enzyme biology and spctrophotometry. The first one (Chapter 2) concerns the synthesis and evaluation of new CAIs with Carbon Monoxide (CO) releasing properties for the management of RA. The reported compounds have been fully characterized, their CA inhibitory properties along with the CO releasing effect were assessed. In particular, a spectrophotometric assay was properly set with slight modifications of the protocols reported in the literature. This allowed to obtain a precise and quantitative evaluation of CO released over time from our compounds. The pain refief effect of the designed CAI-CORMs was also evaluated in a rat model of RA with very promising results. The second project (Chapter 3) was aimed to synthetize a small series of CAI-AZT hybrids and to evaluate them as Telomerase Inhibitors, thus with possible antitumoral applications. The compounds synthetized have been profiled in vitro on seven CA isoforms (i.e. I, II, Va, VB, VII, IX and XII). The effects of our compounds on Telomerase Activity have been also determined showing a low-medium inhibition potency. Two promising derivatives have been identified with good IC50 and IC90 values. Co-crystallyzation of selected compounds in adduct with hCA II has been performed and their binding modes were determined. The third project (Chapter 4) was entirely carried out during my six-months visiting student experience at the University of Poitiers in France, and it concerns the synthesis in Superacid medium of new mono and di-fluorinated diamines as CAIs. Insertion of one or more C-F bonds is a validated strategy in Medicinal Chemistry. Fluorine insertion can modulate pharmacokinetic and pharmacodynamic properties of the compounds, thus being an attractive tool in the design of bioactive compounds. Another unrelated project included in this Chapter, is the synthesis of enantiopure fluorinated tricyclic scaffolds obtained by means of a diastereoselective approach.
2020
Claudiu Supuran, Alessandro Mugelli
Emanuela Berrino, Claudiu Supuran, Alessandro Mugelli, Fabrizio Carta
File in questo prodotto:
File Dimensione Formato  
PhD Thesis Emanuela Berrino.pdf

accesso aperto

Descrizione: Tesi di Dottorato
Tipologia: Tesi di dottorato
Licenza: Open Access
Dimensione 5.47 MB
Formato Adobe PDF
5.47 MB Adobe PDF

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1188882
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact