Corvino, Angela
(2015)
Novel tools for the elucidation of physio-pathological role of H2S.
[Tesi di dottorato]
| Tipologia del documento: |
Tesi di dottorato
|
| Lingua: |
English |
| Titolo: |
Novel tools for the elucidation of physio-pathological role of H2S |
| Autori: |
| Autore | Email |
|---|
| Corvino, Angela | angela.corvino@unina.it |
|
| Data: |
31 Marzo 2015 |
| Istituzione: |
Università degli Studi di Napoli Federico II |
| Dipartimento: |
Farmacia |
| Scuola di dottorato: |
Scienze farmaceutiche |
| Dottorato: |
Scienza del farmaco |
| Ciclo di dottorato: |
27 |
| Coordinatore del Corso di dottorato: |
| nome | email |
|---|
| D'Auria, Maria Valeria | madauria@unina.it |
|
| Tutor: |
| nome | email |
|---|
| Severino, Beatrice | [non definito] |
|
| Data: |
31 Marzo 2015 |
| Parole chiave: |
CBS/CSE inhibitors; H2S donors |
| Settori scientifico-disciplinari del MIUR: |
Area 03 - Scienze chimiche > CHIM/08 - Chimica farmaceutica |
[error in script]
[error in script]
| Depositato il: |
10 Apr 2015 11:57 |
| Ultima modifica: |
28 Apr 2016 01:00 |
| URI: |
http://www.fedoa.unina.it/id/eprint/10546 |
| DOI: |
10.6092/UNINA/FEDOA/10546 |
Abstract
Hydrogen sulphide is endogenously synthesized mainly by two pyridoxal-5′-phosphate-dependent
enzymes involved in L-cysteine metabolism: cystathionine-ß-synthase (CBS) and cystathionine-γ-
lyase (CSE). The H2S pathway has been proposed to be involved in the pathophysiology of several
diseases. At the present stage the research in this field is impaired by the lack of pharmacological
tools such as selective enzymatic inhibitors. The goal of our study is the development compounds
that selectively regulate enzymatic activity. Here we present the synthesis and the activity of a
selective CSE inhibitor.
We preliminarily selected and tested commercially available cysteine surrogates because of the
unavailability of a pharmacophoric model as a lead for rational design of targeted enzyme
inhibitors. The catalytic profiles of recombinant CBS and CSE were assessed in the presence of
the selected compounds. On the basis of the results obtained were designed new compounds
aiming to obtain novel molecular entities embodying the structural features of both cysteine and the
well known CSE inhibitor, DL-propargylglycine. The synthetically modified compounds, obtained in
our laboratory, were tested in vitro by using rat aortic rings. The compound showing maximal
inhibitory effects in this test was an oxothiazolidine derivative, dubbed compound VII. The effects
of this compound on the enzyme kinetics was further tested on the purified enzymes using a
metabolomic approach based on nuclear magnetic resonance techniques. These studies clearly
showed that compound VII is a potent enzyme inhibitor of CSE, without affecting the CBS
kinetics. The identification of this highly selective CSE inhibitor may help to better define the role of
CSE vs CBS in the pathophysiology of the diseases where a role for the H2S pathway has been
proposed.
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