ETD system

Electronic theses and dissertations repository

 

Tesi etd-03252015-105356


Thesis type
Tesi di laurea magistrale LM5
Author
CATOCCI, SARA
URN
etd-03252015-105356
Title
New Arylsulfonamido-based MMP9 Inhibitors with Improved Selectivity
Struttura
FARMACIA
Corso di studi
CHIMICA E TECNOLOGIA FARMACEUTICHE
Commissione
relatore Dott.ssa Nuti, Elisa
relatore Prof. Rossello, Armando
Parole chiave
  • Arylsulfonamido; selectivity; MMP9
Data inizio appello
15/04/2015;
Consultabilità
parziale
Data di rilascio
15/04/2018
Riassunto analitico
Analytical abstract <br>Matrix Metalloproteinases (MMPs) are multidomain zinc endopeptidases which play a central role in degradation of the extracellular matrix but also in a number of other biological processes such as embryogenesis, normal tissue remodelling and angiogenesis. Their activity is finely regulated by endogenous protein inhibitors (TIMPs) but in many diseases this balance is destroyed. Because of their wide spectrum of activities and expression sites, they are attractive subjects of many research studies. <br>In my Thesis project my attention was focused on MMP9 (gelatinase B) which is deeply involved in inflammatory processes and tumor progression. More recent studies showed the important role of MMP9 in cardiovascular and auto-immune diseases which, taken altogether, represent a leading cause of mortality and morbidity in Western countries. <br>Broad-spectrum inhibitors have shown high toxicity and poor efficacy in cancer clinical trials as they hit various members of the MMP’s family including those considered antitarget in therapy. Therefore is extremely important to design and synthesize selective MMP9 inhibitors that can represent lead compounds with druggable properties. <br>In recent years, some promising MMP inhibitors have been developed in my laboratory and in my Thesis project I tried to synthesize a series of new selective inhibitors for MMP9 starting from the previously developed compounds. The new compounds 1-4 are arylsulfonamido-based hydroxamates bearing various substituents (P1, P1’ and P2’ groups) on the arylsulfonamide scaffold.<br>The newly synthesized hydroxamates have been tested on the principal target, MMP-9, to assess their activity and on other MMPs such as MMP1; MMP2 and MMP14, to determinate their selectivity profile. The assays have been conducted in vitro on human recombinant MMPs by fluorometric HTS methods, using a fluorogenic peptide as substrate. All new compounds showed a nanomolar activity on MMP9 and an improved selectivity over the other tested MMPs with respect to the starting compounds previously reported.<br>
File