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Tesi etd-10292012-174634

Thesis type
Tesi di laurea specialistica LC5
Indole-based modulators of p53-MDM2 interaction as antitumoral agents
Corso di studi
relatore Dott.ssa Taliani, Sabrina
relatore Dott.ssa Barresi, Elisabetta
Parole chiave
  • p53
  • MDM2
  • antitumor agents
Data inizio appello
Riassunto analitico
Indole-based modulators of p53-MDM2 interaction as<br>antitumoral agents.<br>The tumor suppressor protein p53, also know as the guardian of genoma, is a a transcription factor<br>that controls cellular response to stress which may be caused by hypoxia and DNA damage. To<br>maintain genomic integrity, p53 can: (I) activate DNA repair proteins when DNA has sustained<br>damage; (ii) induce cell cycle arrest by holding the cell cycle at the G1\S regulation point by the<br>expression of the cyclin-dependent kinase inhibitor p21; (iii) initiate apoptosis, if DNA damage<br>proves to be irreparable. Under normal conditions, p53 is maintained at a low steady-state level<br>through proteasome-mediated degradation, while in human cancer its level is frequently altered<br>(1.2). The inactivation of p53 is often due to the overexpression of its mean negative regulator the<br>this the ubiquitine E3 Ligase Murine Double Minute 2 protein, MDM2. The aminoacid implicated<br>in the interaction between p53 and MDM2 are three: Phe19, Trp23, and Leu26 which are inserted<br>into a deep hydrophobic pocket on the surface of MDM2 (3). The first reported potent and and<br>selective small molecule MDM2 antagonists were a class of cis-imidazolines, the nutlins. Other<br>small molecules have been developed, such as calchones, benzodiazepinones and spiro-oxindoles<br>(4).<br>In this research, we have developed novel small molecules able to activate the p53 through the<br>inhibiton of the MDM2-p53 interaction. In the rational design of these novel inhibitors, we have<br>considered indole based scaffolds as indole is frequently used as “privileged structure” in biology<br>and medicine due to its favorable physico-chemical properties (5). Functionalization of the central<br>scaffold was driven by molecular modeling studies in order to mimic the contacts and the<br>orientations of the key aminoacid side chains implied in the protein-protein binding. In particular,<br>we designed a number of 2-phenylindol-3-ylglyoxyl derivatives featuring anilide (series I), or<br>dipeptide moieties on the amide side chain (series II).<br>(1) Meulmeester, E.; Jochemsen, A. Curr. Cancer Drug Targets 2008, 8, 87-97.<br>(2) Lakin, N. D.; Jackson, S. P. Oncogene 1999, 18, 7644-7655.<br>(3) Kussie, P. H.; Gorina, S.; Marechal, V. Science 1996, 274, 948-953.<br>(4) Vassilaev, L. T.; Vu, B. T.; Graves, B. Science 2004, 303, 844-848.<br>(5) Welsch, M.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347-361.