Tesi di laurea specialistica LC5
DESIGN AND SYNTHESIS OF NOVEL INDOLE-BASED MODULATORS OF P53/MDM2 INTERACTION.
Corso di studi
relatore Taliani, Sabrina
relatore Pugliesi, Isabella
relatore Pugliesi, Isabella
Data inizio appello
The tumor suppressor protein p53, also know as the guardian of genoma, is a a transcription factor that controls cellular response to stress which may be caused by hypoxia and DNA damage. To maintain genomic integrity, p53 can: (1) activate DNA repair proteins when DNA has sustained damage; (2) induce cell cycle arrest by holding the cell cycle at the G1\S regulation point by the expression of the cyclin-dependent kinase inhibitor p21; (3) initiate apoptosis, if DNA damage proves to be irreparable. Under normal conditions, p53 is maintained at a low steady-state level through proteasome-mediated degradation, while in human cancer its level is frequently altered. The inactivation of p53 is often due to the overexpression of its mean negative regulator the this the ubiquitine E3 Ligase Murine Double Minute 2 protein, MDM2. The aminoacid implicated in the interaction between p53 and MDM2 are three: Phe19, Trp23, and Leu26 which are inserted into a deep hydrophobic pocket on the surface of MDM2. These structural data leads to the hypothesis that a synthetic molecule displaying three hydrophobic groups in an orientation that mimics the presentation of the Phe19, Trp23, and Leu26 side chains of p53 should occupy the MDM2 cleft and thereby inhibit the p53-MDM2 interaction. The first reported potent and selective small molecule MDM2 antagonists were a class of cis-imidazolines, the nutlins. Other small molecules have been developed, such as calchones, benzodiazepinones and spiro-oxindoles. Most of the small molecule inhibitors share the common feature of a rigid heterocyclic scaffold, decorated with p-halophenyl appendages that are projected toward the phenylalanine and tryptophan hydrophobic binding pockets on the surface of MDM2. The aim of this work is to develop novel small molecules able to activate the p53 through the inhibition of the MDM2-p53 interaction, designed by joining the two concepts of 'privileged structures' (single molecular framework able to provide ligands for diverse receptors), and "needles" (molecular fragments of ligands specifically binding to particular protein family members) that can determine the binding to the considered protein and modulate the interaction with p53. In view of these findings and our expertise, we considered indole-based p53/MDM2 inhibitors, as indole is frequently used as “privileged scaffold” in biology and medicine due to its favorable physical properties, including water solubility and cell permeability. In particular, we have designed and synthesized a small library of novel indole-based scaffold small molecules as potential inhibitors of MDM2-p53 interaction