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The tumor suppressor protein p53, also known as the guardian of genoma, is a transcription factor that controls cellular response to stress which may be caused by hypoxia and DNA damage. To maintain genomic integrity, p53 can: (i) activate DNA repair proteins when DNA has sustained damage; (ii) 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; (iii) initiate apoptosis, if DNA damage proves to be irreparable. Under normal conditions, p53 is maintained at a low of 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 over-expression of its mean negative regulator that is the ubiquitine E3 Ligase Murine Double Minute 2 protein, MDM2. The aminoacids implicated in the interaction between p53 and MDM2 are three: Phe19, Trp23 and Leu26 which are inserted into a deep hydrophobic pocket in the surface of MDM2. The first reported potent and selective small molecule MDM2 antagonists were a class of cis-imidazoline, the nutlins. Other small molecules have been developed, such as calchones, benzodiazepinones and spiro-oxindoles.
In this research, we have developed novel small molecules which could be able to activate p53 through the inhibition of the MDM2-p53 interaction. In the rational design of these novel inhibitors, we have considered indole-based scaffold as indole is frequently used as “privileged structure” in biology and medicine due to its favourable phsyco-chemical properties. Functionalization of the central scaffold was driven by molecular modelling studies in order to mimic the contact and the orientations of the key aminoacid side chains implied in the protein-protein binding. In particular
we have designed a number of 2-phenilindol-3-ylglyoxyl derivates featuring Phenilalanine, Leucine and Valine, in their ethyl ester form.