• antitumor agents
• MDM2
• p53

Indole-based modulators of p53-MDM2 interaction as
antitumoral agents.
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: (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 steady-state level
through proteasome-mediated degradation, while in human cancer its level is frequently altered
(1.2). 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 (3). The first reported potent and 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
(4).
In this research, we have developed novel small molecules able to activate the p53 through the
inhibiton of the MDM2-p53 interaction. In the rational design of these novel inhibitors, we have
considered indole based scaffolds as indole is frequently used as “privileged structure” in biology
and medicine due to its favorable physico-chemical properties (5). Functionalization of the central
scaffold was driven by molecular modeling studies in order to mimic the contacts and the
orientations of the key aminoacid side chains implied in the protein-protein binding. In particular,
we designed a number of 2-phenylindol-3-ylglyoxyl derivatives featuring anilide (series I), or
dipeptide moieties on the amide side chain (series II).
(1) Meulmeester, E.; Jochemsen, A. Curr. Cancer Drug Targets 2008, 8, 87-97.
(2) Lakin, N. D.; Jackson, S. P. Oncogene 1999, 18, 7644-7655.
(3) Kussie, P. H.; Gorina, S.; Marechal, V. Science 1996, 274, 948-953.
(4) Vassilaev, L. T.; Vu, B. T.; Graves, B. Science 2004, 303, 844-848.
(5) Welsch, M.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347-361.