Synthesis and biochemical evaluation of wild-type and mutant p53 oxazoloisoindolinones reactivators derived from tryptophanol

The tumor suppressor p53 is responsible for the genome integrity of the cells, controlling cell cycle arrest and apoptosis in response to stress signals. However, in virtually all human cancers p53 is inactivated either by negative regulation or direct mutation. Thus, there is a high interest to reactivate its tumor suppressor functions. So far, there are no mut-p53 reactivators approved for clinical use and most mut-p53 reactivators fail due to toxic side effects and/or pharmacodynamics properties. So, the development of new and more selective small molecules with less toxic side effects is extremely important.

In the last years, our research group has developed mut- and wt- p53 small molecule activators based on the tryptophanol-derived oxazoloisoindolinone scaffold with promising in vitro and in vivo activity. These compounds are obtained by enantioselective cyclocondensation of (R)- or (S)- tryptophanol with different oxo-acids in toluene under reflux using a Dean-Stark apparatus. Hit compound was optimized, leading to the discovery of (R)- and (S)- tryptophanol-derived oxazoloisoindolinones . Specifically, one compound showed 6-fold higher antiproliferative activity, as well as increased selectivity for HCT116 p53^+/+ over HCT116 p53^-/- compared with the hit compound and is selective towards cancer cells over normal cells .

In this poster communication we will present our recent results on the hit-to-lead optimization process, synthesis and also, the development of a differential scanning fluorimetry assay.