Potency and selectivity optimization of tryptophanol-derived oxazoloisoindolinones: novel p53 activators in human colorectal cancer

Colorectal Cancer

ChemMedChem. 2020 Jul 31. doi: 10.1002/cmdc.202000522. Online ahead of print.


To search for novel p53 activators, four series of novel ( S )- and ( R )-tryptophanol-derived oxazoloisoindolinones have been straightforwardly synthesized and their antiproliferative activity evaluated in human colorectal cancer HCT116 cell line. Structural optimization of the hit compound SLMP53-1 led to the identification of a ( R )-tryptophanol-derived isoindolinone 6-fold more active and with increased selectivity for colon cancer HCT116 cells with p53 and with low toxicity in normal

cells. Binding studies with MDM2 showed that the antiproliferative activity of tryptophanol-derived isoindolinones does not involve the inhibition of the main negative regulator of the p53 protein. Molecular docking simulations showed that although these molecules establish hydrophobic interactions with MDM2, they do not possess the required features to bind MDM2.