Spirocyclic oxindoles with interesting biological activities. In the recent years, our group focused its research in the development of several chemical libraries to obtain new compounds able to activate the p53 tumour suppressor function. Structure-based computational studies performed with these molecules as p53-MDMs protein-protein interaction (PPI) inhibitors demonstrates that compounds need to mimic the three critical amino acids (Phe19, Trp 23 and Leu26) of p53 that are projected in the deep hydrophobic cleft of MDM2/X and have a hydrogen at the oxindole nitrogen.

Among the several hits synthesized in the group and evaluated in cancer cell lines expressing wild-type p53, a spiropyrazoline oxindole has emerged. This compound has good antiproliferative activity in breast cancer cells (MCF-7) and also in the human colon cancer cells (HCT116). However, binding studies shown that the compound did not bind to MDM2. To further explore the potential of this scaffold for the development of novel anti-cancer agents, in this work we explored modifications on the indole nitrogen, to improve the anti-proliferative activity and the chemical stability properties of the hit compound previously identified. Different substituents were added on the nitrogen and the new compounds were screened in cell lines for anticancer activity. Furthermore, HPLC stability studies in PBS and human plasma were also performed for the derivatives with better activity.