TP53 and cancer: Herein, we describe the synthesis of some diastereomerically pure nucleobase-containing spiro-(indane isoxazolidine) derivatives as potential anti-cancer substrates, supported by a computational study about a possible inhibition of MDM2–p53 interaction and by their antiproliferative evaluation against A549 human lung carcinoma cells and human SH-SY5Y neuroblastoma cells.