Discovery of spirooxindole-ferrocene hybrids as novel MDM2 inhibitors

A series of spirooxindole-ferrocene hybrids bearing five or four contiguous chiral centers were designed and synthesized via organocatalysis. In vitro protein binding and cellular proliferation assays suggested that compound 5d was the most potent mouse double minute 2 homolog (MDM2) inhibitor. In addition, mechanistic studies indicated that compound 5d suppressed MDM2-mediated p53 degradation, induced apoptosis and promoted oxidative damage. Molecular docking studies have suggested that 5d binds to MDM2 by mimicking the Trp23 and Leu26 residues of p53. This work can provide a basis for the development of novel multifunctional MDM2 inhibitors. The further exploration of more derivatives from this library and additional investigation of organocatalysis application in the development of new molecules may generate new potential lead compounds for cancer-targeted therapy. (c) 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.