A series of novel polycyclic spiro-fused carbocyclicoxindoles were synthesized and investigated for their in vitro antiproliferative activities against nine human cancer cell lines. Five compounds (10i, 101, 10n, 10p, and 10r) demonstrated anticancer activities against A2780s cells with IC50 values of less than 30 mu M. In particular, compound 10i showed anticancer activities against seven cancer cell lines and stronger activities than cisplatin in A2780s, A2780T, L126, and HCT116 cells. Further studies illustrated that compound 101 arrested cell cycle in G1 phase and induced apoptosis of HCT116 cells. This compound also effectively increased the protein levels of cleaved caspase-3, p53, and MDM2. Molecular docking results revealed that compound 101 could bind well to the p53-binding site on MDM2, indicating that it might work by blocking the MDM2-p53 interactions. (C) 2016 Elsevier Masson SAS. All rights reserved.