Design, synthesis, and biological evaluation of nitroisoxazole-containing spiro[pyrrolidin-oxindole] derivatives as novel glutathione peroxidase 4/mouse double minute 2 dual inhibitors that inhibit breast adenocarcinoma cell proliferation.

A series of highly active CF3-containing 3'-(nitroisoxazole)spiro[pyrrolidin-3,2'-oxindoles] were synthesized and found to be novel glutathione peroxidase 4 (GPX4)/mouse double minute 2 (MDM2) dual inhibitors. Bioactive spirooxindole and isoxazole skeletons were combined, and the resulting compounds exhibited strong activities against both targets. In particular, compound 3d displayed excellent activity in the suppression of MDM2-mediated degradation of p53, as well as levels of GPX4, in MCF-7 breast cancer cells. Moreover, 3d also exhibited inhibitory effects on MDM2 and GPX4 in MCF-7 xenograft model to trigger ferroptotic and apoptotic cell death in in vivo experiments, which was consistent with the results of in vitro experiments.

Asymmetric synthesis of tetrahydroisoquinoline-fused spirooxindoles as Ras-GTP inhibitors that inhibit colon adenocarcinoma cell proliferation and invasion.

Here we report the synthesis of a library of chiral THIQ-fused spirooxindoles, which combine two privileged scaffolds in antitumor medicinal chemistry. Some of the library members inhibit the proliferation and invasion ability of Ras-mutated colon adenocarcinoma cells. Mechanistic studies suggest that the most potent compound, 3m, inhibits Ras-GTP and thereby suppresses downstream signaling mediated by MAPK, PI3K-Akt and Wnt. Ultimately this leads to mitochondrial apoptosis.