Design, synthesis, and evaluation of novel pinane-based thiazolidione derivatives with anti-glioblastoma activity.

Abstract

A series of pinane-based thiazolidione derivatives were synthesised, and their anti-proliferative effects were investigated by CCK-8 assay. All these compounds exhibited anti-proliferation activity against three glioblastoma cell lines (U87, T98G, and U251). Compound C5 exhibited the strongest inhibition effect against all three cell lines. Through cellular thermal shift (CETSA) assay and drug affinity responsive target stability (DARTS) assay, compound C5 was demonstrated to directly interact with the CDK2 protein. Additional analyses revealed that C5 inhibited cell migration and arrested the cell cycle in glioblastoma cells while also induced mitochondrial apoptosis and autophagy. Immunoblotting analysis indicated that C5 induced the up-regulation of Bax, cleaved caspase 3, cleaved PARP-1, P62, and LC3B, and the down-regulation of Bcl-2, caspase 3, and PARP-1. Importantly, C5 also demonstrated efficacy in a 3D cell culture model. Together, these results highlight the potential of C5 as a lead compound for the development of novel therapies for glioblastoma.