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

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 <b>C5</b> 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 <b>C5</b> was demonstrated to directly interact with the CDK2 protein. Additional analyses revealed that <b>C5</b> inhibited cell migration and arrested the cell cycle in glioblastoma cells while also induced mitochondrial apoptosis and autophagy. Immunoblotting analysis indicated that <b>C5</b> 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, <b>C5</b> also demonstrated efficacy in a 3D cell culture model. Together, these results highlight the potential of <b>C5</b> as a lead compound for the development of novel therapies for glioblastoma.