Compound 5o(University of Siena)

Histone deacetylases 6 and 8 (HDAC6/8) have emerged as promising therapeutic targets in aggressive neural tumors such as neuroblastoma and glioblastoma. Herein, we report the design, synthesis, and comprehensive biological evaluation of a novel series of hydroxamic acid-based inhibitors (5a-p), featuring nature-inspired vanillyl CAP groups. Structure-activity relationship (SAR) analysis, supported by molecular docking, elucidated the role of CAP, connecting unit, and linker structure, alongside zinc-binding group orientation, on isoform selectivity and potency. Among the series, compound 5o emerged as a highly potent and preferential HDAC6 inhibitor (IC₅₀ = 4.5 nM). In SH-SY5Y neuroblastoma cells, 5o induced dose-dependent α-tubulin hyperacetylation, caspase-3/7 activation that indicates apoptosis, a minor autophagy stimulation and showing negligible cytotoxicity in HEK-293 cells. Furthermore, 5o significantly reduced cell viability in multiple glioblastoma models (U87-MG, T98G, U251-MG), disrupting mitotic progression and promoting G2/M cell cycle arrest, as evidenced by decreased phosphorylation of p-cdc2 (Tyr15). These findings validate the therapeutic relevance of HDAC inhibition in neural tumors and suggest that compound 5o deserves further investigation as an epigenetic modulator in cancer therapy.