New Vanillyl-capped HDAC inhibitors exhibit anti-tumor efficacy in neuroblastoma and glioblastoma cells

  • Bioorg Chem. 2025 Nov:166:109085. doi: 10.1016/j.bioorg.2025.109085.
Ilaria Cursaro  1 ,  Luca Frattaruolo  2 ,  Laura Scalvini  3 ,  Chiara Contri  4 ,  Alessia Bichicchi  5 ,  Nicola Tardiolo  1 ,  Valeria Tudino  1 ,  Sara Rossi  1 ,  Eugenia Nicol Manti  2 ,  Martina Cappello  4 ,  Chiara Papulino  6 ,  Emilia Maellaro  7 ,  Paola Marcolongo  7 ,  Rosaria Benedetti  8 ,  Lucia Altucci  9 ,  Katia Varani  4 ,  Marco Mor  10 ,  Maria Frosini  5 ,  Fabrizio Vincenzi  4 ,  Anna Rita Cappello  2 ,  Alessio Lodola  3 ,  Simona Saponara  5 ,  Stefania Butini  1 ,  Gabriele Carullo  11 ,  Sandra Gemma  12 ,  Giuseppe Campiani  1
Affiliations
  • 1. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
  • 2. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Edificio Polifunzionale, 87036 Rende, (CS), Italy.
  • 3. Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, Campus Universitario, 43124 Parma, Italy.
  • 4. Department of Translational Medicine, University of Ferrara, Via Luigi Borsari 46, 44121, Ferrara, Italy.
  • 5. Department of Life Sciences, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
  • 6. Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via de Crecchio 7, 80138, Naples, Italy.
  • 7. Department of Molecular and Developmental Medicine, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
  • 8. Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via de Crecchio 7, 80138, Naples, Italy; Prof. R. Benedetti, Prof. L. Altucci, Program of Medical Epigenetics, Vanvitelli Hospital, 80138, Naples, Italy.
  • 9. Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via de Crecchio 7, 80138, Naples, Italy; Prof. R. Benedetti, Prof. L. Altucci, Program of Medical Epigenetics, Vanvitelli Hospital, 80138, Naples, Italy; Biogem Institute of Molecular and Genetic Biology, 83031, Ariano Irpino, Italy.
  • 10. Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, Campus Universitario, 43124 Parma, Italy; Microbiome Research Hub, University of Parma, Parma, Italy.
  • 11. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy. Electronic address: [email protected].
  • 12. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy. Electronic address: [email protected].
PMID: 41109068 DOI: 10.1016/j.bioorg.2025.109085
Abstract

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.

Keywords
HDAC inhibitors; apoptosis; cell cycle arrest; glioblastoma; neuroblastoma.
Products