Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2, 4′-piperidine] based histone deacetylase inhibitors

Florian Thaler, Mario Varasi, Agnese Abate, Giacomo Carenzi, Andrea Colombo, Chiara Bigogno, Roberto Boggio, Roberto Dal Zuffo, Daniela Rapetti, Anna Resconi, Nickolas Regalia, Stefania Vultaggio, Giulio Dondio, Stefania Gagliardi, Saverio Minucci, Ciro Mercurio

Research output: Contribution to journalArticlepeer-review


Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H-(1,3)-benzoxazine-2,4′-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues.

Original languageEnglish
Pages (from-to)273-284
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 2013


  • Antiproliferation
  • Histone deacetylases
  • Hydroxamates
  • In vivo antitumor activity
  • Pharmacokinetics
  • Privileged scaffolds

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology


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