Synthesis and biological characterization of amidopropenyl hydroxamates as HDAC inhibitors

Florian Thaler, Mario Varasi, Andrea Colombo, Roberto Boggio, Davide Munari, Nickolas Regalia, Marco G. Rozio, Veronica Reali, Anna E. Resconi, Antonello Mai, Stefania Gagliardi, Giulio Dondio, Saverio Minucci, Ciro Mercurio

Research output: Contribution to journalArticle

Abstract

A series of amidopropenyl hydroxamic acid derivatives were prepared as novel inhibitors of human histone deacetylases (HDACs). Several compounds showed potency at 50 values in tests against three tumor cell lines, and remarkable stability in human and mouse microsomes was observed. Three representative compounds were selected for further characterization and submitted to a selectivity profile against a series of class I and class II HDACs as well as to preliminary in vivo pharmacokinetic (PK) experiments. Despite their high microsomal stability, the compounds showed medium-to-high clearance rates in in vivo PK studies as well as in rat and human hepatocytes, indicating that a major metabolic pathway is catalyzed by non-microsomal enzymes.

Original languageEnglish
Pages (from-to)1359-1372
Number of pages14
JournalChemMedChem
Volume5
Issue number8
DOIs
Publication statusPublished - Aug 2 2010

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Keywords

  • Antiproliferation
  • Histone deacetylases
  • Hydroxamates
  • Metabolism
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Thaler, F., Varasi, M., Colombo, A., Boggio, R., Munari, D., Regalia, N., Rozio, M. G., Reali, V., Resconi, A. E., Mai, A., Gagliardi, S., Dondio, G., Minucci, S., & Mercurio, C. (2010). Synthesis and biological characterization of amidopropenyl hydroxamates as HDAC inhibitors. ChemMedChem, 5(8), 1359-1372. https://doi.org/10.1002/cmdc.201000166