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Synthesis and Biological Characterization of Amidopropenyl Hydroxamates as HDAC Inhibitors
Author(s) -
Thaler Florian,
Varasi Mario,
Colombo Andrea,
Boggio Roberto,
Munari Davide,
Regalia Nickolas,
Rozio Marco G.,
Reali Veronica,
Resconi Anna E.,
Mai Antonello,
Gagliardi Stefania,
Dondio Giulio,
Minucci Saverio,
Mercurio Ciro
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000166
Subject(s) - microsome , hydroxamic acid , metabolic stability , in vivo , chemistry , enzyme , biochemistry , in vitro , potency , histone deacetylase , stereochemistry , histone , biology , gene , microbiology and biotechnology
A series of amidopropenyl hydroxamic acid derivatives were prepared as novel inhibitors of human histone deacetylases (HDACs). Several compounds showed potency at <100 n M in the HDAC inhibition assays, sub‐micromolar IC 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.