Non-Natural Macrocyclic Inhibitors of Histone Deacetylases: Design, Synthesis, and Activity

Citations Over TimeTop 10% of 2010 papers

Abstract

Nonpeptidic chiral macrocycles were designed on the basis of an analogue of suberoylanilide hydroxamic acid (2) (SAHA, vorinostat) and evaluated against 11 histone deacetylase (HDAC) isoforms. The identification of critical amino acid residues highly conserved in the cap region of HDACs guided the design of the suberoyl-based macrocycles, which were expected to bear a maximum common substructure required to target the whole HDAC panel. A nanomolar HDAC inhibitory profile was observed for several compounds, which was comparable, if not superior, to that of 2. A promising cytotoxic activity was found for selected macrocycles against lung and colon cancer cell lines. Further elaboration of selected candidates led to compounds with an improved selectivity against HDAC6 over the other isozymes. Pair-fitting analysis was used to compare one of the best candidates with the natural tetrapeptide apicidin, in an effort to define a general pharmacophore that might be useful in the design of surrogates of peptidic macrocycles as potent and isoform-selective inhibitors.

Related Papers

• → Characterization of a new small-molecule inhibitor of HDAC6 in glioblastoma(2020)57 cited
• → Solid Phase Library Synthesis of Cyclic Depsipeptides: Aurilide and Aurilide Analogues(2003)49 cited
• → The structural requirements of histone deacetylase inhibitors: C4-modified SAHA analogs display dual HDAC6/HDAC8 selectivity(2017)46 cited
• HDAC inhibitors in cancer care.(2010)
• → Current Trends in the Development of Histone Deacetylase Inhibitors: A Review of Recent Patent Applications(2012)20 cited