Non-Natural Macrocyclic Inhibitors of Histone Deacetylases

1. Introduction Nonpeptidic chiral macrocycles were designed on the basis of an analogue of HDAC inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) and evaluated against 11 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. 2. Results and Discussion Bearing in mind that recent papers show how HDAC profiling data need to be evaluated with criticism,1 we found2 that macrocycles with two simple aromatic rings in the cap region (R/S-9 for example) displayed a nanomolar activity profile against all isoforms. As expected for hydroxamic acid-containing HDAC inhibitors, a preferential activity against HDAC6 in the nanomolar range was observed for all macrocycles. In particular, a relevant selectivity toward this isoform was detected within the group of diamide-based macrocycles (R/S-36 for esample, 10-500-fold over the other HDACs). An excellent cytotoxic activity was also found for selected macrocycles against lung and colon cancer cell lines.2 3. References [1] Bantscheff, M. et al Nature Biotechnology, Vol. adv. online publication, (January 2011) [2] Auzzas, L. et al J. Med. Chem. 2010, 53, 8387-8399