Oxime amides as a novel zinc binding group in histone deacetylase inhibitors: synthesis, biological activity, and computational evaluation

Several oxime containing molecules, characterized by a SAHA-like struc- ture, were explored to select a potentially new biasing binding element for the zinc in HDAC catalytic site. All compounds were evaluated for their in vitro inhibitory acti- vity against the 11 human HDACs isoforms. After identi!cation of a “hit” molecule, a programmed variation at the cap group and at the linker was carried out in order to increase HDAC inhibition and/or paralogue selectivity. Some of the new derivatives showed increased activity against a number of HDAC isoforms, even if their overall activity range is still far from the inhibition values reported for SAHA. Moreover, di"erent from what was reported for their hydroxamic acid analogues the new R-oxime amide derivatives do not select between class I and class II HDACs; rather they target speci!c isoforms in each class. These somehow contradictory results were !nally rationalized by a computa- tional assisted SAR, which gave us the chance to understand how the oxime derivatives interact with the catalytic site and justify the observed activity pro!le.