Hydroxamic acid derivatives as histone deacetylase inhibitors: a DFT study of their tautomerism and metal affinities/selectivities

Hydroxamic acids are regarded as potent inhibitors of histone deacetylases (HDAC), and can therefore be used to reduce malignancy growth and size in affected organisms. Although there is a substantial body of information on the structures, syntheses, and biological activities of HDAC inhibitors, several important questions regarding their physicochemical properties and metal affinities/selectivities remain answered. First, how do the conformation and ionization of the hydroxamic group depend on its chemical composition and the dielectric properties of themedium? Second, how do these factors affect the affinities and selectivities of HDAC inhibitors for essential biogenic metal cations? Third, what is the preferred deprotonation site of the hydroxamic moiety and its mode of binding to the metal cation? The present work addressed these questions by performing density functional calculations combined with polarizable continuum model computations. The geometry, deprotonation pattern, metal-binding mode, and metal affinity/selectivity of SAHA, a typical HDAC inhibitor, were examined, and key factors affecting its ligation properties were elucidated. Sulfur- and selenium-containing analogs of SAHA were also modeled for the first time, and their potential as efficient metal-binding entities (to Mg2+, Fe2+, and Zn2+ cations) was assessed. The present calculations shed light on the thermodynamics of the binding of HDAC inhibitors to metal ions, and suggest techniques for enhancing their metal-ligating properties.