Book Description

This research aimed to synthesize and characterize Zn2+-ligand complexes that have the same zinc coordination environment as in histone deacetylase (HDAC) and other important zinc dependent enzymes. Mimicking the structural and the functional properties of Zn2+-enzymes will allow us to understand the binding reactivity between Zn2+ and small molecule enzyme inhibitors. The new understanding will help to develop new approaches to target disease states such as cancer. A variety of Zn2+ binary complexes have been synthesized and their interactions with inhibitors such as suberanilohydroxamic acid (SAHA) and 8-Hydroxyquinoline (8HQ) have been studied using 1H NMR, UV-Vis, and fluorescence spectroscopies. Attempts were made to mimic the structure of Zn2+-metalloenzyme active sites by exploring several different supporting ligands to model enzyme active sites. We endeavored to mimic an "O2N" ligand set of HDAC by using reported Zn2+-complexes ligated by Bis(phenolato)amine (H2L1), Bis(2-picolyl) amine (BPA, L2), hydrotris(3-phenyl-5-methylpyrazol-1-yl) (TpPh,Me, L3), and a similar neutral ligand (L4). The binding constants of the ligands with zinc were estimated using UV-Vis studies and calculations based on equilibrium expressions. This data was compared with previously reported data using other methods such as potentiometry and isothermal titration calorimetry. Once the zinc-ligand complexes were obtained, they were examined for mimicking zinc active sites. Attempts were made to study the interaction of inhibitors with the zinc center using 1H NMR, UV-Vis, and fluorescence spectroscopies. In addition, the functional properties of the mimicked structure were explored by attempting to cleave the amide group of a model substrate for HDAC, N-acetylbenzylamine. Although the Zn2+ species were not active, Al 3+ was observed to cleave the amide group at high temperature after extended periods of time. The zinc-ligand 9 structures were also examined using computational methods to support the experimental data. The results of this work are valuable complementary data to previously reported ITC data and the known biological systems.