UC San Diego
Heterocyclic metal-binding Groups for matrix metalloproteinase and anthrax lethal factor inhibition
- Author(s): Lewis, Jana Ann-Sook
- et al.
Heterocyclic metal-binding groups with therapeutic potential have been examined. This dissertation will first discuss the synthesis of thiopyrone and hydroxypyridinethione ligands along with the synthesis and characterization of novel metal complexes with these ligands. The focus will then shift to studying these heterocyclic ligands as metalloprotease inhibitors. Metalloprotein inhibition is important for many potential medicinal applications. Some hydrolytic zinc(II)-dependent enzymes such as matrix metalloproteinases (MMPs) and anthrax lethal factor (LF) represent targets of therapeutic interest. This dissertation discusses a bioinorganic approach to MMP and LF inhibition focusing on the interaction between the zinc-binding group (ZBG) of a potential inhibitor and the catalytic zinc(II) ion. After presenting the syntheses of thiopyrone and hydroxypyridinethione ligands, the coordination chemistry with iron(III), nickel(II), copper(II), cobalt(II), zinc(II), and lead(II) ions will be described. Characterization of these complexes represents a fundamental step for considering the use of heterocyclic ligands for medicinal and environmental applications. The potency, toxicity, and thiol reactivity studies of the heterocyclic chelators are presented. Recombinant and cell culture inhibition assays show that these heterocyclic ligands are more potent MMP inhibitors than acetohydroxamic acid, which represents the ZBG used in most MMP inhibitors synthesized to date. The ZBGs are nontoxic at high micromolar concentrations in cell culture studies. The reactivity of the O,S ligands is much lower than thiol-based ligands. The heterocyclic ZBGs are potent, nontoxic, biocompatible ligands that expand the ZBG library for MMP inhibitors. The heterocyclic ligands are also viable alternatives for inhibitors for other metalloproteases such as anthrax lethal factor (LF). These ZBGs show comparable or improved potency compared to acetohydroxamic acid against LF. Studies with full-length inhibitors based on a thiopyrone ZBG have similar potencies to other LF inhibitors found in the literature. Potential binding modes of the full-length inhibitors are also presented. Finally, co-crystallization studies using the catalytic domain of MMP-3 and pyrone-based inhibitors are described. Comparison of co-crystallization data to model complex structural data and computationally predicted inhibitor conformations would help test the validity of our bioinorganic approach. In conclusion, inhibitors based on the heterocyclic ligands show promise as potent metalloprotein inhibitors