Browsing by Subject "chelator"

Metallosupramolecular polymers are increasingly of interest for functional and degradable polymeric materials. In these materials, the metal-ligand bonds often bear an external mechanical load, but little is yet understood about the nature of mechanically-triggered reactions of metal-ligand bonds and how that reactivity influences the mechanical limits of the material. This dissertation presents a poly(cyclooctene) polymer bearing 2,6-bis(1′-methyl-benzimidazolyl)pyridine (Mebip) ligands on sidechains, which provides easy incorporation into polymer backbones and sidechains, binding to a large variety of metal species, and facile synthesis with sites for future study substituent effects. This platform is employed in proof-of-concept studies comparing the crosslinking behavior of iron(II) trifluoromethanesulfonate and copper(II) trifluoromethanesulfonate. It was found through small molecule spectroscopic studies that both metal species bind in the desired 2:1 MeBip:metal stoichiometry for crosslinking. When these small molecule complexes are polymerized as crosslinkers in gel and solid networks, though the extent of crosslinking is found to be similar, the copper(II)-crosslinked networks exhibited a faster relaxation than the iron(II)-crosslinked networks. Further, under high strains, the copper(II)-crosslinked networks exhibited significantly higher extensibility. This work lays the foundation for further investigations of the effect of metal-ligand bonding on force-coupled properties of materials.

The ability to manipulate the coordination chemistry of metal ions has significant ramifications for the study and treatment of metal-related health concerns, including iron overload, UV skin damage, and microbial infection among many other conditions. To address this concern, chelating agents that change their metal binding characteristics in response to external stimuli have been synthesized and characterized by several spectroscopic and chromatographic analytical methods. The primary stimuli of interest for this work are light and hydrogen peroxide.

Herein we report the previously unrecognized photochemistry of aroylhydrazone metal chelator ((E)-N′-[1-(2-hydroxyphenyl)ethyliden]isonicotinoylhydrazide) (HAPI) and its relation to HAPI metal binding properties. Based on promising initial results, a series of HAPI analogues was prepared to probe the structure-function relationships of aroylhydrazone photochemistry. These efforts elucidate the tunable nature of several aroylhydrazone photoswitching properties.

Ongoing efforts in this laboratory seek to develop compounds called prochelators that exhibit a switch from low to high metal binding affinity upon activation by a stimulus of interest. In this context, we present new strategies to install multiple desired functions into a single structure. The prochelator 2-((E)-1-(2-isonicotinoylhydrazono)ethyl)phenyl (E)-3-(2,4-dihydroxyphenyl)acrylate (PC-HAPI) is masked with a photolabile trans-cinnamic acid protecting group that releases umbelliferone, a UV-absorbing, antioxidant coumarin along with a chelating agent upon UV irradiation. In addition to the antioxidant effects of the coumarin, the released chelator (HAPI) inhibits metal-catalyzed production of damaging reactive oxygen species. Finally a peroxide-sensitive prochelator quinolin-8-yl (Z)-3-(4-hydroxy-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)acrylate (BCQ) has been prepared using a novel synthetic route for functionalized cis-cinnamate esters. BCQ uses a novel masking strategy to trigger a 90-fold increase in fluorescence emission, along with the release of a desired chelator, in the presence of hydrogen peroxide.

New strategies are urgently needed to overcome the growing threat of antibacterial drug resistance. One mechanism of drug resistance commonly employed by bacterial pathogens is expression of β-lactamases, which confer resistance through hydrolysis of β-lactam antibiotics, an important class of antibacterial compounds that target cell wall biosynthesis. We have developed multiple new strategies to take advantage of β-lactamase expression to deliver antibacterial metal chelators to drug-resistant bacteria. First, we describe the copper-dependent activity of an antibacterial prodrug named PcephPT, which is based on the structure of a cephalosporin, a type of β-lactam antibiotic. Using antibacterial susceptibility assays and analytical techniques, we demonstrate that PcephPT disrupts the homeostasis of copper, an essential but toxic metal, by releasing the antimicrobial chelator pyrithione (PT) in response to β-lactamase-mediated hydrolysis. We found that, in addition to inhibiting bacterial growth in a copper-dependent manner, PcephPT leads to inhibition of NDM-1, a β-lactamase that catalyzes hydrolysis using enzyme-bound zinc ions. Bacterial pathogens expressing metallo-β-lactamases such as NDM-1 are difficult to overcome with antibacterial treatment, and the success of PcephPT in inhibiting NDM-1 is a promising indication that chelator-releasing prodrugs (“prochelators”) are a useful strategy for metallo-β-lactamase inhibitor development. Enzymatic and spectroscopic assays reveal important information about the mechanism of PcephPT-mediated NDM-1 inhibition, which involves formation of a ternary complex with the zinc-containing active site and PT, one of the products of PcephPT hydrolysis. We next present progress on synthesizing and evaluating new prochelators that are designed to have increased specificity for drug-resistant strains. These compounds have core structures based on β-lactamase inhibitors, which are not inherently antibacterial, but may still release chelators for both antibacterial activity and metallo-β-lactamase inhibition. Finally, we discover a new class of metallo-β-lactamase inhibitors based on benzimidazole and benzoxazole zinc-chelating agents that form a ternary complex in the active site of NDM-1 and have the potential to be further optimized for inhibitory properties and targeting of drug-resistant bacteria.