Development of Stimulus-Responsive Ligands for the Modulation of Copper and Iron Coordination

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.

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice.

Excessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. Serial analyses of β-thalassemic mice indicate that while hemoglobin levels decrease over time, the concentration of iron in the liver, spleen, and kidneys markedly increases. Iron overload is associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Patients with β-thalassemia also have low hepcidin levels. These observations led us to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis and that increasing the concentration of hepcidin in the body of such patients might be therapeutic, limiting iron overload. Here we demonstrate that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. These data led us to suggest that therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.

Associations between BMI and home, school and route environmental exposures estimated using GPS and GIS: do we see evidence of selective daily mobility bias in children?

BACKGROUND: This study examined whether objective measures of food, physical activity and built environment exposures, in home and non-home settings, contribute to children's body weight. Further, comparing GPS and GIS measures of environmental exposures along routes to and from school, we tested for evidence of selective daily mobility bias when using GPS data. METHODS: This study is a cross-sectional analysis, using objective assessments of body weight in relation to multiple environmental exposures. Data presented are from a sample of 94 school-aged children, aged 5-11 years. Children's heights and weights were measured by trained researchers, and used to calculate BMI z-scores. Participants wore a GPS device for one full week. Environmental exposures were estimated within home and school neighbourhoods, and along GIS (modelled) and GPS (actual) routes from home to school. We directly compared associations between BMI and GIS-modelled versus GPS-derived environmental exposures. The study was conducted in Mebane and Mount Airy, North Carolina, USA, in 2011. RESULTS: In adjusted regression models, greater school walkability was associated with significantly lower mean BMI. Greater home walkability was associated with increased BMI, as was greater school access to green space. Adjusted associations between BMI and route exposure characteristics were null. The use of GPS-actual route exposures did not appear to confound associations between environmental exposures and BMI in this sample. CONCLUSIONS: This study found few associations between environmental exposures in home, school and commuting domains and body weight in children. However, walkability of the school neighbourhood may be important. Of the other significant associations observed, some were in unexpected directions. Importantly, we found no evidence of selective daily mobility bias in this sample, although our study design is in need of replication in a free-living adult sample.