PhD candidate, Chemistry
Duke University, Durham, NC
Research interests
Research at UNC-Wilmington
My research was devoted to the study of interactions between metal ions and preorganized ligand systems. My main focus was on the interactions between cadmium and crown ether molecules and the influence of secondary ligands bound to axial sites on the characteristics of the bonds formed.
Cadmium is a neurotoxin, and crown ethers act as good models for ion channels utilized in neuroreceptors. Thus, the study of this system could lead to important understanding of the interactions involved in neurotoxicity of cadmium. The determined stability constant for the Cd-[18-crown-6] complex was much hi
gher than would have been predicted by the size-exclusion principle of metal ion bonding, and the crystal structures of a series of cadmium-crown ether complexes with different ligands binding through the axial site showed a range of bond lengths, as well as effecting the bond lengths of the Cd-O bonds between the cadmium ion and the crown ether. The variation of bond length with variation in axial ligands demonstrated that cadmium has valence electron orbitals whose hybrid characteristics can be effected by the ionic characteristics of the bonds formed with the axial ligands. It also suggets the involvement of relativistic effects in the bonding of cadmium. These findings are significant, as relativistic effects are generally not viewed as being important in the characteristics of metal ions until much later in the periodic table.
My research also focused on the stability constants of indium with a series of polyamine ligands, as determined by differential pulse voltammetry. This is significant, because indium (III) is an extremely acidic metal ion that will normally precipitate out of solution at higher pH, where voltammetric determinations would take place. The stability constants we determined were also related to theoretical calculations of LFER for the stability of binding of ammonia with the metal ions versus the stability of binding linear polyamines with the metal ions to provide a theoretical method of calculating binding of some ligands with very acidic metal ions.
Another projecct focused on the binding properties of a series of highly preorganized ligands based around a 1,10-phenanthroline backbone with a series of metal ions and the synthesis of those preorganized ligands. This class of ligands has been found to exhibit interesting binding characteristics with a number of metal ions, including uranyl ion, to suggest their possible use in isolation of radioactive materials.
Current Research Interests at Duke University
In biology, iron is a necessary metal ion for organisms to survive. However, iron is a metal ion that easily precipitates from solution as unusable hydroxide complexes. To make iron in the environment biologically available, bacteria produce low-molecular-weight compounds known as siderophores that bind iron specifically and with high affinity to bring it into the cell. Studying these siderophores in the laboratory can be difficult because of their low water-solubility. This problem, however, can be solved by studying compounds of similar structure that have higher solubility.
My major research project involved studying 9-ane-N3 and 6-ane-N2-based siderophore models with hydroxypyridinone donor groups donated by Dr. Aravamudan Gopalan at New Mexico State University. The thermodynamic stability of the iron complexes of these molecules were determined and compared to other natural siderophores. A series of UV/Vis spectrophotometric experiments were used to study the absorptive properties of the complexes, and then use those characteristics in conjunction with competition titrations with EDTA to determine the thermodynamic stability constants of the complexes. pH-dependent spectrophotometric titrations were used to determine the protonation constants of the complexes to provide a fuller view of the behavior of similar complexes in biological systems.
In the future, we will study the electrochemical properties of the complexes by cyclic voltammetry. Determination of the reduction potentials of the complexes will provide insight into possible mechanisms of iron release upon crossing the periplasmic membrane. We also hope to investigate possible host-guest complex formation as a possible method of transport across the cellular membrane. We will investigate the mechanism of exchange between the tris-hydroxypyridinone siderophore complex with iron and desferrioxamine B using UV-Visible spectrophotometry. The thermodynamics of the tertiary complexes between iron-desferrioxamine B and a series of lariat ether and similar molecules will also be studied using spectrophotometric methods to observe the possibility of the formation of inner sphere-outer sphere complex formation.
A second project involves the investigation of the interactions between iron and the siderophore, brasilibactin A. This is a cytotoxic compound that has been shown to activate caspase 3, an enzyme important to apoptosis. Exposure of caspase 3 to iron has been shown to inactivate the enzyme's activity, and exposure to other siderophores has been shown to reactivate it, so brasilibactin's cytotoxic effect is proposed to be due to its iron-binding properties. We will study the thermodynamics of binding of brasilibactin to iron, as well as a series of mutant forms of brasilibactin A with weaker binding groups to determine the structural basis of its binding stability. Brasilibactin A has been shown not to inhibit HDAC, unlike other hydroxamate-binding group small molecules. The small molecule inhibitors that have been discovered are proposed to act due to their ability to bind to the catalytic zinc center of HDAC. The second part of this study will attempt to determine if the lack of inhibition is due to the zinc-binding abilities of brasilibactin A or the architecture of the molecule. We will investigate the thermodynamics of binding of brasilibactin A with zinc through potentiometric and NMR studies of the binding and its exchange with iron.
Personal research interests
My personal research interests can cover a wide range of possible topics, as my interests range from biological to inorganic to analytical chemistry. My strongest desire is to continue in inorganic research, studying the interactions of transition metals with a variety of biologically and industrially relevant molecules. Inorganic chemistry is a rich and diverse field, with coordination chemistry serving as the bedrock for all other fields of inorganic chemistry. I have in the past focused on the structural basis of metal ion binding stability in ligands for the purpose of improved ligand design for use in medical procedures, as this could potentially lead to the development of treatments that could alleviate the suffering of many people afflicted with a variety of illnesses. There are, however, a variety of fields in analytical and environmental chemistry that would be of interest to me, also. The detection of metal ions or carcinogenic organic molecules in complex environmental and biological samples could have widespread implications for public health and safety, as well as medical applications. Metalloprotein binding to metals can provide information about the genetic basis for some diseases, as well as helping us to understand the uptake of a variety of metals in biological systems.
Presentations (presenter underlined)
Harrington, James M., Chittamuru, Sumathi, Jacobs, Hollie K., Gopalan, Aravamudan S., and Crumbliss, Alvin L., Kinetics and mechanism of iron exchange between synthetic hydroxypyridinone chelators and molecules of biological interest. 238th National Meeting of the American Chemical Society, Washington, DC, United States, Aug. 17 (2009).
Harrington, James M., Ying, Yongcheng, Park, Heekwang, Hong, Jiyong, and Crumbliss, Alvin L., Thermodynamic characterization of iron(III) and zinc binding by Brasilibactin A. (Poster) 238th National Meeting of the American Chemical Society, Washington, DC, United States, Aug. 17 (2009).
Harrington, James M., Bioinorganic chemistry in teaching and research: Coordination chemistry of transition metals. (Poster) 238th National Meeting of the American Chemical Society, Washington, DC, United States, Aug. 17 (2009).
Harrington, James M., Dhungana, Suraj, Chittamuru, Sumathi, Jacobs, Hollie K., Gopalan, Aravamudan S., and Crumbliss, Alvin L., Iron(III) sequestration by synthetic hydroxypyridinone siderophores and exchange with desferrioxamine B. 2nd Annual Chemical Sciences Symposium, NCA&T State University, Greensboro, NC, United States, Feb. 28 (2008).
Harrington, James M., Dhungana, Suraj, Chittamuru, S., Jacobs, Hollie K., Gopalan, A. S., Crumbliss, Alvin L., Iron(III) sequestration by synthetic hydroxypyridinone siderophores and exchange with desferrioxamine B. 234th National Meeting of the American Chemical Society, Boston, MA, United States, Aug. 19-23 (2007).
Harrington, James M., Dhungana, Suraj, Crumbliss, Alvin L., Binding of synthetic hydroxypyridinone Siderophores to iron in aqueous solution and exchange mechanism with the iron-desferrioxamine B complex. 121st Local Meeting of the North Carolina American Chemical Society, Durham, NC, United States, Apr. 21 (2007).
Harrington, James M.; Jones, S. Bart; Hancock, Robert D., Investigation of Relativistic effects in the formation of cadmium complexes. (Poster) 56th Southeast Regional Meeting of the American Chemical Society, Research Triangle Park, NC, United States, November 10-13 (2004).
Jones, S.; Harrington, James; Hancock, Robert. Stability of complexes of lead and cadmium with crown ethers, and the role of relativistic effects in the chemistry of group 12 ions>. (Poster) 55th Southeast Regional Meeting of the American Chemical Society, Atlanta, GA, United States, November 16-19, 2003 (2003).