The overarching theme of the proposed research program is to design modular organic receptors containing recognition elements that are optimized to bind anions in solution. The modularity allows for facile substitution of inherently fluorescent organic cores, recognition elements, linkers and functionality. This research will aid in the development of the next generation of molecular probes, sensors and binding agents for anions. The proposed receptors will also help provide a fundamental understanding of the structural role anions play in self-assembly and their interactions with electron- deficient aromatic rings. Long-term applications of this research include cellular and in vitro imaging of anions.
The specific aims of the proposed research are: 1) to synthesize and to study a series of receptors for anions resulting from the proposed modular design strategy, 2) to study the modular receptors as fluorescent molecular probes for applications in chemical biology, and 3) to study the interaction of anions with electron-deficient aromatic rings and design recognition elements to exploit this emerging anion-binding motif. The modularity of the proposed design strategy allows for exploration of a variety of recognition motifs for anions, including electrostatic attractions, hydrogen bond interactions and attractions with electron-deficient arenes (anion-pi, CH---X- hydrogen bonds and weak-sigma complexes). This flexibility allows for the possibility of selectively binding anions that are challenging to target with traditional approaches. Core and linker substitution provides another approach to tuning the selectivity of the receptors by changing the shape and size of the binding pocket. The functionality of the receptors can also be adjusted to provide a route to make the molecules water-soluble or even permeable to cell membranes, as applications in cellular imaging are pursued once the solution chemistries are worked out. Studying new recognition motifs for anions, such as the emerging interaction between anions and electron-deficient arenes, requires understanding the basic science of manipulating these new theoretical binding motifs in order to design novel receptors. Applications from this research have the potential to be transferred to the design of new materials for remediation and sensing and may provide insights on the interaction between anions and biological substrates. The proposed research may also shed light on self-assembly processes in more complex biological systems. Therefore understanding anion binding on a molecular level is of paramount importance if one wishes to elucidate the roles of anions in the much more complicated biological processes.

Public Health Relevance

Anions are problematic environmental contaminants and are vital to many processes in nature, with anion binding proteins and transport channels implicated in the mechanisms of many disease pathways. The research proposed in this application will lead to new organic receptors that selectively bind and sense anions. These molecules will have long-term applications in sensing, imaging and/or remediating anions, which will impact public health in both discovering and removing environmental contaminants and imaging the role anions play in biological processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM087398-03
Application #
8270506
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fabian, Miles
Project Start
2010-05-15
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$240,293
Indirect Cost
$59,618
Name
University of Oregon
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
948117312
City
Eugene
State
OR
Country
United States
Zip Code
97403
Engle, Jeffrey M; Singh, Pushpinder S; Vonnegut, Chris L et al. (2014) Synthesis and solid-state structures of a macrocyclic receptor based on the 2,6-bis(2-anilinoethynyl)pyridine scaffold. CrystEngComm 16:3703-3706
Gavette, Jesse V; Evoniuk, Christopher J; Zakharov, Lev N et al. (2014) Exploring Anion-Induced Conformational Flexibility and Molecular Switching in a Series of Heteroaryl-Urea Receptors. Chem Sci 5:2899-2905
Gavette, Jesse V; Klug, Christina M; Zakharov, Lev N et al. (2014) Intramolecular N-H···Cl hydrogen bonds in the outer coordination sphere of a bipyridyl bisurea-based ligand stabilize a tetrahedral FeLCl2 complex. Chem Commun (Camb) 50:7173-5
Tresca, Blakely W; Zakharov, Lev N; Carroll, Calden N et al. (2013) Aryl C-HýýýýýýCl(-) hydrogen bonding in a fluorescent anion sensor. Chem Commun (Camb) 49:7240-2
Gavette, Jesse V; Lara, Juven; Reling, Linda L et al. (2013) Lithium-selective phosphine oxide-based ditopic receptors show enhanced halide binding upon alkali metal ion coordination. Chem Sci 4:585-590
Gavette, Jesse V; Mills, Nancy S; Zakharov, Lev N et al. (2013) An anion-modulated three-way supramolecular switch that selectively binds dihydrogen phosphate, H2PO4-. Angew Chem Int Ed Engl 52:10270-4
Watt, Michelle M; Zakharov, Lev N; Haley, Michael M et al. (2013) Selective nitrate binding in competitive hydrogen bonding solvents: do anion-? interactions facilitate nitrate selectivity? Angew Chem Int Ed Engl 52:10275-80
Gavette, Jesse V; Lara, Juven; Berryman, Orion B et al. (2011) Lithium cation enhances anion binding in a tripodal phosphine oxide-based ditopic receptor. Chem Commun (Camb) 47:7653-5
Engle, Jeffrey M; Lakshminarayanan, P S; Carroll, Calden N et al. (2011) Molecular Self Assembly: Solvent Guests Tune the Conformation of a Series of 2,6-Bis(2-anilinoethynyl)pyridine-Based Ureas. Cryst Growth Des 11:5144-5152
Carroll, Calden N; Coombs, Brian A; McClintock, Sean P et al. (2011) Anion-dependent fluorescence in bis(anilinoethynyl)pyridine derivatives: switchable ON-OFF and OFF-ON responses. Chem Commun (Camb) 47:5539-41

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