This research program seeks to develop a modular approach to synthesize highly-conjugated arylethynyl receptors for anion recognition. Unlike the majority of fluorescent anion sensors, these sensors contain an inherently fluorescent backbone as opposed to a pendant fluorophore. The research will address fundamental problems in the development of molecular probes and binding agents for anions and focuses on three main areas: (1) investigating the similarities and differences in reversible binding of chloride and hydrosulfide anions through physical organic studies; (2) synthesizing and quantifying anion binding properties of receptors featuring new and emerging recognition motifs that feature electron-deficient aromatic rings; and (3) studying the feasibility of these compounds as fluorescent molecular probes for chloride and, longer-term, for other anions (e.g., phosphates, bicarbonate, hydrosulfide) through studies in cellular environments. The proposed receptors will also help provide a fundamental understanding of anion coordination chemistry. Anions are vital to many biological processes (endocytosis, lysosome activity, kinase function, etc.), they are increasingly recognized as problematic environmental contaminants, and anion binding proteins and transport channels are implicated in the mechanisms of many disease pathways and biological functions. This research will provide fundamental insight into emerging new approaches to target anions (e.g., C-H???anion hydrogen bonding, halogen bonding) and will provide selective anion binding receptors that maintain binding affinity and a fluorescent response even in aqueous solvent mixtures. Understanding anion binding on a molecular level is of paramount importance if one wishes to elucidate the roles of anions in more complicated biological processes and this proposal seeks to provide fluorescent probes as tools for this pursuit.
The specific aims of the proposed research are: (1) to investigate the reversible binding of chloride and hydrosulfide to hosts by developing design rules to understand the surprisingly similar recognition chemistry of these disparate anions; (2) to synthesize and study new series of inherently fluorescent receptors that use ?non-traditional? anion recognition motifs; and (3) to develop new water-soluble small molecule fluorescent probes for anions and to screen successful candidates in cell/lysate assays. We will investigate receptors developed on this project first using modern physical organic methods, including: molecular modeling for host design; host-guest titrations to quantify the energetics of binding interactions; linear free energy relationships and equilibrium isotope effects to understand the fundamental nature of anion binding interactions; and a variety of spectroscopic techniques to assess solution speciation. Collaborations will enable screening of successful host molecules as molecular probes for in vitro and in vivo applications and provide computational assistance for the physical organic and receptor design studies. In the long term, probes developed in this project can be broadly used by researchers studying anion homeostasis and ion transport.

Public Health Relevance

Anions are negatively charged molecules that can exist as problematic environmental contaminants and are vital to many processes in nature; for instance, anion binding proteins and anion transport channels are implicated in the mechanisms of many disease pathways. The research proposed in this application will lead to new fluorescent ?turn-on? probes that can selectively bind and sense anions and will contribute to fundamental understanding of the nature of anion binding interactions. 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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Aslan, Kadir
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University of Oregon
Schools of Arts and Sciences
United States
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Tresca, Blakely W; Brueckner, Alexander C; Haley, Michael M et al. (2017) Computational and Experimental Evidence of Emergent Equilibrium Isotope Effects in Anion Receptor Complexes. J Am Chem Soc 139:3962-3965
Eytel, Lisa M; Gilbert, Annie K; Görner, Paul et al. (2017) Do CH-Anion and Anion-? Interactions Alter the Mechanism of 2:1 Host-Guest Complexation in Arylethynyl Monourea Anion Receptors? Chemistry 23:4051-4054
Hartle, Matthew D; Hansen, Ryan J; Tresca, Blakely W et al. (2016) A Synthetic Supramolecular Receptor for the Hydrosulfide Anion. Angew Chem Int Ed Engl 55:11480-4
Vonnegut, Chris L; Shonkwiler, Airlia M; Zakharov, Lev N et al. (2016) Harnessing solid-state packing for selective detection of chloride in a macrocyclic anionophore. Chem Commun (Camb) 52:9506-9
Tresca, Blakely W; Berryman, Orion B; Zakharov, Lev N et al. (2016) Anion-directed self-assembly of a 2,6-bis(2-anilinoethynyl)pyridine bis(amide) scaffold. Supramol Chem 28:37-44
Vonnegut, Chris L; Shonkwiler, Airlia M; Khalifa, Muhammad M et al. (2015) Facile Synthesis and Properties of 2-?(5)-Phosphaquinolines and 2-?(5)-Phosphaquinolin-2-ones. Angew Chem Int Ed Engl 54:13318-22
Watt, Michelle M; Engle, Jeffrey M; Fairley, Kurtis C et al. (2015) ""Off-on"" aggregation-based fluorescent sensor for the detection of chloride in water. Org Biomol Chem 13:4266-70
Vonnegut, Chris L; Tresca, Blakely W; Johnson, Darren W et al. (2015) Ion and molecular recognition using aryl-ethynyl scaffolding. Chem Asian J 10:522-35
Berryman, Orion B; Johnson 2nd, Charles A; Vonnegut, Chris L et al. (2015) Solid-State Examination of Conformationally Diverse Sulfonamide Receptors Based on Bis(2-anilinoethynyl)pyridine, -Bipyridine, and -Thiophene. Cryst Growth Des 15:1502-1511
Tresca, Blakely W; Hansen, Ryan J; Chau, Calvin V et al. (2015) Substituent Effects in CH Hydrogen Bond Interactions: Linear Free Energy Relationships and Influence of Anions. J Am Chem Soc 137:14959-67

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