The overarching theme of this research program is the utilization of a modular approach to synthesize highly-conjugated arylethynyl and P,N-heterocyclic receptors for anion recognition. Unlike the majority of fluorescent anion sensors, these sensors contain an inherently fluorescent backbone as opposed to a pendant fluorophore unit. The research will address fundamental problems in the development of the next generation of molecular probes and binding agents for anions and focuses on three main areas: (1) synthesizing and studying new recognition motifs and scaffolds to advance our modular design strategy; (2) quantifying the interactions of these receptors with anions, and (3) applying these compounds as new fluorescent molecular probes for chloride. The proposed receptors will also help provide a fundamental understanding of anion coordination chemistry. Anions are increasingly recognized as problematic environmental contaminants and are vital to many processes in nature, ranging from developing tertiary structure in proteins and DNA, to ?synergistic? binding of metals in proteins, to their increasingly understood role in biological processes including endocytosis, lysosome activity and kinase function, among others. Anion binding proteins and transport channels also may be involved in the mechanisms of a variety of disease pathways (e.g., Cystic Fibrosis, osteopetrosis, Alzheimer's disease, cancers, etc.). This research will provide fundamental insight into emerging new approaches to target anions (?anion-?-type? interactions, C-Hanion hydrogen bonding) and may provide novel selectivity in anion coordination. 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.
The specific aims of the proposed research are: (1) to synthesize and study a series of receptors for anions that exhibit tunable OFF-ON fluorescence resulting from the modular design; (2) to elaborate a new class of fluorescent P,N-heterocycles as anion binding agents; 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 kinetic 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. In the long term, probes developed in this project can be used broadly by researchers studying anion homeostasis and ion transport.

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 fluorescent ?turn-on? receptors 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM087398-06A1
Application #
9194789
Study Section
Special Emphasis Panel (ZRG1-BCMB-W (02)M)
Program Officer
Fabian, Miles
Project Start
2010-05-15
Project End
2018-08-31
Budget Start
2016-09-15
Budget End
2017-08-31
Support Year
6
Fiscal Year
2016
Total Cost
$250,271
Indirect Cost
$75,271
Name
University of Oregon
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Eugene
State
OR
Country
United States
Zip Code
97403
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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