APPLICATIONS OF DYNAMIC COMBINATORIAL LIBRARIES TO IMPRINT-AND- REPORT DIFFERENTIAL SENSOR ARRAYS

Sensor arrays allow for discrimination of analytes using a set of supramolecular hosts via differential indicator displacement responses. While many recent advances have been made in this field, the design, synthesis, and characterization of hosts for an array still greatly hinder the development of new supramolecular sensing systems. Dynamic combinatorial chemistry (DCC) has streamlined host development, but the hosts are still typically generated on preparatory scale and used in isolation. Moreover, examples of sensor arrays that have the capacity to differentiate mixtures of analytes, especially in complex matrices such as biological fluids, are lacking.The work described herein represents a novel approach to the development of sensor arrays and demonstrates adaptability of the method to several sets of analytes. Instead of discrete hosts, we show that entire dynamic combinatorial libraries (DCLs) can function as sensors to generate an array. The DCLs are templated with either the analyte or the fluorophore and allowed to fully equilibrate and oxidize. Addition of the other component (fluorophore or analyte, respectively) then creates a signal based on the distribution of species present in the DCL and the affinities with which they bind to the analyte and fluorophore. We call this method “imprint-and-report,” referring to the generation of an imprinted DCL that is no longer exchanging, followed by the measurement of a fluorescence report once both the analyte and indicator are present.We first demonstrate the differentiation of all methylation states of lysine and arginine, important disease biomarkers. We then use different DCLs to differentiate dietary metabolites, including trimethylamine N-oxide (TMAO), a biomarker for future cardiac events, and we show that the DCLs can also be used to discriminate metabolite mixtures. Notably, human plasma samples containing elevated TMAO are differentiated from those with a healthy level. Finally, we incorporate a fluorinated building block into a set of DCLs to differentiate polyfluoroalkyl species (PFAS) at the lowest concentrations achieved by a fluorescent sensor. Imprint-and-report represents an important advancement in supramolecular sensors, as it has a significantly streamlined workflow, powerful analyte differentiation resulting from interactions with the mixtures of species in each DCL, and adaptability to various analytes.Doctor of Philosoph