Application of an Imprint-and-Report Sensor Array for Detection of the Dietary Metabolite Trimethylamine N-Oxide and Its Precursors in Complex Mixtures.

Trimethylamine N-oxide (TMAO) is produced in the gut via metabolism of dietary betaine, choline, and carnitine, and elevated TMAO in plasma is associated with adverse health effects, including cardiovascular events. Currently, we lack high throughput methods for sensing these metabolites and detecting high TMAO. Thus, we have adapted our previously described "imprint-and-report" fluorescent sensing method using dynamic combinatorial libraries (DCLs) to create a sensor array for these four metabolites that functions at physiologically relevant concentrations. Templation of DCLs with dye and subsequent addition of analytes generates a fluorescent fingerprint for each metabolite and allows for differentiation via principal component analysis (PCA). Furthermore, we demonstrate that this system can be used to characterize mixtures of the metabolites in both buffer and human plasma samples. Using three to six DCLs, we can distinguish between plasma samples with healthy and elevated levels of TMAO.

Development of "Imprint-and-Report" Dynamic Combinatorial Libraries for Differential Sensing Applications.

Sensor arrays using synthetic receptors have found great utility in analyte detection, resulting from their ability to distinguish analytes based on differential signals via indicator displacement. However, synthesis and characterization of receptors for an array remain a bottleneck in the field. Receptor discovery has been streamlined using dynamic combinatorial libraries (DCLs), but the resulting receptors have primarily been utilized in isolation rather than as part of the entire library, with only a few examples that make use of the complexity of a library of receptors. Herein, we demonstrate a unique sensor array approach using "imprint-and-report" DCLs that obviates the need for receptor synthesis and isolation. This strategy leverages information stored in DCLs in the form of differential library speciation to provide a high-throughput method for both developing a sensor array and analyzing data for analyte differentiation. First, each DCL is templated with analyte to give an imprinted library, followed by in situ fluorescent indicator displacement analysis. We further demonstrate that the reverse strategy, imprinting with the fluorescent reporter followed by displacement with each analyte, provides a more sensitive method for differentiating analytes. We describe the development of this differential sensing system using the methylated Arg and Lys post-translational modifications (PTMs). Altogether, 19 combinations of 3-5 DCL data sets that discriminate all 7 PTMs were identified. Thus, a comparable sensor array workflow results in a larger payoff due to the immense information stored within multiple noncovalent networks.

Mimicking Biological Recognition: Lessons in Binding Hydrophilic Guests in Water.

Selective molecular recognition of hydrophilic guests in water plays a fundamental role in a vast number of biological processes, but synthetic mimicry of biomolecular recognition in water still proves challenging both in terms of achieving comparable affinities and selectivities. This Review highlights strategies that have been developed in the field of supramolecular chemistry to selectively and non-covalently bind three classes of biologically relevant molecules: nucleotides, carbohydrates, and amino acids. As several groups have systematically modified receptors for a specific guest, an evolutionary perspective is also provided in some cases. Trends in the most effective binding forces for each class are described, providing insight into selectivity and potential directions for future work.

(Cyclopentadienone)iron-Catalyzed Transfer Dehydrogenation of Symmetrical and Unsymmetrical Diols to Lactones.

Air-stable iron carbonyl compounds bearing cyclopentadienone ligands with varying substitution were explored as catalysts in dehydrogenative diol lactonization reactions using acetone as both the solvent and hydrogen acceptor. Two catalysts with trimethylsilyl groups in the 2- and 5-positions, [2,5-(SiMe3)2-3,4-(CH2)4(η4-C4C═O)]Fe(CO)3 (1) and [2,5-(SiMe3)2-3,4-(CH2)3(η4-C4C═O)]Fe(CO)3 (2), were found to be the most active, with 2 being the most selective in the lactonization of diols containing both primary and secondary alcohols. Lactones containing five-, six-, and seven-membered rings were successfully synthesized, and no over-oxidations to carboxylic acids were detected. The lactonization of unsymmetrical diols containing two primary alcohols occurred with catalyst 1, but selectivity was low based on alcohol electronics and modest based on alcohol sterics. Evidence for a transfer dehydrogenation mechanism was found, and insight into the origin of selectivity in the lactonization of 1°/2° diols was obtained. Additionally, spectroscopic evidence for a trimethylamine-ligated iron species formed in solution during the reaction was discovered.

Detection and differentiation of per- and polyfluoroalkyl substances (PFAS) in water using a fluorescent imprint-and-report sensor array.

Widespread industrial use of per- and polyfluoroalkyl substances (PFAS) as surfactants has led to global contamination of water sources with these persistent, highly stable chemicals. As a result, humans and wildlife are regularly exposed to PFAS, which have been shown to bioaccumulate and cause adverse health effects. Methods for detecting PFAS in water are currently limited and primarily utilize mass spectrometry (MS), which is time-consuming and requires expensive instrumentation. Thus, new methods are needed to rapidly and reliably assess the pollution level of water sources. While some fluorescent PFAS sensors exist, they typically function in high nanomolar or micromolar concentration ranges and focus on sensing only 1-2 individual PFAS. Our work aims to address this problem by developing a fluorescent sensor for both individual PFAS, as well as complex PFAS mixtures, and demonstrate its functionality in tap water samples. Here we show that dynamic combinatorial libraries (DCLs) with simple building blocks can be templated with a fluorophore and subsequently used as sensors to form an array that differentially detects each PFAS species and various mixtures thereof. Our method is a high-throughput analysis technique that allows many samples to be analyzed simultaneously with a plate reader. This is one of the first examples of a fluorescent PFAS sensor array that functions at low nanomolar concentrations, and herein we report its use for the rapid detection of PFAS contamination in water.