A new autoinductive cascade employing benzoyl fluoride as a latent source of fluoride is reported for signal amplification and optical detection of fluoride. The autoinduction leads to a maximum ...4-fold signal enhancement for each fluoride generated, as well as a self-propagating cycle that generates three fluorophores for each single fluoride released. A two-step integrated protocol creates a more rapid autoinductive cascade than previously reported, as well as a highly sensitive diagnostic assay for the ultratrace quantitation of a phosphoryl fluoride nerve agent surrogate.
Dynamic covalent chemistry-based sensors have recently emerged as powerful tools to rapidly determine the enantiomeric excess of organic small molecules. While a bevy of sensors have been developed, ...those for flexible molecules with stereocenters remote to the functional group that binds the chiroptical sensor remain scarce. In this study, we develop an iterative, data-driven workflow to design and analyze a chiroptical sensor capable of assessing challenging acyclic γ-stereogenic alcohols. Following sensor optimization, the mechanism of sensing was probed with a combination of computational parametrization of the sensor molecules, statistical modeling, and high-level density functional theory (DFT) calculations. These were used to elucidate the mechanism of stereochemical recognition and revealed that competing attractive noncovalent interactions (NCIs) determine the overall performance of the sensor. It is anticipated that the data-driven workflows developed herein will be generally applicable to the development and understanding of dynamic covalent and supramolecular sensors.
Chemical warfare agents (CWAs) are toxic chemicals that have been intentionally developed for targeted and deadly use on humans. Although intended for military targets, the use of CWAs more often ...than not results in mass civilian casualties. To prevent further atrocities from occurring during conflicts, a global ban was implemented through the chemical weapons convention, with the aim of eliminating the development, stockpiling, and use of CWAs. Unfortunately, because of their relatively low cost, ease of manufacture and effectiveness on mass populations, CWAs still exist in today's world. CWAs have been used in several recent terrorist-related incidents and conflicts (
e.g.
, Syria). Therefore, they continue to remain serious threats to public health and safety and to global peace and stability. Analytical methods that can accurately detect CWAs are essential to global security measures and for forensic analysis. Small molecule fluorescent probes have emerged as attractive chemical tools for CWA detection, due to their simplicity, ease of use, excellent selectivity and high sensitivity, as well as their ability to be translated into handheld devices. This includes the ability to non-invasively image CWA distribution within living systems (
in vitro
and
in vivo
) to permit in-depth evaluation of their biological interactions and allow potential identification of therapeutic countermeasures. In this review, we provide an overview of the various reported fluorescent probes that have been designed for the detection of CWAs. The mechanism for CWA detection, change in optical output and application for each fluorescent probe are described in detail. The limitations and challenges of currently developed fluorescent probes are discussed providing insight into the future development of this research area. We hope the information provided in this review will give readers a clear understanding of how to design a fluorescent probe for the detection of a specific CWA. We anticipate that this will advance our security systems and provide new tools for environmental and toxicology monitoring.
In this review, we comprehensively summarize the fluorescent probes reported in the literature for all known kinds of chemical warfare agents (CWAs).
The identification and quantification of proteins lags behind DNA-sequencing methods in scale, sensitivity, and dynamic range. Here, we show that sparse amino acid-sequence information can be ...obtained for individual protein molecules for thousands to millions of molecules in parallel. We demonstrate selective fluorescence labeling of cysteine and lysine residues in peptide samples, immobilization of labeled peptides on a glass surface, and imaging by total internal reflection microscopy to monitor decreases in each molecule's fluorescence after consecutive rounds of Edman degradation. The obtained sparse fluorescent sequence of each molecule was then assigned to its parent protein in a reference database. We tested the method on synthetic and naturally derived peptide molecules in zeptomole-scale quantities. We also fluorescently labeled phosphoserines and achieved single-molecule positional readout of the phosphorylated sites. We measured >93% efficiencies for dye labeling, survival, and cleavage; further improvements should enable studies of increasingly complex proteomic mixtures, with the high sensitivity and digital quantification offered by single-molecule sequencing.
Ricin toxin A-chain (RTA), a toxic protein from Ricinus communis, inactivates ribosomes to induce toxicity. The active site of RTA consists of two binding pockets. Many studies have focused on ...developing RTA inhibitors that can simultaneously bind to these critical pockets; however, almost all the inhibitors developed so far interact with only one pocket. In the present study, we discovered that pterin-7-carboxamides with aromatic l-amino acid pendants interacted with the active site of the enzyme in a 2-to-1 mode, where one inhibitor molecule bound to the primary pocket and the second one entered the secondary pocket in the active site of RTA. X-ray crystallographic analysis of inhibitor/RTA complexes revealed that the conformational changes of Tyr80 and Asn122 in RTA were critical for triggering the entry of inhibitor molecules into the secondary pocket of the RTA active site.
•Ricin toxin A chain (RTA) has two specific pockets in its active site.•No small molecular inhibitor was reported to bind to the secondary pocket of RTA.•Some pterin-7-carboxamides bind to the RTA active site in a 2-to-1 mode.•This is the first exaple of small molecules binding to the secondary pocket of RTA.•Movements of Tyr80 and Asn122 triggers the crucial binding of inhibitors to RTA.
A protocol for the rapid determination of the absolute configuration and enantiomeric excess (ee) of α‐chiral primary amines with potential applications in asymmetric reaction discovery has been ...developed. The protocol requires derivatization of α‐chiral primary amines through condensation with pyridine carboxaldehyde to quantitatively yield the corresponding imine. The CuI complex with 2,2′‐bis (diphenylphosphino)‐1,1′‐dinaphthyl (BINAPCuI) with the imine yields a metal‐to‐ligand charge‐transfer (MLCT) band in the visible region of the circular dichroism (CD) spectrum upon binding. Diastereomeric host–guest complexes give CD signals of the same signs but different amplitudes, allowing for differentiation of enantiomers. Processing the primary optical data from the CD spectrum with linear discriminant analysis (LDA) allows for the determination of the absolute configuration and identification of the amines, and processing with a supervised multilayer perceptron artificial neural network (MLP‐ANN) allows for the simultaneous determination of the ee and concentration. The primary optical data necessary to determine the ee of unknown samples is obtained in two minutes per sample. To demonstrate the utility of the protocol in asymmetric reaction discovery, the ee values and concentrations for an asymmetric metal‐catalyzed reaction are determined. The potential of the application of this protocol in high‐throughput screening (HTS) of ee is discussed.
New protocols: By employing pattern‐recognition techniques based on the monitorization of MLCT bands of simple receptors in the circular dichroism (CD) spectra, rapid and simultaneous ee and concentration determination of chiral amines was accomplished (see scheme). This protocol was also applied to determine the ee of the crude products of an asymmetric catalytic reaction by simple derivatization.
The design of a sensor array that uses a single entity as both the host and the indicator (squaraine dye, SQ) to differentiate a series of metal ions and a series of thiols is reported. The metal ...ions and thiols act as both analytes and “modulators” of the squaraine response allowing pattern-based discrimination. Mercury(II), palladium(II), copper(II), iron(II), and nickel(II) can be discriminated when combining SQ with five thiols: propane thiol (PT), 3-mercaptopropionic acid (MPA), naphthalene-2-thiol (NT), 2,3-dimercaptopropanol (DMP), and 2-acetylamino-3-mercaptopropionic acid methyl ester (ACM). Likewise, the five thiols can be discriminated using SQ and the five metals. For example, SQ in combination with 2-acetylamino-3-mercaptopropionic acid methyl ester (ACM) afforded very good differentiation of all five metal ions. However, propanethiol, 3-mercaptopropionic acid, and naphthalene-2-thiol produced very similar differentiation of the considered metal ions. On the other hand, all metal ions considered in this study are able to discriminate 2,3-dimercaptopropanol (DMP) and 2-acetylamino-3-mercaptopropionic acid methyl ester (ACM) clearly and completely, both from one another and from the other three thiols (PT, NT, MPA). Importantly, mercury(II) is the only metal ion able to effect the discrimination of naphthalenethiol (NT) from PT and MPA, thus giving the best discrimination overall. The study shows that complex discrimination of widely diverse classes, metal ions and thiols, can be achieved via a single receptor/indicator.
A critical step in repurposing the cellular translation machinery for the synthesis of polymeric products is the acylation of transfer RNA (tRNA) with unnatural monomers. Toward this goal, ...flexizymes, ribozymes capable of aminoacylation, have emerged as a uniquely adept tool for charging tRNA with ever increasingly diverse substrates. In this review, we present a library of monomer substrates that have been tested for tRNA acylation with the flexizyme system. From this mile-high view, we provide insights for understanding the chemical factors that influence flexizyme-mediated tRNA acylation. We conclude that flexizymes are primitive esterification catalysts that display a modest binding affinity to the monomer’s aromatic recognition element. Together, these robust, yet flexible, flexizyme systems provide researchers with unprecedented access for preparing unnatural acyl-tRNA and the opportunity to repurpose the translation machinery for the synthesis of novel biologically derived structures beyond native proteins and peptides.
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A critical hurdle to repurposing the translation machinery for the synthesis of unnatural polymeric products is the acylation of tRNA with unnatural monomers. Coronado et al. compile a comprehensive list of substrates that have been tested for flexizyme-mediated tRNA acylation and provide insight for understanding the factors that affect acylation.
Organic chemistry is replete with complex relationships: for example, how a reactant’s structure relates to the resulting product formed; how reaction conditions relate to yield; how a catalyst’s ...structure relates to enantioselectivity. Questions like these are at the foundation of understanding reactivity and developing novel and improved reactions. An approach to probing these questions that is both longstanding and contemporary is data-driven modeling. Here, we provide a synopsis of the history of data-driven modeling in organic chemistry and the terms used to describe these endeavors. We include a timeline of the steps that led to its current state. The case studies included highlight how, as a community, we have advanced physical organic chemistry tools with the aid of computers and data to augment the intuition of expert chemists and to facilitate the prediction of structure–activity and structure–property relationships.
Asymmetric hydrogenation of unprotected NH imines catalyzed by rhodium/bis(phosphine)‐thiourea provided chiral amines with up to 97 % yield and 95 % ee. 1H NMR studies, coupled with control ...experiments, implied that catalytic chloride‐bound intermediates were involved in the mechanism through a dual hydrogen‐bonding interaction. Deuteration experiments proved that the hydrogenation proceeded through a pathway consistent with an imine.
In a bind: A bis(phosphine)‐thiourea ligand was successfully used in the rhodium‐catalyzed asymmetric hydrogenation of unprotected iminium salts. Control experiments and 1H NMR studies implied that the anion binding between the thiourea and chloride ions was involved in the mechanism. Deuteration experiments proved that the hydrogenation proceeded through a pathway consistent with an imine.
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