Theranostic Fluorescent Probes.

The ability to gain spatiotemporal information, and in some cases achieve spatiotemporal control, in the context of drug delivery makes theranostic fluorescent probes an attractive and intensely investigated research topic. This interest is reflected in the steep rise in publications on the topic that have appeared over the past decade. Theranostic fluorescent probes, in their various incarnations, generally comprise a fluorophore linked to a masked drug, in which the drug is released as the result of certain stimuli, with both intrinsic and extrinsic stimuli being reported. This release is then signaled by the emergence of a fluorescent signal. Importantly, the use of appropriate fluorophores has enabled not only this emerging fluorescence as a spatiotemporal marker for drug delivery but also has provided modalities useful in photodynamic, photothermal, and sonodynamic therapeutic applications. In this review we highlight recent work on theranostic fluorescent probes with a particular focus on probes that are activated in tumor microenvironments. We also summarize efforts to develop probes for other applications, such as neurodegenerative diseases and antibacterials. This review celebrates the diversity of designs reported to date, from discrete small-molecule systems to nanomaterials. Our aim is to provide insights into the potential clinical impact of this still-emerging research direction.

Fluorogenic Peptide Sensor Array Derived from Angiotensin-Converting Enzyme 2 Classifies Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern.

The devastating COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made society acutely aware of the urgency in developing effective techniques to timely monitor the outbreak of previously unknown viral species as well as their mutants, which could be even more lethal and/or contagious. Here, we report a fluorogenic sensor array consisting of peptides truncated from the binding domain of human angiotensin-converting enzyme 2 (hACE2) for SARS-CoV-2. A set of five fluorescently tagged peptides were used to construct the senor array in the presence of different low-dimensional quenching materials. When orthogonally incubated with the wild-type SARS-CoV-2 and its variants of concern (VOCs), the fluorescence of each peptide probe was specifically recovered, and the different recovery rates provide a "fingerprint" characteristic of each viral strain. This, in turn, allows them to be differentiated from each other using principal component analysis. Interestingly, the classification result from our sensor array agrees well with the evolutionary relationship similarity of the VOCs. This study offers insight into the development of effective sensing tools for highly contagious viruses and their mutants based on rationally truncating peptide ligands from human receptors.

Engineered Phenylalanine Ammonia-Lyases for the Enantioselective Synthesis of Aspartic Acid Derivatives.

Biocatalytic hydroamination of alkenes is an efficient and selective method to synthesize natural and unnatural amino acids. Phenylalanine ammonia-lyases (PALs) have been previously engineered to access a range of substituted phenylalanines and heteroarylalanines, but their substrate scope remains limited, typically including only arylacrylic acids. Moreover, the enantioselectivity in the hydroamination of electron-deficient substrates is often poor. Here, we report the structure-based engineering of PAL from Planctomyces brasiliensis (PbPAL), enabling preparative-scale enantioselective hydroaminations of previously inaccessible yet synthetically useful substrates, such as amide- and ester-containing fumaric acid derivatives. Through the elucidation of cryo-electron microscopy (cryo-EM) PbPAL structure and screening of the structure-based mutagenesis library, we identified the key active site residue L205 as pivotal for dramatically enhancing the enantioselectivity of hydroamination reactions involving electron-deficient substrates. Our engineered PALs demonstrated exclusive α-regioselectivity, high enantioselectivity, and broad substrate scope. The potential utility of the developed biocatalysts was further demonstrated by a preparative-scale hydroamination yielding tert-butyl protected l-aspartic acid, widely used as intermediate in peptide solid-phase synthesis.

Deoxygenative Transformation of Alcohols via Phosphoranyl Radical from Exogenous Radical Addition.

A general approach to the direct deoxygenative transformation of primary, secondary, and tertiary alcohols has been developed. It undergoes through phosphoranyl radical intermediates generated by the addition of exogenous iodine radical to trivalent alkoxylphosphanes. Since these alkoxylphosphanes are readily in situ obtained from alcohols and commercially available, inexpensive chlorodiphenylphosphine, a diverse range of alcohols with various functional groups can be utilized to proceed deoxygenative cross-couplings with alkenes or aryl iodides. The selective transformation of polyhydroxy substrates and the rapid synthesis of complex organic molecules are also demonstrated with this method.

Regiodivergent and Enantioselective Synthesis of Cyclic Sulfones via Ligand-Controlled Nickel-Catalyzed Hydroalkylation.

Cyclic sulfones have demonstrated important applications in drug discovery. However, the catalytic and enantioselective synthesis of chiral cyclic sulfones remains challenging. Herein, we develop nickel-catalyzed regiodivergent and enantioselective hydroalkylation of sulfolenes to streamline the synthesis of chiral alkyl cyclic sulfones. The method has broad scope and high functional group tolerance. The regioselectivity can be controlled by ligands only. A neutral PYROX ligand favors C3-alkylation whereas an anionic BOX ligand favors C2-alkylation. This control is kinetic in origin as the C2-bound Ni intermediates are always thermodynamically more stable. Reactivity study of a wide range of relevant Ni intermediates reveal a NiI/NiIII catalytic cycle with a NiII-H species as the resting state. The regio- and enantio-determining step is the insertion of this NiII-H species into 2-sulfolene. This work provides an efficient catalytic method for the synthesis of an important class of organic compounds and enhances the mechanistic understanding of Ni-catalyzed stereoselective hydroalkylation.

Phenotyping of Methicillin-Resistant Staphylococcus aureus Using a Ratiometric Sensor Array.

Chemical tools capable of classifying multidrug-resistant bacteria (superbugs) can facilitate early-stage disease diagnosis and help guide precision therapy. Here, we report a sensor array that permits the facile phenotyping of methicillin-resistant Staphylococcus aureus (MRSA), a clinically common superbug. The array consists of a panel of eight separate ratiometric fluorescent probes that provide characteristic vibration-induced emission (VIE) profiles. These probes bear a pair of quaternary ammonium salts in different substitution positions around a known VIEgen core. The differences in the substituents result in varying interactions with the negatively charged cell walls of bacteria. This, in turn, dictates the molecular conformation of the probes and affects their blue-to-red fluorescence intensity ratios (ratiometric changes). Within the sensor array, the differences in the ratiometric changes for the probes result in "fingerprints" for MRSA of different genotypes. This allows them to be identified using principal component analysis (PCA) without the need for cell lysis and nucleic acid isolation. The results obtained with the present sensor array agree well with those obtained using polymerase chain reaction (PCR) analysis.

An efficient nickel hydrogen oxidation catalyst for hydroxide exchange membrane fuel cells.

The hydroxide exchange membrane fuel cell (HEMFC) is a promising energy conversion technology but is limited by the need for platinum group metal (PGM) electrocatalysts, especially for the hydrogen oxidation reaction (HOR). Here we report a Ni-based HOR catalyst that exhibits an electrochemical surface area-normalized exchange current density of 70 µA cm-2, the highest among PGM-free catalysts. The catalyst comprises Ni nanoparticles embedded in a nitrogen-doped carbon support. According to X-ray and ultraviolet photoelectron spectroscopy as well as H2 chemisorption data, the electronic interaction between the Ni nanoparticles and the support leads to balanced hydrogen and hydroxide binding energies, which are the likely origin of the catalyst's high activity. PGM-free HEMFCs employing this Ni-based HOR catalyst give a peak power density of 488 mW cm-2, up to 6.4 times higher than previous best-performing analogous HEMFCs. This work demonstrates the feasibility of efficient PGM-free HEMFCs.

Human serum albumin-based supramolecular host-guest boronate probe for enhanced peroxynitrite sensing.

Peroxynitrite (ONOO-) is an important oxygen/nitrogen reactive species implicated in a number of physiological and pathological processes. However, due to the complexity of the cellular micro-environment, the sensitive and accurate detection of ONOO- remains a challenging task. Here, we developed a long-wavelength fluorescent probe based on the conjugation between a TCF scaffold and phenylboronate; the resulting conjugate is capable of supramolecular host-guest assembly with human serum albumin (HSA) for the fluorogenic sensing of ONOO-. The probe exhibited an enhanced fluorescence over a low concentration range of ONOO- (0-9.6 µM), whist the fluorescence was quenched when the concentration of ONOO- exceeded 9.6 µM. In addition, when human serum albumin (HSA) was added, the initial fluorescence of the probe was significantly enhanced, which enabled the more sensitive detection of low-concentrations of ONOO- in aqueous buffer solution and in cells. The molecular structure of the supramolecular host-guest ensemble was determined using small-angle X-ray scattering.

Anion Exchange Membranes for Hydrogen Technologies: Challenges and Progress.

Anion exchange membrane fuel cells (AEMFCs) are considered one of the most promising and efficient hydrogen conversion technologies due to their ability to use cost-effective materials. However, AEMFCs are still in the early stage of development and the lack of suitable anion exchange membranes (AEMs) is one major obstacle. In this review, we highlight three major challenges in AEMs development and discuss recent scientific advancements that address these challenges. We identify current trends and provide a perspective on future development of AEMs.

Manganese Transfer Hydrogenases Based on the Biotin-Streptavidin Technology.

Artificial (transfer) hydrogenases have been developed for organic synthesis, but they rely on precious metals. Native hydrogenases use Earth-abundant metals, but these cannot be applied for organic synthesis due, in part, to their substrate specificity. Herein, we report the design and development of manganese transfer hydrogenases based on the biotin-streptavidin technology. By incorporating bio-mimetic Mn(I) complexes into the binding cavity of streptavidin, and through chemo-genetic optimization, we have obtained artificial enzymes that hydrogenate ketones with nearly quantitative yield and up to 98 % enantiomeric excess (ee). These enzymes exhibit broad substrate scope and high functional-group tolerance. According to QM/MM calculations and X-ray crystallography, the S112Y mutation, combined with the appropriate chemical structure of the Mn cofactor plays a critical role in the reactivity and enantioselectivity of the artificial metalloenzyme (ArMs). Our work highlights the potential of ArMs incorporating base-meal cofactors for enantioselective organic synthesis.

Streamlined Alkylation via Nickel-Hydride-Catalyzed Hydrocarbonation of Alkenes.

Compounds rich in sp3-hybridized carbons are desirable in drug discovery. Nickel-catalyzed hydrocarbonation of alkenes is a potentially efficient method to synthesize these compounds. By using abundant, readily available, and stable alkenes as pro-nucleophiles, these reactions can have broad scope and high functional group tolerance. However, this methodology is still in an early stage of development, as the first efficient examples were reported only in 2016. Herein, we summarize the progress of this emerging field, with an emphasis on enantioselective reactions. We highlight major developments, critically discuss a wide range of possible mechanisms, and offer our perspective of the state and challenges of the field. We hope this Perspective will stimulate future works in this area, making the methodology widely applicable in organic synthesis.

Tuning the Solid- and Solution-State Fluorescence of the Iron-Chelator Deferasirox.

Deferasirox, an FDA-approved iron chelator, has gained increasing attention for use in anticancer and antimicrobial applications. Recent efforts by our group led to the identification of this core as an easy-to-visualize aggregation-induced emission platform, or AIEgen, that provides a therapeutic effect equivalent to deferasirox (J. Am. Chem. Soc. 2021, 143, 3, 1278-1283). However, the emission wavelength of the first-generation system overlapped with that of Syto9, a green emissive dye used to indicate live cells. Here, we report a library of deferasirox derivatives with various fluorescence emission profiles designed to overcome this limitation. We propose referring to systems that show promise as both therapeutic and optical imaging agents as "illuminoceuticals". The color differences between the derivatives were observable to the unaided eye (solid- and solution-state) and were in accord with the Commission Internationale de L'Eclairage (CIE) chromaticity diagram 1913. Each fluorescent derivative successfully imaged the respective spherical and rod shapes of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. They also displayed iron-dependent antibiotic activity. Three derivatives, ExNMe2 (3), ExTrisT (11), and ExDCM (13), display emission features that are sufficiently distinct so as to permit the multiplex (triplex) imaging of both MRSA and P. aeruginosa via stimulated emission depletion microscopy. The present deferasirox derivatives allowed for the construction of a multi-fluorophore sensor array. This array enabled the successful discrimination between Gram-positive/Gram-negative and drug-sensitive/drug-resistant bacteria. Antibiotic sensitivity and drug-resistant mutants from clinically isolated strains could also be identified and differentiated.

Correction: Fluorescent glycoconjugates and their applications.

Correction for 'Fluorescent glycoconjugates and their applications' by Baptiste Thomas et al., Chem. Soc. Rev., 2020, 49, 593-641, DOI: 10.1039/C8CS00118A.

A Cation Concentration Gradient Approach to Tune the Selectivity and Activity of CO2 Electroreduction.

The linear scaling relationship of the binding energies of different intermediates limits the catalyst performance in CO2 electroreduction. Here we demonstrate a cation concentration gradient strategy to promote the activity and tune the selectivity of CO2 electroreduction, thereby breaking the scaling relationship. In optimal concentrations of the potassium acetate (KAc) electrolyte, Cu, Ag and In catalysts deliver current densities that are 7.1, 3.2, 2.7 times higher than those obtained in 0.5 M KAc for C2 H4 , CO, and formate production, respectively. Increasing the concentration of KAc also changes the selectivity from CO to formate on Ag, and from CO to C2 products on Cu. In situ surface-enhanced Raman spectroscopy and computational simulations reveal that the binding energies of intermediates are changed at different electrolyte concentrations, which is due to a local electrostatic interaction modulated by potassium cations at the electrode surface.

Oxidase-Type C-H/C-H Coupling Using an Isoquinoline-Derived Organic Photocatalyst.

Oxidase-type oxidation is an attractive strategy in organic synthesis due to the use of O2 as the terminal oxidant. Organic photocatalysis can effect metal-free oxidase chemistry. Nevertheless, current methods are limited in reaction scope, possibly due to the lack of suitable photocatalysts. Here we report an isoquinoline-derived diaryl ketone-type photocatalyst, which has much enhanced absorption of blue and visible light compared to conventional diaryl ketones. This photocatalyst enables dehydrogenative cross-coupling of heteroarenes with unactivated and activated alkanes as well as aldehydes using air as the oxidant. A wide range of heterocycles with various functional groups are suitable substrates. Transient absorption and excited-state quenching experiments point to an unconventional mechanism that involves an excited state "self-quenching" process to generate the N-radical cation form of the sensitizer, which subsequently abstracts a hydrogen atom from the alkane substrate to yield a reactive alkyl radical.

Branched Poly(Aryl Piperidinium) Membranes for Anion-Exchange Membrane Fuel Cells.

Anion-exchange membrane fuel cells (AEMFCs) are a promising, next-generation fuel cell technology. AEMFCs require highly conductive and robust anion-exchange membranes (AEMs), which are challenging to develop due to the tradeoff between conductivity and water uptake. Here we report a method to prepare high-molecular-weight branched poly(aryl piperidinium) AEMs. We show that branching reduces water uptake, leading to improved dimensional stability. The optimized membrane, b-PTP-2.5, exhibits simultaneously high OH- conductivity (>145 mS cm-1 at 80 °C), high mechanical strength and dimensional stability, good processability, and excellent alkaline stability (>1500 h) in 1 M KOH at 80 °C. AEMFCs based on b-PTP-2.5 reached peak power densities of 2.3 W cm-2 in H2 -O2 and 1.3 W cm-2 in H2 -air at 80 °C. The AEMFCs can run stably under a constant current of 0.2 A cm-2 over 500 h, during which the b-PTP-2.5 membrane remains stable.

Electronic Regulation of Nickel Single Atoms by Confined Nickel Nanoparticles for Energy-Efficient CO2 Electroreduction.

Modulating the electronic structure of atomically dispersed active sites is promising to boost catalytic activity but is challenging to achieve. Here we show a cooperative Ni single-atom-on-nanoparticle catalyst (NiSA/NP) prepared via direct solid-state pyrolysis, where Ni nanoparticles donate electrons to Ni(i)-N-C sites via a network of carbon nanotubes, achieving a high CO current density of 346 mA cm-2 at -0.5 V vs RHE in an alkaline flow cell. When coupled with a NiFe-based anode in a zero-gap membrane electrolyzer, the catalyst delivers an industrially relevant CO current density of 310 mA cm-2 at a low cell voltage of -2.3 V, corresponding to an overall energy efficiency of 57 %. The superior CO2 electroreduction performance is attributed to the enhanced adsorption of key intermediate COOH* on the electron-rich Ni single atoms, as well as a high density of active sites.

In Vitro Biosynthesis of the [Fe]-Hydrogenase Cofactor Verifies the Proposed Biosynthetic Precursors.

In the FeGP cofactor of [Fe]-hydrogenase, low-spin FeII is in complex with two CO ligands and a pyridinol derivative; the latter ligates the iron with a 6-acylmethyl substituent and the pyridinol nitrogen. A guanylylpyridinol derivative, 6-carboxymethyl-3,5-dimethyl-4-guanylyl-2-pyridinol (3), is produced by the decomposition of the FeGP cofactor under irradiation with UV-A/blue light and is also postulated to be a precursor of FeGP cofactor biosynthesis. HcgC and HcgB catalyze consecutive biosynthesis steps leading to 3. Here, we report an in vitro biosynthesis assay of the FeGP cofactor using the cell extract of the ΔhcgBΔhcgC strain of Methanococcus maripaludis, which does not biosynthesize 3. We chemically synthesized pyridinol precursors 1 and 2, and detected the production of the FeGP cofactor from 1, 2 and 3. These results indicated that 1, 2 and 3 are the precursors of the FeGP cofactor, and the carboxy group of 3 is converted to the acyl ligand.

The Function of Two Radical-SAM Enzymes, HcgA and HcgG, in the Biosynthesis of the [Fe]-Hydrogenase Cofactor.

In the biosynthesis of the iron-guanylylpyridinol (FeGP) cofactor, 6-carboxymethyl-5-methyl-4-hydroxy-2-pyridinol (1) is 3-methylated to form 2, then 4-guanylylated to form 3, and converted into the full cofactor. HcgA-G proteins catalyze the biosynthetic reactions. Herein, we report the function of two radical S-adenosyl methionine enzymes, HcgA and HcgG, as uncovered by in vitro complementation experiments and the use of purified enzymes. In vitro biosynthesis using the cell extract from the Methanococcus maripaludis ΔhcgA strain was complemented with HcgA or precursors 1, 2 or 3. The results suggested that HcgA catalyzes the biosynthetic reaction that forms 1. We demonstrated the formation of 1 by HcgA using the 3 kDa cell extract filtrate as the substrate. Biosynthesis in the ΔhcgG system was recovered by HcgG but not by 3, which indicated that HcgG catalyzes the reactions after the biosynthesis of 3. The data indicated that HcgG contributes to the formation of CO and completes biosynthesis of the FeGP cofactor.

Chiral Alkyl Amine Synthesis via Catalytic Enantioselective Hydroalkylation of Enecarbamates.

Chiral alkyl amines are omnipresent as bioactive molecules and synthetic intermediates. The catalytic and enantioselective synthesis of alkyl amines from readily accessible precursors is challenging. Here we develop a nickel-catalyzed hydroalkylation method to assemble a wide range of chiral alkyl amines from enecarbamates (N-Cbz-protected enamines) and alkyl halides with high regio- and enantioselectivity. The method works for both nonactivated and activated alkyl halides and is able to produce enantiomerically enriched amines with two minimally differentiated α-alkyl substituents. The mild conditions lead to high functional group tolerance, which is demonstrated in the postproduct functionalization of many natural products and drug molecules, as well as the synthesis of chiral building blocks and key intermediates to bioactive compounds.