Compared with peripheral late-stage transformations mainly focusing on carbon–hydrogen functionalizations, reliable strategies to directly edit the core skeleton of pharmaceutical lead compounds ...still remain scarce despite the recent flurry of activity in this area. Herein, we report the skeletal editing of indoles through nitrogen atom insertion, accessing the corresponding quinazoline or quinoxaline bioisosteres by trapping of an electrophilic nitrene species generated from ammonium carbamate and hypervalent iodine. This reactivity relies on the strategic use of a silyl group as a labile protecting group that can facilitate subsequent product release. The utility of this highly functional group-compatible methodology in the context of late-stage skeletal editing of several commercial drugs is demonstrated.
Squeezing nitrogen into indole
Numerous pharmaceutical compounds contain five- or six-membered rings composed of carbon and nitrogen. Chemical reactions that interconvert these motifs can therefore be very helpful during drug development research. Reisenbauer
et al
. present a method to insert a nitrogen atom into the five-membered rings of silyl-protected indoles, thereby expanding them into six-membered quinazoline or quinoxaline compounds depending on their substitution pattern at the outset. The chemistry relies on nitrene generation using hypervalent iodine and is compatible with many common functional groups. —JSY
Nitrene chemistry expands indole rings by inserting nitrogen.
Selective and sensitive molecular probes for hydrogen peroxide (H2O2), which plays diverse roles in oxidative stress and redox signaling, are urgently needed to investigate the physiological and ...pathological effects of H2O2. A lack of reliable tools for in vivo imaging has hampered the development of H2O2 mediated therapeutics. By combining a specific tandem Payne/Dakin reaction with a chemiluminescent scaffold, H2O2‐CL‐510 was developed as a highly selective and sensitive probe for detection of H2O2 both in vitro and in vivo. A rapid 430‐fold enhancement of chemiluminescence was triggered directly by H2O2 without any laser excitation. Arsenic trioxide induced oxidative damage in leukemia was successfully detected. In particular, cerebral ischemia‐reperfusion injury‐induced H2O2 fluxes were visualized in rat brains using H2O2‐CL‐510, providing a new chemical tool for real‐time monitoring of H2O2 dynamics in living animals.
Peroxide triggered, peroxide excited: Real‐time monitoring of hydrogen peroxide (H2O2) in rat brains has been achieved by combining a unique H2O2 sensing strategy and a peroxide bond excited chemiluminescent scaffold. This direct activation of phenoxy‐dioxetane by a tandem Payne/Dakin reaction provides a highly selective, sensitive, and rapid detection of H2O2 in chemical systems, the cellular environment, and living animals.
Formaldehyde (FA) is a common environmental toxin that is also produced naturally in the body through a wide range of metabolic and epigenetic processes, motivating the development of new ...technologies to monitor this reactive carbonyl species (RCS) in living systems. Herein, we report a pair of first‐generation chemiluminescent probes for selective formaldehyde detection. Caging phenoxy‐dioxetane scaffolds bearing different electron‐withdrawing groups with a general 2‐aza‐Cope reactive formaldehyde trigger provides chemiluminescent formaldehyde probes 540 and 700 (CFAP540 and CFAP700) for visible and near‐IR detection of FA in living cells and mice, respectively. In particular, CFAP700 is capable of visualizing FA release derived from endogenous folate metabolism, providing a starting point for the use of CFAPs and related chemical tools to probe FA physiology and pathology, as well as for the development of a broader palette of chemiluminescent activity‐based sensing (ABS) probes that can be employed from in vitro biochemical to cell to animal models.
Metabolic sensing: A first‐generation set of chemiluminescent activity‐based probes for in vivo imaging of formaldehyde (FA) is reported. A FA‐selective trigger is used to cage a phenoxy‐dioxetane scaffold that emits a photon after aza‐Cope‐dependent uncaging. These reagents were used to image FA fluxes in living cells and mice, enabling the unique identification of endogenous FA production from metabolic folate cycles in vivo.
Despite incremental improvements in the field of tissue engineering, no technology is currently available for producing completely autologous implants where both the cells and the scaffolding ...material are generated from the patient, and thus do not provoke an immune response that may lead to implant rejection. Here, a new approach is introduced to efficiently engineer any tissue type, which its differentiation cues are known, from one small tissue biopsy. Pieces of omental tissues are extracted from patients and, while the cells are reprogrammed to become induced pluripotent stem cells, the extracellular matrix is processed into an immunologically matching, thermoresponsive hydrogel. Efficient cell differentiation within a large 3D hydrogel is reported, and, as a proof of concept, the generation of functional cardiac, cortical, spinal cord, and adipogenic tissue implants is demonstrated. This versatile bioengineering approach may assist to regenerate any tissue and organ with a minimal risk for immune rejection.
Fatty tissues are extracted from patients and the cellular and a‐cellular materials are separated. While the cells are reprogrammed to induced pluripotent stem cells (iPSCs), the extracellular matrix is processed to a personalized, nonimmunogenic hydrogel. The iPSCs are encapsulated within the hydrogel and differentiated to engineer autologous cardiac, cortical, dopaminergic, spinal cord, and adipogenic implants.
Activatable (turn‐on) probes that permit the rapid, sensitive, selective, and accurate identification of cancer‐associated biomarkers can help drive advances in cancer research. Herein, a ...NAD(P)H:quinone oxidoreductase‐1 (NQO1)‐specific chemiluminescent probe 1 is reported that allows the differentiation between cancer subtypes. Probe 1 incorporates an NQO1‐specific trimethyl‐locked quinone trigger moiety covalently tethered to a phenoxy‐dioxetane moiety through a para‐aminobenzyl alcohol linker. Bio‐reduction of the quinone to the corresponding hydroquinone results in a chemiluminescent signal. As inferred from a combination of in vitro cell culture analyses and in vivo mice studies, the probe is safe, cell permeable, and capable of producing a “turn‐on” luminescence response in an NQO1‐positive A549 lung cancer model. On this basis, probe 1 can be used to identify cancerous cells and tissues characterized by elevated NQO1 levels.
An activatable chemiluminescence probe was developed for imaging endogenous NOQ1 in cells and mice without the requirement of additional components. The advantages of this probe include rapid response, good selectivity, and high signal‐to‐noise ratio.
Detection of Salmonella and L. monocytogenes in food samples by current diagnostic methods requires relatively long time to results (2–6 days). Furthermore, the ability to perform environmental ...monitoring at the factory site for these pathogens is limited due to the need for laboratory facilities. Herein, we report new chemiluminescence probes for the ultrasensitive direct detection of viable pathogenic bacteria. The probes are composed of a bright phenoxy‐dioxetane luminophore masked by triggering group, which is activated by a specific bacterial enzyme, and could detect their corresponding bacteria with an LOD value of about 600‐fold lower than that of fluorescent probes. Moreover, we were able to detect a minimum of 10 Salmonella cells within 6 h incubation. The assay allows for bacterial enrichment and detection in one test tube without further sample preparation. We anticipate that this design strategy will be used to prepare analogous chemiluminescence probes for other enzymes relevant to specific bacteria detection and point‐of‐care diagnostics.
Salmon and Lister would be proud: The development of new chemiluminescence probes for the direct detection of two of the most widely distributed and deadliest food‐borne pathogenic bacteria, Salmonella and Listeria monocytogenes, is described. The two probes could detect their corresponding bacteria with a limit of detection about 600‐fold lower than that of fluorescent probes.
Chemiluminescence probes are considered to be among the most sensitive diagnostic tools that provide high signal-to-noise ratio for various applications such as DNA detection and immunoassays. We ...have developed a new molecular methodology to design and foresee light-emission properties of turn-ON chemiluminescence dioxetane probes suitable for use under physiological conditions. The methodology is based on incorporation of a substituent on the benzoate species obtained during the chemiexcitation pathway of Schaap’s adamantylidene–dioxetane probe. The substituent effect was initially evaluated on the fluorescence emission generated by the benzoate species and then on the chemiluminescence of the dioxetane luminophores. A striking substituent effect on the chemiluminescence efficiency of the probes was obtained when acrylate and acrylonitrile electron-withdrawing groups were installed. The chemiluminescence quantum yield of the best probe was more than 3 orders of magnitude higher than that of a standard, commercially available adamantylidene–dioxetane probe. These are the most powerful chemiluminescence dioxetane probes synthesized to date that are suitable for use under aqueous conditions. One of our probes was capable of providing high-quality chemiluminescence cell images based on endogenous activity of β-galactosidase. This is the first demonstration of cell imaging achieved by a non-luciferin small-molecule probe with direct chemiluminescence mode of emission. We anticipate that the strategy presented here will lead to development of efficient chemiluminescence probes for various applications in the field of sensing and imaging.
The sensitive detection of bacterial infections is a prerequisite for their successful treatment. The use of a chemiluminescent readout was so far hampered by an insufficient probe enrichment at the ...pathogens. We coupled siderophore moieties, that harness the unique iron transport system of bacteria, with enzyme‐activatable dioxetanes and obtained seven trifunctional probes with high signal‐to‐background ratios (S/B=426‐859). Conjugates with efficient iron transport capability into bacteria were identified through a growth recovery assay. All ESKAPE pathogens were labelled brightly by desferrioxamine conjugates, while catechols were weaker due to self‐quenching. Bacteria could also be detected inside lung epithelial cells. The best probe 8 detected 9.1×103 CFU mL−1 of S. aureus and 5.0×104 CFU mL−1 of P. aeruginosa, while the analogous fluorescent probe 10 was 205–305fold less sensitive. This qualifies siderophore dioxetane probes for the selective and sensitive detection of bacteria.
A sensitive diagnosis is crucial for the successful treatment of bacterial infections. The conjugation of bacteria‐specific, uptake‐enhancing siderophore vectors with enzyme‐inducible chemiluminescent dioxetanes enabled the broad‐spectrum detection of “ESKAPE” pathogens. The probes displayed a high sensitivity in human plasma and also detected intracellular Gram‐positive and ‐negative bacteria.
The utility of dioxetane-based chemiluminescent probes in biosensing and bioimaging is being increasingly recognized. While phenoxy-dioxetane luminophores with fast chemiexcitation kinetics are ...highly desired, current luminophores suffer from slow chemiexcitation. Herein we describe a rational, computationally-supported design of phenoxy-dioxetanes with fast chemiexcitation kinetics. These new luminophores were designed to contain a substituent that promotes rapid chemiexcitation, emitting light up to 100-fold faster than currently known dioxetanes. We demonstrate the superiority of the new phenoxy-dioxetanes by preparing three chemiluminescent probes for NAD(P)H, which differ from each other in the rate of the chemiexcitation. Comparison of these probes reveals a correlation between the chemiexcitation rate and the probe sensitivity. We anticipate that these new phenoxy-dioxetanes could serve as an ideal platform for designing chemiluminescence probes with enhanced sensitivity for numerous bioassays.
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