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Thermosets having low dielectric constant (Dk < 3) and low dielectric dissipation factor (Df < 0.003), high glass transition temperature (Tg > 150 °C), and good adhesion to copper are desirable for the low loss layers of the copper clad laminates (CCL) in next generation printed circuit boards. Three different difunctional diazirines are evaluated for both thermal and photochemical crosslinking of a high Tg vinyl‐addition polynorbornene resin: poly(5‐hexyl‐1‐norbornene) (poly(HNB)). The substrate polymer, crosslinked by the carbenes generated from the activated diazirines, forms thermosets with Dk < 2.3 and Df < 0.001 at 10 GHz depending on the identity of the diazirine and the loading. The Dk and Df values for one composition are stable for 1600 h at 125 °C in air and for 1400 h at 85 °C and 85% relative humidity, suggesting good long‐term reliability of this thermoset. Adhesion of poly(HNB) to copper can be enhanced by priming the copper surface with a diazirine prior to high temperature lamination; peel strength values of greater than 7.5 N cm−1 are achieved. Negative‐tone photopatterning of poly(HNB) with diazirines upon exposure to 365 nm light is demonstrated. [ABSTRACT FROM AUTHOR]

Glycine derivatives are prevalent structural motifs that can be easily found in many bioactive molecules and natural isolates. To date, chemical synthesis of hydrazino-containing glycine derivatives has mainly focused on the utilization of metal catalysts or light-irradiation methods. Herein, we report a three-component reaction of amines, azodicarboxylates, and diazoalkanes under green and sustainable reaction conditions, leading to a wide range of hydrazino-containing glycine derivatives in good to excellent yields. Compared to the reported methods, the as-developed method does not require catalysts or light irradiation. The success of the scale-up reaction, synthetic transformation of the formed glycine products, and the direct aqueous media synthesis further rendered the method attractive and valuable. Control experiments together with detailed mechanism studies revealed that the in situ formed diaziridines are the key reaction intermediates. [ABSTRACT FROM AUTHOR]

Nitrogen-containing compounds, such as amines, hydrazines, and heterocycles, play an indispensable role in medicine, agriculture, and materials. Alkylated derivatives of these compounds, especially in sterically congested environments, remain a challenge to prepare. Here we report a versatile method for the regioselective hydroamination of readily available unactivated olefins with diazirines. Over fifty examples are reported, including the protecting group-free amination of fourteen different natural products. A broad functional group tolerance includes alcohols, ketones, aldehydes, and epoxides. The proximate products of these reactions are diaziridines, which, under mild conditions, are converted to primary amines, hydrazines, and heterocycles. Five target- and diversity-oriented syntheses of pharmaceutical compounds are shown, along with the preparation of a bis-15N diazirine validated in the late-stage isotopic labeling of an RNA splicing modulator candidate. In this work, we report using diazirine (1) as an electrophilic nitrogen source in a regioselective hydroamination reaction, and the diversification of the resulting diaziridines. Nitrogen-containing compounds play an indispensable role in medicine, agriculture and materials, but alkylated derivatives especially in sterically congested environments, remain a challenge to prepare. Here, the authors report a versatile method for the regioselective hydroamination of readily available unactivated olefins with diazirines. [ABSTRACT FROM AUTHOR]

The cyclopropanation reaction of alkenes with photolytically‐generated chlorocarbenes from chlorodiazirines is reported as an effective way to prepare substituted 3‐chloro‐3‐aryl‐cyclopropanes. This practical and efficient approach allows the synthesis of various 3‐chloro‐3‐aryl‐cyclopropanes (32 examples) in continuous flow in 5‐minute residence time under light‐emitting diode (LED) irradiation. The conditions using 380 nm LED irradiation were successfully extended to the synthesis of substituted 3‐bromo‐3‐aryl‐cyclopropanes (3 examples). [ABSTRACT FROM AUTHOR]

Organic electrochemical transistors (OECTs) rely on both efficient ionic doping/de‐doping process and carrier transport in the mixed ionic‐electronic channel under the modulation of gate bias. Moreover, channels that hold photopatterning capability are highly desired to minimize parasitic capacitance and simplify the fabrication process/cost. However, yielding photo‐patternable channels with both precise/robust patterning capability and controllable ionic‐electronic coupling is still challenging. Herein, double‐end trifluoromethyl diazirines (DtFDA) with different chain lengths are introduced in the OECT channel to act as both photo‐crosslinker and medium to regulate ionic‐electronic transport. Specifically, high‐resolution patterns with a minimum line width/gap of 2 μm are realized in p(g2T‐T) or Homo‐gDPP based channels by introducing DtFDA. Maximum transconductances of 68.6 mS and 81.6 mS, current on/off ratio of 106 and 107 (under a drain voltage of only ±0.1 V), are achieved in p‐ and n‐type vertical OECTs (vOECTs), respectively, along with current densities exceeding 1 kA cm−2 and good cycling stability of more than 100,000 cycles (2000 seconds). This work provides a new and facile strategy for the fabrication of vOECT channels with high resolution and high performance via the introduction of a simple and efficient crosslinker. [ABSTRACT FROM AUTHOR]

The coupling of diaziridines with donor–acceptor aziridines (DAAs) has been achieved using Zn-catalysis to furnish imidazopyrazole-4,4-dicarboxylates via [1,4]-hydride shift. The use of Zn-catalysis, [1,4]-hydride shift, natural product modification and a late-stage molecular docking study are important practical features. [ABSTRACT FROM AUTHOR]

bis -Diazirine reagents are increasingly being used as polymer crosslinkers, adhesives, and photopatterning agents in the materials sciences literature, but little effort has been made thus far to document their chemical safety profile. Here, we describe the results of a detailed toxicity assessment of a representative bis -diazirine. Safety was evaluated by a series of in vitro assays, which found the product to be non-mutagenic in bacterial tester strains TA98 and TA100, non-corrosive and non-irritating to skin, and requiring no classification for eye irritation or serious damage. While in vitro tests do not capture the integrated whole animal system, and thus cannot completely rule out the possibility of adverse responses, the results of this study suggest a desirable safety profile for bis -diazirine reagents and provide a solid foundation upon which to add in vivo assessment of safety risk and dose-response studies. [ABSTRACT FROM AUTHOR]

Glycan recognition by glycan‐binding proteins is central to the biology of all living organisms. The efficient capture and characterization of relatively weak non‐covalent interactions remains an important challenge in various fields of research. Photoaffinity labeling strategies can create covalent bonds between interacting partners, and photoactive scaffolds such as benzophenone, diazirines and aryl azides have proved widely useful. Since their first introduction, relatively few improvements have been advanced and products of photoaffinity labeling remain difficult to detect. We report a fluorinated azido‐coumarin scaffold which enables photolabeling under fast and mild activation, and which can leave a fluorescent tag on crosslinked species. Coupling this scaffold to an α‐fucoside, we demonstrate fluorogenic photolabeling of glycan‐protein interactions over a wide range of affinities. We expect this strategy to be broadly applicable to other chromophores and we envision that such "fluoro‐crosslinkers" could become important tools for the traceable capture of non‐covalent binding events. [ABSTRACT FROM AUTHOR]

The process of identifying the protein targets and off-targets of a biologically active compound is of great importance in modern drug discovery. Various chemical proteomics approaches have been established for this purpose. To compare the different approaches, and to understand which method would provide the best results, we have chosen the EGFR inhibitor lapatinib as an example molecule. Lapatinib derivatives were designed using linkers with motifs, including amino (amidation), alkyne (click chemistry) and the diazirine group (photo-affinity). These modified lapatinib analogues were validated for their ability to inhibit EGFR activity in vitro and were shown to pull down purified recombinant EGFR protein. In all of the approaches evaluated here, we identified EGFR as the main protein target from the lysate of immortalised cell line expressing EGFR, thus validating its potential use to identify unknown protein targets. Taken together, the results reported here give insight into the cellular activities of lapatinib. [ABSTRACT FROM AUTHOR]

The process of identifying the protein targets and off-targets of a biologically active compound is of great importance in modern drug discovery. Various chemical proteomics approaches have been established for this purpose. To compare the different approaches, and to understand which method would provide the best results, we have chosen the EGFR inhibitor lapatinib as an example molecule. Lapatinib derivatives were designed using linkers with motifs, including amino (amidation), alkyne (click chemistry) and the diazirine group (photo-affinity). These modified lapatinib analogues were validated for their ability to inhibit EGFR activity in vitro and were shown to pull down purified recombinant EGFR protein. In all of the approaches evaluated here, we identified EGFR as the main protein target from the lysate of immortalised cell line expressing EGFR, thus validating its potential use to identify unknown protein targets. Taken together, the results reported here give insight into the cellular activities of lapatinib.

We demonstrate that arylchlorodiazirines serve as photo‐activated halocarbene precursors for the selective one‐carbon ring expansion of N‐substituted pyrroles and indoles to the corresponding pyridinium and quinolinium salts. Preliminary investigations indicate that the same strategy also enables the conversion of N‐substituted pyrazoles to pyrimidinium salts. The N‐substituent of the substrate plays an essential role in: (1) increasing substrate scope by preventing product degradation, (2) enhancing yields by suppressing co‐product inhibition, and (3) activating the azinium products towards subsequent synthetic manipulations. This latter point is illustrated by subjecting the quinolinium salts to four complementary partial reductions, which provide concise access to ring‐expanded products with different degrees of increased C(sp3) character. Thermal analysis of the diazirines by differential scanning calorimetry (DSC) provides detailed insight into their energetic properties, and highlights the safety benefits of photolyzing—rather than thermolyzing—these reagents. [ABSTRACT FROM AUTHOR]

Covalently crosslinked polymeric materials, known as thermosets, possess enhanced mechanical strength and thermal stability relative to the corresponding uncrosslinked thermoplastics. However, the presence of covalent inter‐chain crosslinks that makes thermosets so attractive is precisely what makes them so difficult to reprocess and recycle. Here, we demonstrate the introduction of chemically cleavable groups into a bis‐diazirine crosslinker. Application of this cleavable crosslinker reagent to commercial low‐functionality polyolefins (or to a small‐molecule model) results in the rapid, efficient introduction of molecular crosslinks that can be uncoupled by specific chemical inputs. These proof‐of‐concept findings provide one potential strategy for circularization of the thermoplastic/thermoset plastics economy, and may allow crosslinked polyolefins to be manufactured, used, reprocessed, and re‐used without losing value. As an added benefit, the method allows the ready introduction of functionality into non‐functionalized commodity polymers. [ABSTRACT FROM AUTHOR]

Efficient annulation of in situ formed azaoxyallyl cations using a base has been accomplished with diaziridines to provide 1,2,4-triazines at room temperature. The substrate scope, scale up, functional group tolerance and transition-metal free reaction conditions are the important practical features. [ABSTRACT FROM AUTHOR]

In materials (polymer) science and medicinal chemistry, heteroaromatic derivatives play the role of the central skeleton in development of novel devices and discovery of new drugs. On the other hand, (3-trifluoromethyl)phenyldiazirine (TPD) is a crucial chemical method for understanding biological processes such as ligand–receptor, nucleic acid–protein, lipid–protein, and protein–protein interactions. In particular, use of TPD has increased in recent materials science to create novel electric and polymer devices with comparative ease and reduced costs. Therefore, a combination of heteroaromatics and (3-trifluoromethyl)diazirine is a promising option for creating better materials and elucidating the unknown mechanisms of action of bioactive heteroaromatic compounds. In this review, a comprehensive synthesis of (3-trifluoromethyl)diazirine-substituted heteroaromatics is described. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 Mpro is a chymotrypsin-like cysteine protease playing a relevant role during the replication and infectivity of SARS-CoV-2, the coronavirus responsible for COVID-19. The binding site of Mpro is characterized by the presence of a catalytic Cys145 which carries out the hydrolytic activity of the enzyme. As a consequence, several Mpro inhibitors have been proposed to date in order to fight the COVID-19 pandemic. In our work, we designed, synthesized and biologically evaluated MPD112, a novel inhibitor of SARS-CoV-2 Mpro bearing a trifluoromethyl diazirine moiety. MPD112 displayed in vitro inhibition activity against SARS-CoV-2 Mpro at a low micromolar level (IC50 = 4.1 μM) in a FRET-based assay. Moreover, an inhibition assay against PLpro revealed lack of inhibition, assuring the selectivity of the compound for the Mpro. Furthermore, the target compound MPD112 was docked within the binding site of the enzyme to predict the established intermolecular interactions in silico. MPD112 was subsequently tested on the HCT-8 cell line to evaluate its effect on human cells' viability, displaying good tolerability, demonstrating the promising biological compatibility and activity of a trifluoromethyl diazirine moiety in the design and development of SARS-CoV-2 Mpro binders. [ABSTRACT FROM AUTHOR]

Halodiazirines have emerged as very useful reagents in photochemically or thermally mediated cyclopropanation reactions with alkenes. This short review highlights the synthetic applications of these reagents as precursors of halocarbenes in transformations with various alkenes. 1 Introduction 2 Cyclopropanation of Aryl Halodiazirines 3 Tandem Reactions Using Aryl Halodiazirines 4 Cyclopropanation of Alkyl- and Benzyl-halodiazirines 5 Cyclopropanation of Other Halodiazirines 6 Reactions of Halodiazirines with Alkynes 7 Conclusion and Outlook [ABSTRACT FROM AUTHOR]

Unsubstituted and 1‐methyl‐substituted 1,3,4,8b‐tetrahydrodiazirino[3,1‐a]isoquinolines (diaziridines 1 and 2) demonstrate different reactivities toward aryl isocyanates and aryl isothiocyanates. Diaziridine 1 reacts with aryl isocyanates as a nucleophile to afford novel 1,5,6,10b‐tetrahydro[1,2,4]triazolo[5,1‐a]isoquinolines. The addition of a Lewis or Brønsted acid switches the reaction pathway, producing seven‐membered 2,3‐benzodiazepines. In reactions of diaziridine 1 with aryl isothiocyanates, unusual zwitterionic compounds – 2‐thioxo‐5,6‐dihydro‐2H‐[1,2,4]triazolo[5,1‐a]isoquinolin‐1‐ium‐3‐ides – and products of the addition of two molecules of diaziridine 1 to one molecule of aryl isothiocyanate are obtained. However, in reactions with aryl iso(thio)cyanates under heating or acid catalysis, diaziridine 2 is first converted into an azomethine imine, the 1,3‐dipolar cycloaddition of which to the dipolarophile produces substituted triazolo[5,1‐a]isoquinolin‐2(3H)‐(thi)ones. Proposed is a new method for azomethine imine generation from diaziridine 2 enabled by Brønsted acid catalysis. Antitumour activity of select compounds obtained was assayed to help guide future drug discovery efforts. [ABSTRACT FROM AUTHOR]

Target identification of bioactive compounds is important for understanding their mechanisms of action and provides critical insights into their therapeutic utility. While it remains a challenge, unbiased chemoproteomics strategy using clickable photoaffinity probes is a useful and validated approach for target identification. One major limitation of this approach is the efficient synthesis of appropriately substituted clickable photoaffinity probes. Herein, we describe an efficient and consistent method to prepare such probes. We further employed this method to prepare a highly stereo-congested probe based on naturally occurring triterpenoid betulinic acid. With this photoaffinity probe, we identified tropomyosin as a novel target for betulinic acid that can account for the unique biological phenotype on cellular cytoskeleton induced by betulinic acid. A new method was developed to reliably prepare stereo-hindered clickable diazirines for target identification. Tropomyosin was identified as a new target for betulinic acid. [Display omitted] [ABSTRACT FROM AUTHOR]

SARS-CoV-2 Mpro is a chymotrypsin-like cysteine protease playing a relevant role during the replication and infectivity of SARS-CoV-2, the coronavirus responsible for COVID-19. The binding site of Mpro is characterized by the presence of a catalytic Cys145 which carries out the hydrolytic activity of the enzyme. As a consequence, several Mpro inhibitors have been proposed to date in order to fight the COVID-19 pandemic. In our work, we designed, synthesized and biologically evaluated MPD112, a novel inhibitor of SARS-CoV-2 Mpro bearing a trifluoromethyl diazirine moiety. MPD112 displayed in vitro inhibition activity against SARS-CoV-2 Mpro at a low micromolar level (IC50 = 4.1 μM) in a FRET-based assay. Moreover, an inhibition assay against PLpro revealed lack of inhibition, assuring the selectivity of the compound for the Mpro. Furthermore, the target compound MPD112 was docked within the binding site of the enzyme to predict the established intermolecular interactions in silico. MPD112 was subsequently tested on the HCT-8 cell line to evaluate its effect on human cells’ viability, displaying good tolerability, demonstrating the promising biological compatibility and activity of a trifluoromethyl diazirine moiety in the design and development of SARS-CoV-2 Mpro binders.

The reaction of 2-(1-hydroxyimino-2-oxo-2-phenylethyl)-6-R-pyrimidin-4(3H)-ones with an excess of p-toluenesulfochloride proceeds in two stages involving consecutive oxidation of the oxygen atom of the hydroxyimino group and the oxygen atom of the amide fragment of the pyrimidine ring. The reaction of the resulting ditosylates with ethylenediamine proceeds via replacement of the sulfonyl group in the 2-position of the pyrimidine ring. The examples of 2-[1-benzoyl-2-(2-furyl)vinyl]-6-methylpyrimidin-4(3H)-one, 2-[2-(4-nitrophenyl)vinyl]-6-methylpyrimidine-4(3H)-one, and 6-methyl-2-(2-oxo-2-phenylethylthio)pyrimidin-4(3H)-one were used to consider the relationship between the structure of the substrate and the direction of the tosylation reaction. [ABSTRACT FROM AUTHOR]

The discovery and studies of chemistry of dichlorocarbene and other electron deficient carbenes are discussed. [ABSTRACT FROM AUTHOR]

Nitrogen-containing motifs are widely present in natural products, bioactive molecules, and drugs. Accordingly, effective synthetic methods with high efficiency and diversity are highly desirable. Here, we present the invention of a facile, visible light-mediated decarboxylative C(sp3)-N bond-forming reaction by employing abundant carboxylic acids as the feedstock and a commercial diazirine as a nitrogen donor. This process is amenable to access both imines and diaziridines, as the corresponding masked amines and hydrazines, through a selectable single or double nitrogen transfer from the diazirine, respectively. This divergent approach works well in both directions with various alkyl carboxylic acids, including primary, secondary, and tertiary acids, as well as natural products and drugs, thus affording a rapid, metal-free approach to build nitrogen-containing molecule libraries with considerable structural diversity, which could thus benefit the related study in context of chemical biology and drug discovery. [ABSTRACT FROM AUTHOR]

Broad scope one‐pot diazirine synthesis strategies have been developed using two different oxidants depending on the nature of the starting material. In all cases, an inexpensive commercial solution of ammonia (NH3) in methanol (MeOH) was employed, avoiding the difficult use of liquid ammonia. With aliphatic ketones, t‐butyl hypochlorite (t‐BuOCl) was found to be the best oxidant whereas it is preferable to use phenyliodine diacetate (PIDA) with aromatic ketones, aldehydes and imines. The nature of the imine‐protecting group is essential and only t‐butyl imine allowed the synthesis of 15N2‐diazirine with complete 15N incorporation, emphasizing a key trans‐imination step in the reaction mechanism. These methods are operationally simple, and tolerant to most functional groups, providing diazirines with yields ranging from 20 to 99%. [ABSTRACT FROM AUTHOR]

The synthesis of a series of fused diaziridines, which are difficult to access by existing methods, was achieved by the reaction of cyclic secondary amines with p -toluenesulfonamide in the presence of N -bromosuccinimide (NBS) and a suitable base. This oxidation system enables the efficient in situ formation of the key intermediates, which are N -bromoamines (a precursor of cyclic imines) and N -bromosulfonamides. In addition, an alternative method using N -bromo- N -sodio- p -toluenesulfonamide (bromamine-T) in the presence of a catalytic amount of CF3 CO2 H for the synthesis of fused diaziridines is also reported. [ABSTRACT FROM AUTHOR]

d-Erythrosyl aziridines were obtained from d-erythrosyl triazoles either by photolysis or through diazirine intermediates. These were found to undergo rich, high yielding chemistry by reaction with protic acids (HCl, BiI3/H2O and trifluoroacetic acid) leading to two types of furanoid sugar α-amino acids, and polyhydroxylprolines. Based on experimental evidence, reaction mechanisms have been proposed for the syntheses. [ABSTRACT FROM AUTHOR]

Oxaziridines and diaziridines have been used as versatile intermediates due to their high ring strain as well as the reactive C−O/N bond, for the synthesis of diverse range of nitrogen containing compounds. In the past few decades, numerous novel and handy methodologies on the preparations and utilizations of both the oxaziridines and diaziridines have been developed. In spite of few published reviews in the area (almost a decade back), the synthetic communities have made tremendous progress in their preparations and utilizations. This review has demonstrated the comprehensive advancement in the chemistry of oxaziridines and diaziridines for the last few years (almost a decade). [ABSTRACT FROM AUTHOR]

Photoaffinity labeling is frequently employed for the investigation of ligand–receptor interactions in solution. We have employed an interdisciplinary methodology to achieve facile photolabeling of the lectin FimH, which is a bacterial protein, crucial for adhesion, colonization and infection. Following our earlier work, we have here designed and synthesized diazirine-functionalized mannosides as high-affinity FimH ligands and performed an extensive study on photo-crosslinking of the best ligand (mannoside 3) with a series of model peptides and FimH. Notably, we have employed high-performance mass spectrometry to be able to detect radiation results with the highest possible accuracy. We are concluding from this study that photolabeling of FimH with sugar diazirines has only very limited success and cannot be regarded a facile approach for covalent modification of FimH.

Iron-catalyzed stereospecific [3+3]-annulation of aziridines with diaziridines is described to furnish [1,2,4]-triazines in high yield at room temperature. The use of an inexpensive iron salt catalyst, substrate scope and enantiomeric purity are the important practical features. [ABSTRACT FROM AUTHOR]

This review focuses on diaziridine, a high strained three-membered heterocycle with two nitrogen atoms that plays an important role as one of the most important precursors of diazirine photoaffinity probes, as well as their formation and transformation. Recent research trends can be grouped into three categories, based on whether they have examined non-substituted, N-monosubstituted, or N,N-disubstituted diaziridines. The discussion expands on the conventional methods for recent applications, the current spread of studies, and the unconventional synthesis approaches arising over the last decade of publications.

Construction of a fluorophore or high‐sensitive mass tag on target molecules would promise the facile analysis in photoaffinity labeling. A novel 2‐nitrobenzenesulfonyl (nosyl; Ns) diazirine, which exhibits bifunctional properties for efficient photoaffinity labeling, was designed. This strategy highlights the simplicity of the chemical probe and its ability to install identification tags via Meisenheimer complex by SNAr after photo‐labelling. Herein, in this study, we synthesized new Ns diazirine and demonstrated further studies in terms of photoactivation and SNAr reaction in aqueous condition. [ABSTRACT FROM AUTHOR]

A chiral copper(I) complex catalyzes reactions of symmetric diaziridines with enol diazo compounds, which react through N−N bond ring opening in a formal [3+3] cycloaddition to form four chiral centers with high stereocontrol. A broad spectrum of bridged dinitrogen heterocycles were obtained in high yields and excellent diastereo‐ and enantioselectivities from γ‐substituted enol diazoacetates, while their geometrical isomers gave different enantioselectivities. Donor–acceptor cyclopropenes formed from the geometrical isomers of the γ‐substituted enol diazoacetates underwent catalytic ring opening to give only the Z isomer of the metalloenolcarbene intermediate, provided excellent yields and selectivities for the 1,5‐diazabicyclo[n.3.1]non‐2‐ene derivatives. [ABSTRACT FROM AUTHOR]

Substituted pyrazolines were obtained by Ni(ClO4)2·6H2O‐catalyzed reaction of 1,5‐diazabicyclo[3.1.0]hexanes with donor‐acceptor cyclopropanes. The mechanism of this reaction includes alkylation of diaziridine nitrogen with Lewis acid‐activated donor‐acceptor cyclopropane followed by hydration of the formed 1,6‐zwitterionic intermediate and oxidation of pyrazolidine with air oxygen. This pathway is realized when starting bicyclic diaziridines have bulky alkyl substituent(s) at the C(6) atom preventing (3+3)‐annulation of two three‐membered rings. [ABSTRACT FROM AUTHOR]

Diazirine moieties are chemically stable and have been incorporated into biomolecules without impediment of biological activity. The 15N2 labeled diazirines are appealing motifs for hyperpolarization supporting relaxation protected states with long‐lived lifetimes. The (‐CH15N2) diazirine groups investigated here are analogues to methyl groups, which provides the opportunity to transfer polarization stored on a relaxation protected (‐CH15N2) moiety to 1H, thus combining the advantages of long lifetimes of 15N polarization with superior sensitivity of 1H detection. Despite the proximity of 1H to 15N nuclei in the diazirine moiety, 15N T1 times of up to (4.6±0.4) min and singlet lifetimes Ts of up to (17.5±3.8) min are observed. Furthermore, we found terminal diazirines to support hyperpolarized 1H2 singlet states in CH2 groups of chiral molecules. The singlet lifetime of 1H singlets is up to (9.2±1.8) min, thus exceeding 1H T1 relaxation time (at 8.45 T) by a factor of ≈100. [ABSTRACT FROM AUTHOR]

Photochemical reactivity of pentacycloundecane (PCU) and adamantane diazirines was investigated by preparative irradiation in different solvents, laser flash photolysis (LFP) and quantum chemical computations. In addition, formation of inclusion complexes for diazirines with cucurbit[7]uril, β- and γ-cyclodextrin (β- and γ-CD) was investigated by 1H NMR spectroscopy, isothermal microcalorimetry and circular dichroism spectroscopy, followed by the investigation of photochemical reactivity of the formed complexes. Diazirines undergo efficient photochemical elimination of nitrogen (ΦR ＞ 0.5) and deliver the corresponding singlet carbenes. Singlet carbenes react in intra- and intermolecular reactions and we found a rare singlet carbene pathway in CH3OH involving protonation and formation of a carbocation, detected due to the specific rearrangement of the pentacycloundecane skeleton. Singlet diazirines undergo intersystem crossing and deliver triplet carbenes that react with oxygen to form ketones which were isolated after irradiation. Our main finding is that the formation of diazirine inclusion complexes with β-CD and γ-CD changes the relative ratio of singlet vs. triplet pathways, with singlet carbene products being dominant from the chemistry of the irradiated complexes. Our combined theoretical and experimental studies provide new insights into the supramolecular control of carbene reactivity which has possible applications for the control of product distribution by solvent effects and the choice of constrained media. [ABSTRACT FROM AUTHOR]

An approach to the synthesis of spirocyclic diazirines from cyclic ketones was examined on a series of carbo‐ and heterocyclic substrates containing the amine or carboxylic acid moiety. A mini‐library of stereochemically diverse functionalized spirocyclic diazirines was synthesized on a multigram scale with 30–81 % yield. [ABSTRACT FROM AUTHOR]

The elucidation of substrate–protein interactions is an important component of the drug development process. Due to the complexity of native cellular environments, elucidating these fundamental biochemical interactions remains challenging. Photoaffinity labeling (PAL) is a versatile technique that can provide insight into ligand‐target interactions. By judicious modification of substrates with a photoreactive group, PAL creates a covalent crosslink between a substrate and its biological target following UV‐irradiation. Among the commonly employed photoreactive groups, diazirines have emerged as the gold standard. In this Minireview, recent developments in the field of diazirine‐based photoaffinity labeling will be discussed, with emphasis being placed on their applications in chemical proteomic studies. The elucidation of substrate–protein interactions is an important component of the drug development process. Photoaffinity labeling (PAL) is a versatile technique that can provide insight into ligand–target interactions. Among the commonly employed photoreactive groups, diazirines have emerged as the gold standard. In this Minireview, recent developments in the field of diazirine‐based PAL are discussed, with emphasis on their applications in proteomic studies. [ABSTRACT FROM AUTHOR]

We developed a novel diazirine‐based photolabeling agent having a (coumarin‐4‐yl)methyl ester scaffold, which exhibited multiple photochemical properties of crosslinking, fluorogenicity and cleavage. These properties can be kinetically regulated via photoinduced electron transfer between diazirine and coumarin moieties. The C−O bond of (coumarin‐4‐yl)methyl ester can be cleaved via photochemical excitation of coumarin moiety, that function has been initially quenched by the diazirine moiety. Upon diazirine photolysis with 365‐nm light, interacting protein was stably captured with photoactivatable ligand probe. Then, the unlocked cleavage function was activated with 313 nm light, and the reaction was accelerated in a weakly‐basic solution. The crosslinked protein could be selectively isolated with attachment of a small coumarin tag on the surface. This multi‐functional labeling agent has a great potential to facilitate LC‐MS/MS‐based protein identification. Getting an agent: A coumarin‐fused diazirine photolabeling agent exhibited multiple photochemical properties of crosslinking, fluorogenicity and cleavage, and their kinetic regulation via photoinduced electron transfer between diazirine and coumarin moieties holds great potential to facilitate the LC‐MS/MS‐based protein identification process through analysis of the labeled peptide. [ABSTRACT FROM AUTHOR]

Abstract Pregnanolone and allopregnanolone-type ligands exert general anesthetic, anticonvulsant and anxiolytic effects due to their positive modulatory interactions with the GABA A receptors in the brain. Binding sites for these neurosteroids have been recently identified at subunit interfaces in the transmembrane domain (TMD) of homomeric β3 GABA A receptors using photoaffinity labeling techniques, and in homomeric chimeric receptors containing GABA A receptor α subunit TMDs by crystallography. Steroid binding sites have yet to be determined in human, heteromeric, functionally reconstituted, full-length, glycosylated GABA A receptors. Here, we report on the synthesis and pharmacological characterization of several photoaffinity analogs of pregnanolone and allopregnanolone, of which 21-[4-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzoxy]allopregnanolone (21-pTFDBzox-AP) was the most potent ligand. It is a partial positive modulator of the human α1β3 and α1β3γ2L GABA A receptors at sub-micromolar concentrations. [3H]21-pTFDBzox-AP photoincorporated in a pharmacologically specific manner into the α and β subunits of those receptors, with the β3 subunit photolabeled most efficiently. Importantly, photolabeling by [3H]21-pTFDBzox-AP was inhibited by the positive steroid modulators alphaxalone, pregnanolone and allopregnanolone, but not by inhibitory neurosteroid pregnenolone sulfate or by two potent general anesthetics and GABA A R positive allosteric modulators, etomidate and an anesthetic barbiturate. The latter two ligands bind to sites at subunit interfaces in the GABA A R that are different from those interacting with neurosteroids. 21-pTFDBzox-AP's potency and pharmacological specificity of photolabeling indicate its suitability for characterizing neurosteroid binding sites in native GABA A receptors. Graphical abstract Image 1 Highlights • Three photoreactive neurosteroid modulators of GABA A R were synthesized and evaluated. • The ligand modified at the 21-position displayed strong binding. • This ligands interacts with GABA A R at a site distinct from etomidate or barbiturate site. • It photolabels predominantly β-subunit in α1β3γ2-GABA A R. • Photolabeling was strongly inhibited by other neurosteroid modulators. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Complexes of pSer, pThr, and pTyr phosphopeptides with diazirine-tagged Arg peptides. • Photodissociative crosslinking at 355 nm forms covalent bonds. • High fractions of stable complexes are detected after photodissociation. • Crosslinking efficiency depends on phosphor and photopeptide modifications. Abstract We report a study of non-covalent complexes of phosphopeptides pXAAAA and N -Ac-pXAAAA (X = Ser, Thr, Tyr) with arginine-containing peptides carrying diazirine 4,4-azipentyl tags at the N -terminus, *LGG(A) n R, or in the photoleucine residue, L*GG(A) n R (n = 3–5). Complexes with *LGG(A) n R were successfully generated as singly charged ions in the gas phase in 0.6–3.5% yields. In contrast, complexes with L*GG(A) n R were formed in negligible (<0.1%) yields. Selective photodissociation at 355 nm of the diazirine ring in [*LGG(A) n R + pXAAAA + H]+ ions resulted in loss of N 2 , producing large (75–95%) fractions of non-dissociating complexes that were further probed by collision-induced dissociation tandem mass spectrometry (CID-MS3). Covalent cross-links in the complexes produced by photoinduced carbene insertion were identified by specific CID-MS3 dissociations involving H 3 PO 4 transfer and backbone fragmentations. N -acetylation in the phosphopeptides was found to have a substantial negative effect on the formation of covalent cross-links. Amongst the phosphorylated amino acid residues, pTyr showed the highest tendency (up to 92%) to form covalent cross-links. The fractions of covalent cross-links substantially increased with the length of the photopeptide chain. Born-Oppenheimer molecular dynamics (BOMD) calculations of canonical and zwitterionic protomers of the (pYAAAA + *LGGAAAR + H)+ complex indicated multiple close contacts between the incipient carbene of the diazirine ring and the X H bonds (X C, N, O) in the phosphopeptide. BOMD in combination with structural analysis by density functional theory calculations were used to interpret the experimental data and explain the cross-linking efficiencies. [ABSTRACT FROM AUTHOR]

Analysing protein complexes by chemical crosslinking‐mass spectrometry (XL‐MS) is limited by the side‐chain reactivities and sizes of available crosslinkers, their slow reaction rates, and difficulties in crosslink enrichment, especially for rare, transient or dynamic complexes. Here we describe two new XL reagents that incorporate a methanethiosulfonate (MTS) group to label a reactive cysteine introduced into the bait protein, and a residue‐unbiased diazirine‐based photoactivatable XL group to trap its interacting partner(s). Reductive removal of the bait transfers a thiol‐containing fragment of the crosslinking reagent onto the target that can be alkylated and located by MS sequencing and exploited for enrichment, enabling the detection of low abundance crosslinks. Using these reagents and a bespoke UV LED irradiation platform, we show that maximum crosslinking yield is achieved within 10 seconds. The utility of this "tag and transfer" approach is demonstrated using a well‐defined peptide/protein regulatory interaction (BID80‐102/MCL‐1), and the dynamic interaction interface of a chaperone/substrate complex (Skp/OmpA). [ABSTRACT FROM AUTHOR]

Abstract Irradiation of 2-azidovinylbenzene ( 1 ) in a cryogenic argon matrix with a 254 nm bandpass filter results in 2-phenyl-2 H -azirine ( 2 ) as the major product, some ketenimine 5 , and a small amount of cis - 1 , whereas irradiation of vinyl azide 1 with light above 300 nm forms only azirine 2 and ketenimine 5. Prolonged irradiation of azirine 2 through a 254 nm bandpass filter produces ylide 3 selectively. Laser flash photolysis with excitation at 308 nm demonstrated that azirine 2 forms triplet vinylnitrene 4 ( λ ∼ 440 nm), whereas vinyl azide 1 does not exhibit transient absorption on a nanosecond timescale. DFT calculations (B3LYP/6-31 + G(d)) were used to aid the characterization of the photoproducts and to support the proposed formation mechanisms. Graphical abstract Image 1 Highlights • The photochemistry of 2-azidovinylbenzene and 2-phenyl-2 H -azirine was investigated as a function of wavelength irradiation. [ABSTRACT FROM AUTHOR]

Abstract The reactions of methylsulfonylnitrene 1a and trifluoromethylsulfonylnitrene 1b with acetylene 2 , dimethylacetylene 3 , acetylenedicarboxylic acid 4 , hydrogen cyanide 5 , acetonitrile 6 , cyanoformic acid 7 were studied theoretically at the CBS-QB3 level of theory. The main products of the reaction of triplet sulfonylnitrenes 3 1 with alkynes 2 – 4 are 1,2,3-oxathiazole 2-oxides 10 formed from triplet diradical adducts after intersystem crossing (ISC) to their singlet spin-isomers. Products 10 are also formed from singlet nitrenes 1 1 along with N -vinylidenesulfonamides 9 and 1-(alkylsulfonyl)-1 Н -azirines 11. The latter, being antiaromatic, isomerize exothermically to 2-(alkylsulfonyl)-2 Н -azirines 12. In a similar way, both singlet and triplet sulfonylnitrenes 1 react with nitriles 5 – 7 to give 1-(alkylsulfonyl)-1 H -diazirines 16. With singlet nitrenes, nitriles 5 – 7 can also react with the formation of 2-(methylidyne)-1-(alkylsulfonyl)diazan-2-ium-1-ides 14 , which undergo either intramolecular 1,3-cyclization to 3-(alkylsulfonyl)-3 H -diazirines 17 or intramolecular 1,5-cyclization to 1,2,3,4-oxathiadiazole 2-oxides 15. Relative stability of the key products and activation barriers of their interconversion are discussed. Graphical abstract Image 1 Highlights • The reactions of singlet and triplet sulfonylnitrenes with acetylenes and nitriles were studied theoretically (CBS-QB3). • The mechanism of formation of various linear and heterocyclic products was suggested and their relative energies compared. • Transition states connecting the minima on the PES corresponding to different products were located. [ABSTRACT FROM AUTHOR]

Graphical abstract A facile, diastereoselective method for the synthesis of diaziridines with C - and N -cyclopropyl substituents has been developed, N -cyclopropyldiaziridines being for the first time synthesized. The method is based on one-pot three-component condensation of cyclopropyl-containing carbonyl compounds, primary aliphatic amines including cyclopropylamine, and N -chloroalkylamines in organic solvents in the presence of bases under mild conditions. [ABSTRACT FROM AUTHOR]

Abstract: The first example of (3+3)‐annulation of two different three‐membered rings is reported herein. Donor‐acceptor cyclopropanes in reaction with diaziridines were found to afford perhydropyridazine derivatives in high yields and diastereoselectivity under mild Lewis acid catalysis. The disclosed reaction is applicable for the broad substrate scope and exhibits an excellent functional group tolerance. [ABSTRACT FROM AUTHOR]

Abstract: The small neuroprotective peptide Cys‐Ala‐Gln‐Lys (CAQK) was selectively tagged with a diazirine group and its photochemical cross‐linking was studied with model target peptides. Experimental results in combination with Born–Oppenheimer molecular dynamics revealed the structural preferences for binding to the amino acid residues in the target peptides. Effects of the target peptide sequence and N‐ and C‐terminal modifications are discussed. [ABSTRACT FROM AUTHOR]

We report the synthesis of an electronically-tuned minimally interfering photo-affinity label (MI-PAL), a compact five-carbon tag functionalized with an alkyl diazirine and alkyne handle. MI-PAL is compatible with protein photo-conjugation, click chemistry and mass spectrometry and readily installed to complex molecules for biological target identification. [ABSTRACT FROM AUTHOR]

The molecular structure and conformational behavior of 3-cyclopropyl-1,2-dimethyldiaziridine have been for the first time experimentally studied by gas-phase electron diffraction and quantum chemical calculations. The two most stable conformers at 298 K possess anti and gauche mutual ring orientation (with prevalence of the anti conformer) whereas only one anti conformer is observed in solution. The determined structural parameters of gaseous 3-cyclopropyl-1,2-dimethyldiaziridine have been compared with those for 3,3-bidiaziridine structural analogues in the crystal phase. The simple and convenient procedure for the synthesis of 3-cyclopropyl-1,2-dimethyldiaziridine comprising cyclopropane and diaziridine rings in one molecule was developed. The standard enthalpy of formation of 3-cyclopropyl-1,2-dimethyldiaziridine in the gas phase was calculated using Gaussian-4 theory, yielding value of 281.9 ± 5.0 kJ/mol. [ABSTRACT FROM AUTHOR]

Bioadhesives are a current unmet clinical need for mending of blood contacting soft tissues without inducing thrombosis. Recent development of carbene precursor bioadhesives with the advantages of on-demand curing, tuneable modulus, and wet adhesion have been synthesized by grafting diazirine onto poly (amidoamine) (PAMAM-G5) dendrimers. Herein, the structure activity relationships of platelet adhesion and activation is evaluated for the first time on the cured PAMAM-g-diazirine bioadhesives. Three strategies were employed to prevent healthy human donor platelets from adhering and activating on light-cured bioadhesive surfaces: (1) Attenuation of cationic surface charge, (2) antifouling composites by incorporating heparin and alginate in uncured formulation, and (3) heparin wash of cured bioadhesive surface. Topographical imaging of cured and ethanol dehydrated bioadhesive surfaces was used to quantify the adhered and activated platelets with scanning electron microscopy, whose resolution allowed identification of round senescent, short dendritic, and long dendritic platelets. Cured surfaces of PAMAM-g-diazirine (15%) had 10300 ± 500 adhered platelets mm-2 with 99.7% activation into short/long dendritic cells. Reduction of primary amines by higher degree of diazirine grafting or capping of free amines by acetylation reduces platelet adherence (2400 ± 200 vs 3000 ± 300, respectively). Physical incorporation of heparin and alginate in the formulations reduced the activated platelet; 1300 ± 300 and 300 ± 50, activated platelets mm-2, in comparison with additive free adhesive formulation. Similarly, heparin rinse of the surface of additive free bioadhesive reduced the activated platelet to platelets of heparin composites at 600 ± 100 platelets mm-2. PAMAM-g-diazirine (15%) bioadhesive retained the photocured mechanical properties and lap shear adhesion despite the addition of heparin and alginate additives. [ABSTRACT FROM AUTHOR]