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Chemotherapy is a powerful tool in the armoury against cancer, but it is fraught with problems due to its global systemic toxicity. Here we report the proof of concept of a chemistry-based strategy, whereby gamma/X-ray irradiation mediates the activation of a cancer prodrug, thereby enabling simultaneous chemo-radiotherapy with radiotherapy locally activating a prodrug. In an initial demonstration, we show the activation of a fluorescent probe using this approach. Expanding on this, we show how sulfonyl azide- and phenyl azide-caged prodrugs of pazopanib and doxorubicin can be liberated using clinically relevant doses of ionizing radiation. This strategy is different to conventional chemo-radiotherapy radiation, where chemo-sensitization of the cancer takes place so that subsequent radiotherapy is more effective. This approach could enable site-directed chemotherapy, rather than systemic chemotherapy, with ‘real time’ drug decaging at the tumour site. As such, it opens up a new era in targeted and directed chemotherapy.Prodrugs offer one route to treat cancer, but they require activation once they have been delivered to the tumour. Now, a simultaneous chemo-radiotherapy strategy has been demonstrated in mice that uses gamma or X-ray irradiation to locally activate an anticancer prodrug.

Click chemistry is a concept in which modular synthesis is used to rapidly find new molecules with desirable properties 1 . Copper( i )-catalysed azide–alkyne cycloaddition (CuAAC) triazole annulation and sulfur( vi ) fluoride exchange (SuFEx) catalysis are widely regarded as click reactions 2 – 4 , providing rapid access to their products in yields approaching 100% while being largely orthogonal to other reactions. However, in the case of CuAAC reactions, the availability of azide reagents is limited owing to their potential toxicity and the risk of explosion involved in their preparation. Here we report another reaction to add to the click reaction family: the formation of azides from primary amines, one of the most abundant functional groups 5 . The reaction uses just one equivalent of a simple diazotizing species, fluorosulfuryl azide 6 – 11 (FSO 2 N 3 ), and enables the preparation of over 1,200 azides on 96-well plates in a safe and practical manner. This reliable transformation is a powerful tool for the CuAAC triazole annulation, the most widely used click reaction at present. This method greatly expands the number of accessible azides and 1,2,3-triazoles and, given the ubiquity of the CuAAC reaction, it should find application in organic synthesis, medicinal chemistry, chemical biology and materials science. A ‘click’ reaction is developed for the simple and rapid formation of azides from primary amines, and is used to prepare a library of over 1,200 azides for subsequent use in the existing triazole annulation click reaction.

Chemical reactions that enable selective biomolecule labeling in living organisms offer a means to probe biological processes in vivo. Very few reactions possess the requisite bioorthogonality, and, among these, only the Staudinger ligation between azides and triarylphosphines has been employed for direct covalent modification of biomolecules with probes in the mouse, an important model organism for studies of human disease. Here we explore an alternative bioorthogonal reaction, the 1,3-dipolar cycloaddition of azides and cyclooctynes, also known as \"Cu-free click chemistry,\" for labeling biomolecules in live mice. Mice were administered peracetylated N-azidoacetylmannosamine (Ac₄ManNAz) to metabolically label cell-surface sialic acids with azides. After subsequent injection with cyclooctyne reagents, glycoconjugate labeling was observed on isolated splenocytes and in a variety of tissues including the intestines, heart, and liver, with no apparent toxicity. The cyclooctynes tested displayed various labeling efficiencies that likely reflect the combined influence of intrinsic reactivity and bioavailability. These studies establish Cu-free click chemistry as a bioorthogonal reaction that can be executed in the physiologically relevant context of a mouse.

Organic azides are key motifs in compounds of relevance to chemical biology, medicinal chemistry and materials science. In addition, they also serve as useful building blocks due to their remarkable reactivity. Therefore, the development of efficient protocols to synthesize these compounds is of great significance. This paper reviews the major applications and development of azidation in difunctionalization of olefins using azide reagents.

This review accounts for the most recent and significant research results from the literature on the design and synthesis of 1,2,3-triazole compounds and their usefulness as molecular well-defined corrosion inhibitors for steels, copper, iron, aluminum, and their alloys in several aggressive media. Of particular interest are the 1,4-disubstituted 1,2,3-triazole derivatives prepared in a regioselective manner under copper-catalyzed azide-alkyne cycloaddition (CuAAC) click reactions. They are easily and straightforwardly prepared compounds, non-toxic, environmentally friendly, and stable products to the hydrolysis under acidic conditions. Moreover, they have shown a good efficiency as corrosion inhibitors for metals and their alloys in different acidic media. The inhibition efficiencies (IEs) are evaluated from electrochemical impedance spectroscopy (EIS) parameters with different concentrations and environmental conditions. Mechanistic aspects of the 1,2,3-triazoles mediated corrosion inhibition in metals and metal alloy materials are also overviewed.

The exceptional reactivity of the azide group makes organic azides a highly versatile family of compounds in chemistry and the material sciences. One of the most prominent reactions employing organic azides is the regioselective copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition with alkynes yielding 1,2,3-triazoles. Other named reactions include the Staudinger reduction, the aza-Wittig reaction, and the Curtius rearrangement. The popularity of organic azides in material sciences is mostly based on their propensity to release nitrogen by thermal activation or photolysis. On the one hand, this scission reaction is accompanied with a considerable output of energy, making them interesting as highly energetic materials. On the other hand, it produces highly reactive nitrenes that show extraordinary efficiency in polymer crosslinking, a process used to alter the physical properties of polymers and to boost efficiencies of polymer-based devices such as membrane fuel cells, organic solar cells (OSCs), light-emitting diodes (LEDs), and organic field-effect transistors (OFETs). Thermosets are also suitable application areas. In most cases, organic azides with multiple azide functions are employed which can either be small molecules or oligo- and polymers. This review focuses on nitrene-based applications of multivalent organic azides in the material and life sciences.

Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC 50 between 1.2 and 4.3 μM, depending on viruses or cells, and selective index (SI) in 15–83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use ( n  = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1–9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2–25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.

Copper(I)-catalyzed azide-alkyne cycloaddition has become a commonly employed method for the synthesis of complex molecular architectures under challenging conditions. Despite the widespread use of copper-catalyzed cycloaddition reactions, the mechanism of these processes has remained difficult to establish due to the involvement of multiple equilibria between several reactive intermediates. Real-time monitoring of a representative cycloaddition process via heat-flow reaction calorimetry revealed that monomeric copper acetylide complexes are not reactive toward organic azides unless an exogenous copper catalyst is added. Furthermore, crossover experiments with an isotopically enriched exogenous copper source illustrated the stepwise nature of the carbon-nitrogen bond-forming events and the equivalence of the two copper atoms within the cycloaddition steps.

Vicinal diamines are a common structural motif in bioactive natural products, therapeutic agents, and molecular catalysts, motivating the continuing development of efficient, selective, and sustainable technologies for their preparation. We report an operationally simple and environmentally friendly protocol that converts alkenes and sodium azide—both readily available feedstocks—to 1,2-diazides. Powered by electricity and catalyzed by Earth-abundant manganese, this transformation proceeds under mild conditions and exhibits exceptional substrate generality and functional group compatibility. Using standard protocols, the resultant 1,2-diazides can be smoothly reduced to vicinal diamines in a single step, with high chemoselectivity. Mechanistic studies are consistent with metal-mediated azidyl radical transfer as the predominant pathway, enabling dual carbon-nitrogen bond formation.

The azidofunctionalization of alkenes has emerged as a powerful difunctionalization strategy, expanding the toolbox of synthetic chemistry. This transformation enables the simultaneous installation of an azide and a second functional group onto an alkene, facilitating access to diverse nitrogen‐containing compounds. The azidofunctionalization is particularly valuable in pharmaceutical and materials chemistry, as azides serve as key intermediates in the synthesis of bioactive molecules and polymers. Various catalytic and radical‐mediated approaches are developed. Photoredox catalysis, transition metal‐mediated reactions, and hypervalent iodine chemistry have enabled regio‐ and stereoselective transformations under mild conditions. Radical‐mediated methods, in particular, provide high efficiency and broad substrate scope, enabling the incorporation of azide groups even in complex molecular scaffolds. Recent advances have also explored enantioselective azidofunctionalization using chiral catalysts, opening new opportunities for the asymmetric synthesis of nitrogen‐containing derivatives. This review provides a comprehensive overview of azidofunctionalization methodologies, highlighting the diverse functional groups that have been introduced in a single‐step alongside an azide. The azidofunctionalization of alkenes offers a powerful strategy for synthesizing nitrogen‐containing compounds by installing both an azide and a second functional group in one step. This approach, employing photoredox catalysis, transition metals, and radical methods, is efficient, selective, and versatile, with applications in pharmaceuticals and materials chemistry.