Cannabinoid receptor 2 (CB2) modulators: A patent review (2016-2024).

Cannabinoid receptors CB1 and CB2 play critical roles in regulating numerous central and peripheral physiological activities. While efforts have been made to develop ligands for both CB1 and CB2 receptors, CB1 receptor ligands often have restricted use due to undesirable psychotropic side effects. Consequently, recent cannabis research has increasingly focused on CB2-specific ligands. Pharmacological agonists of CB2 receptors have shown potential in managing pain, inflammation, arthritis, neuroprotection, cancer, and other disorders. Despite several CB2 receptor ligands entering clinical trials, none have achieved market approval except natural cannabinoids and their derivatives, primarily due to insufficient CB2/CB1 receptor selectivity. However, new-generation ligands developed in recent years have demonstrated improved selectivity. This review covers patent literature on CB2 modulators from 2016 to 2024, highlighting the major advances in the field. During this period, the majority of research has concentrated on using CB2 modulators to alleviate inflammation and pain. Additionally, patents have explored CB2 modulators for a range of specific diseases, including: psychiatric and neuropsychiatric disorders, schizophrenia, multiple myeloma and osteoporosis, ocular inflammation and neuropathic Pain, cancer anorexia and weight loss, antioxidant and anti-aging agents, lymphocytopenia, hearing loss, Alzheimer's disease, cancer and non-malignant tumors. Notably, recent years have seen increased interest in CB2 antagonists/inverse agonists, with few candidates advancing to clinical studies. Significant progress has been made in the synthesis and modulation of selective CB2 agonists and antagonists, paving the way for future developments in CB2 modulators. This review provides insights and prospects for the continued evolution of CB2-targeted therapies.

Fluvoxamine maleate alleviates amyloid-beta load and neuroinflammation in 5XFAD mice to ameliorate Alzheimer disease pathology.

Introduction: Alzheimer pathology (AD) is characterized by the deposition of amyloid beta (Aß) and chronic neuroinflammation, with the NLRP3 inflammasome playing a significant role. This study demonstrated that the OCD drug fluvoxamine maleate (FXN) can potently ameliorate AD pathology in 5XFAD mice by promoting autophagy-mediated clearance of Aß and inhibiting the NLRP3 inflammasome. Methods: We used mice primary astrocytes to establish the mechanism of action of FXN against NLRP3 inflammasome by using various techniques like ELISA, Western blotting, confocal microscopy, Immunofluorescence, etc. The anti-AD activity of FXN was validated in transgenic 5XFAD mice following two months of treatment. This was followed by behavior analysis, examination of inflammatory and autophagy proteins and immunohistochemistry analysis for Aß load in the hippocampi. Results: Our data showed that FXN, at a low concentration of 78 nM, induces autophagy to inhibit NF-κB and the NLRP3 inflammasome, apart from directly inhibiting NLRP3 inflammasome in primary astrocytes. FXN activated the PRKAA2 pathway through CAMKK2 signaling, leading to autophagy induction. It inhibited the ATP-mediated NLRP3 inflammasome activation by promoting the autophagic degradation of NF-κB, resulting in the downregulation of pro-IL-1ß and NLRP3. The anti-NLRP3 inflammasome effect of FXN was reversed when autophagy was inhibited by either genetic knockdown of the PRKAA2 pathway or pharmacological inhibition with bafilomycin A1. Furthermore, FXN treatment led to improved AD pathology in 5XFAD mice, resulting in significant improvements in various behavioral parameters such as working memory and neuromuscular coordination, making their behavior more similar to that of wild-type animals. FXN improved behavior in 5XFAD mice by clearing the Aß deposits from the hippocampi and significantly reducing multiple inflammatory proteins, including NF-κB, GFAP, IBA1, IL-1ß, TNF-α, and IL-6, which are associated with NF-κB and NLRP3 inflammasome in the brain. Moreover, these changes were accompanied by increased expression of autophagic proteins. Discussion: Our data suggest that FXN ameliorates AD pathology, by simultaneously targeting two key pathological features: Aß deposits and neuroinflammation. As an already approved drug, FXN holds potential as a candidate for human studies against AD.

Identification of a novel GSK3ß inhibitor involved in abrogating KRas dependent pancreatic tumors in Wnt/beta-catenin and NF-kB dependent manner.

Pancreatic cancer is an aggressive malignancy with a poor survival rate because it is difficult to diagnose the disease during its early stages. The currently available treatments, which include surgery, chemotherapy and radiation therapy, offer only limited survival benefit. Pharmacological interventions to inhibit Glycogen Synthase Kinase-3beta (GSK3ß) activity is an important therapeutic strategy for the treatment of pancreatic cancer because GSK3ß is one of the key factors involved in the onset, progression as well as in the acquisition of chemoresistance in pancreatic cancer. Here, we report the identification of MJ34 as a potent GSK3ß inhibitor that significantly reduced growth and survival of human mutant KRas dependent pancreatic tumors. MJ34 mediated GSK3ß inhibition was seen to induce apoptosis in a ß-catenin dependent manner and downregulate NF-kB activity in MiaPaCa-2 cells thereby impeding cell survival and anti-apoptotic processes in these cells as well as in the xenograft model of pancreatic cancer. In vivo acute toxicity and in vitro cardiotoxicity studies indicate that MJ34 is well tolerated without any adverse effects. Taken together, we report the discovery of MJ34 as a potential drug candidate for the therapeutic treatment of mutant KRas-dependent human cancers through pharmacological inhibition of GSK3ß.

Third Generation Solid Dispersion-Based Formulation of Novel Anti-Tubercular Agent Exhibited Improvement in Solubility, Dissolution and Biological Activity.

The long treatment period and development of drug resistance in tuberculosis (TB) necessitates the discovery of new anti-tubercular agents. The drug discovery program of the institute leads to the development of an anti-tubercular lead (IIIM-019), which is an analogue of nitrodihydroimidazooxazole and exhibited promising anti-tubercular action. However, IIIM-019 displays poor aqueous solubility (1.2 µg/mL), which demands suitable dosage form for its efficient oral administration. In the present study, third generation solid dispersion-based formulation was developed to increase the solubility and dissolution of IIIM-019. The solubility profile of IIIM-019 using various polymeric carriers was determined and subsequently, PVP K-30 and P-407 were selected for preparation of binary and ternary solid dispersion. The third-generation ternary solid dispersion comprising PVP K-30 and P-407 revealed a remarkable enhancement in the aqueous solubility of IIIM-019. Physicochemical characterization of the developed formulations was done by employing FTIR spectroscopy, scanning electron microscopy, X-ray diffraction analysis, differential scanning calorimetry, and dynamic light scattering analysis. The dissolution study indicated an impressive release profile with the optimized formulation. The optimized formulation was further examined for cytotoxicity, cellular uptake, and hemolytic activity. The results indicated that the formulation had no apparent cytotoxicity on Caco-2 cells and was non-hemolytic in nature. Moreover, the optimized formulation showed significantly improved anti-tubercular activity compared to the native molecule. These findings showed that the developed third generation ternary solid dispersion could be a promising option for the oral delivery of investigated anti-tubercular molecule.

Discovery of a novel and highly selective JAK3 inhibitor as a potent hair growth promoter.

JAK-STAT signalling pathway inhibitors have emerged as promising therapeutic agents for the treatment of hair loss. Among different JAK isoforms, JAK3 has become an ideal target for drug discovery because it only regulates a narrow spectrum of γc cytokines. Here, we report the discovery of MJ04, a novel and highly selective 3-pyrimidinylazaindole based JAK3 inhibitor, as a potential hair growth promoter with an IC50 of 2.03 nM. During in vivo efficacy assays, topical application of MJ04 on DHT-challenged AGA and athymic nude mice resulted in early onset of hair regrowth. Furthermore, MJ04 significantly promoted the growth of human hair follicles under ex-vivo conditions. MJ04 exhibited a reasonably good pharmacokinetic profile and demonstrated a favourable safety profile under in vivo and in vitro conditions. Taken together, we report MJ04 as a highly potent and selective JAK3 inhibitor that exhibits overall properties suitable for topical drug development and advancement to human clinical trials.

Unraveling Dilemmas and Lacunae in the Escalating Drug Resistance of Mycobacterium tuberculosis to Bedaquiline, Delamanid, and Pretomanid.

Delamanid, bedaquiline, and pretomanid have been recently added in the anti-tuberculosis (anti-TB) treatment regimens and have emerged as potential solutions for combating drug-resistant TB. These drugs have proven to be effective in treating drug-resistant TB when used in combination. However, concerns have been raised about the eventual loss of these drugs due to evolving resistance mechanisms and certain adverse effects such as prolonged QT period, gastrointestinal problems, hepatotoxicity, and renal disorders. This Perspective emphasizes the properties of these first-in-class drugs, including their mechanism of action, pharmacokinetics/pharmacodynamics profiles, clinical studies, adverse events, and underlying resistance mechanisms. A brief coverage of efforts toward the generation of best-in-class leads in each class is also provided. The ongoing clinical trials of new combinations of these drugs are discussed, thus providing a better insight into the use of these drugs while designing an effective treatment regimen for resistant TB cases.

Synthesis and Evaluation of Natural and Unnatural Tetrahydrocannabiorcol for Its Potential Use in Neuropathologies.

(-)-trans-Δ9-Tetrahydrocannabinol (trans-(-)-Δ9-THC) has shown neuroprotective potential, but its medicinal benefits are not fully exploited due to the limitations of psychoactive properties. The lower homologues are non-psychoactive in nature but lack comprehensive scientific validation regarding neuroprotective potential. The present study describes the synthesis of non-psychoactive lower homologues of THC-type compounds and their neuroprotective potential. Both natural tetrahydro-cannabiorcol (trans-(-)-Δ9-THCO) and unnatural Δ9-tetrahydrocannabiorcol (trans-(+)-Δ9-THCO) were successfully synthesized starting from R-limonene and S-limonene, respectively, and investigated for neuroprotective potential in cellular models. The structures of both enantiomers were confirmed by NMR, HMBC, HQSC, NOESY, and COSY experiments. Results indicated that both enantiomers were nontoxic to the cells treated up to 50 µM. Neuroprotective properties of the enantiomers showed that treatments could significantly reverse the corticosterone-induced toxicity in SH-SY5Y cells and simultaneously cause elevated expression of brain-derived neurotrophic factor (BDNF). It was also observed that unnatural trans-(+)-Δ9-THCO displayed better activity than the natural enantiomer and can be further explored for its potential use in neuropathological ailments.

Chemistry and pharmacological aspects of furanoid cannabinoids and related compounds: Is furanoid cannabinoids open a new dimension towards the non-psychoactive cannabinoids?

Cannabinoids have emerged as compelling candidates for medicinal applications, notably following the recent approval of non-psychoactive cannabidiol (CBD) as a medicine. This endorsement has stimulated a growing interest in this class of compounds for drug discovery. Within the cannabis plant, a rich reservoir of over 125 compounds exists. Tetrahydrocannabinol (THC), a member of the dibenzopyran class, is widely recognized for its psychoactive effects. Conversely, the furanoid class, represented by cannabielsoin-type (CBE) and cannabifuran-type (CBF) compounds, has not been reported with psychoactivity and demonstrates a spectrum of pharmacological potential. The transition from the pyran structure of THC to the furan structure of CBE seems to mark a shift from psychoactive to non-psychoactive properties, but a comprehensive examination of other members in this class is essential for a complete understanding. Building on these observations, our thorough review delves into the subject, offering a comprehensive exploration of furanoid cannabinoids, covering aspects such as their biosynthesis, classification, synthesis, and medicinal potential. The aim of this review is to encourage and catalyze increased research focus in this promising area of cannabinoid exploration.

Exploring the Antibacterial Potential of Semisynthetic Phytocannabinoid: Tetrahydrocannabidiol (THCBD) as a Potential Antibacterial Agent against Sensitive and Resistant Strains of Staphylococcus aureus.

Antimicrobial resistance (AMR) is one of the most challenging problems and is responsible for millions of deaths every year. We therefore urgently require new chemical entities with novel mechanisms of action. Phytocannabinoids have been adequately reported for the antimicrobial effect but not seriously pursued because of either stringent regulatory issues or poor drug-like properties. In this regard, the current work demonstrated the antibacterial potential of tetrahydrocannabidiol (THCBD, 4), a semisynthetic phytocannabinoid, against Staphylococcus aureus, the second-most widespread bug recognized by the WHO. THCBD (4) was generated from cannabidiol and subjected to extensive antibacterial screening. In in vitro studies, THCBD (4) demonstrated a potent MIC of 0.25 µg/mL against Gram-positive bacteria, S. aureus ATCC-29213. It is interesting to note that THCBD (4) has demonstrated strong effectiveness against efflux pump-overexpressing (SA-1199B, SA-K2191, SA-K2192, and Mupr-1) and multidrug-resistant (MRSA-15187) S. aureus strains. THCBD (4) has also shown a good effect in kill kinetic assays against ATCC-29213 and MRSA-15187. In the checkerboard assay, THCBD (4) has shown additive/indifference effects with several well-known clinically used antibiotics, tetracycline, mupirocin, penicillin G, and ciprofloxacin. THCBD (4) also exhibited good permeability in the artificial skin model. Most importantly, THCBD (4) has significantly reduced CFU in mice's in vivo skin infection models and also demonstrated decent plasma exposure with 16-17% oral bioavailability. Acute dermal toxicity of THCBD (4) suggests no marked treatment-related impact on gross pathophysiology. This attractive in vitro and in vivo profile of plant-based compounds opens a new direction for new-generation antibiotics and warrants further detailed investigation.

Silver-mediated Room Temperature Reactions for the Synthesis of N-α-Ketoacyl Sulfoximines and N-α,ß-Unsaturated Acyl Sulfoximines.

Here, we report a silver-mediated coupling of acetylenes with sulfoximines to synthesize N-α-ketoacyl sulfoximines and N-α,ß-unsaturated acyl sulfoximines. The reactions are performed under an open atmosphere using the oxidant K2S2O8 and the ligand 2,2-bipyridyl. However, the fate of the product formation is controlled by the type of substrate used. The coupling between aryl acetylenes and sulfoximines afforded the N-α-ketoacylsulfoximines, while the alkyl acetylenes provided the N-α,ß-unsaturated acyl sulfoximines. Controlled experiments reveal the differential reactivity patterns of substrates. The labeling 18O experiments showed that water is the source of the incoming oxygen atom for the keto group of N-α-ketoacyl sulfoximines and N-α,ß-unsaturated acyl sulfoximines.

TCT-mediated click chemistry for the synthesis of nitrogen-containing functionalities: conversion of carboxylic acids to carbamides, carbamates, carbamothioates, amides and amines.

Here, we report a s-trichlorotriazine (TCT, also known as cyanuric chloride) mediated one-pot general method for the conversion of carboxylic acids into ubiquitous functionalities such as carbamides, carbamates, carbamothioates, amides, and amines. The TCT-mediated activation of acids followed by azidation and heating led to the isocyanate formation via Curtius rearrangement which involves click chemistry in the presence of nucleophiles and provided the coupled product. The TCT was employed at ≤40 mol% with respect to the starting materials; however, its bulk availability and low cost provide a unique opportunity towards its applicability in the synthesis of functional molecules. The optimized conditions have also been successfully demonstrated for gram scale synthesis and late-stage functionalization of natural products and drugs such as podophyllotoxin, eugenol, diosgenin, geraniol and fluvoxamine.

Functionalized Nitroimidazole Scaffold Construction and Their Pharmaceutical Applications: A 1950-2021 Comprehensive Overview.

Nitroimidazole represents one of the most essential and unique scaffolds in drug discovery since its discovery in the 1950s. It was K. Maeda in Japan who reported in 1953 the first nitroimidazole as a natural product from Nocardia mesenterica with antibacterial activity, which was later identified as Azomycin 1 (2-nitroimidazole) and remained in focus until now. This natural antibiotic was the starting point for synthesizing numerous analogs and regio-isomers, leading to several life-saving drugs and clinical candidates against a number of diseases, including infections (bacterial, viral, parasitic) and cancers, as well as imaging agents in medicine/diagnosis. In the present decade, the nitroimidazole scaffold has again been given two life-saving drugs (Delamanid and Pretomanid) used to treat MDR (multi-drug resistant) tuberculosis. Keeping in view the highly successful track-record of the nitroimidazole scaffold in providing breakthrough therapeutic drugs, this comprehensive review focuses explicitly on presenting the activity profile and synthetic chemistry of functionalized nitroimidazole (2-, 4- and 5-nitroimidazoles as well as the fused nitroimidazoles) based drugs and leads published from 1950 to 2021. The present review also presents the miscellaneous examples in each class. In addition, the mutagenic profile of nitroimidazole-based drugs and leads and derivatives is also discussed.

Stereoselective Synthesis of Nonpsychotic Natural Cannabidiol and Its Unnatural/Terpenyl/Tail-Modified Analogues.

Here, we report a three-step concise and stereoselective synthesis route to one of the most important phytocannabinoids, namely, (-)-cannabidiol (-CBD), from inexpensive and readily available starting material R-(+)-limonene. The synthesis involved the diastereoselective bifunctionalization of limonene, followed by effective elimination leading to the generation of key chiral p-mentha-2,8-dien-1-ol. The chiral p-mentha-2,8-dien-1-ol on coupling with olivetol under silver catalysis provided regiospecific (-)-CBD, contrary to reported ones which gave a mixture. The newly developed approach was further extended to its structural analogues cannabidiorcin and other tail/terpenyl-modified analogues. Moreover, its opposite isomer (+)-cannabidiol was also successfully synthesized from S-(-)-limonene.

Strategies to target SARS-CoV-2 entry and infection using dual mechanisms of inhibition by acidification inhibitors.

Many viruses utilize the host endo-lysosomal network for infection. Tracing the endocytic itinerary of SARS-CoV-2 can provide insights into viral trafficking and aid in designing new therapeutic strategies. Here, we demonstrate that the receptor binding domain (RBD) of SARS-CoV-2 spike protein is internalized via the pH-dependent CLIC/GEEC (CG) endocytic pathway in human gastric-adenocarcinoma (AGS) cells expressing undetectable levels of ACE2. Ectopic expression of ACE2 (AGS-ACE2) results in RBD traffic via both CG and clathrin-mediated endocytosis. Endosomal acidification inhibitors like BafilomycinA1 and NH4Cl, which inhibit the CG pathway, reduce the uptake of RBD and impede Spike-pseudoviral infection in both AGS and AGS-ACE2 cells. The inhibition by BafilomycinA1 was found to be distinct from Chloroquine which neither affects RBD uptake nor alters endosomal pH, yet attenuates Spike-pseudovirus entry. By screening a subset of FDA-approved inhibitors for functionality similar to BafilomycinA1, we identified Niclosamide as a SARS-CoV-2 entry inhibitor. Further validation using a clinical isolate of SARS-CoV-2 in AGS-ACE2 and Vero cells confirmed its antiviral effect. We propose that Niclosamide, and other drugs which neutralize endosomal pH as well as inhibit the endocytic uptake, could provide broader applicability in subverting infection of viruses entering host cells via a pH-dependent endocytic pathway.

High-throughput screening of compounds library to identify novel inhibitors against latent Mycobacterium tuberculosis using streptomycin-dependent Mycobacterium tuberculosis 18b strain as a model.

One of the significant challenges to treat tuberculosis is the phenotypic resistance adapted by the latent or dormant Mycobacterium tuberculosis (M. tuberculosis) cells against most of the available drugs. Different in-vitro assay such as oxygen depletion model and nutrient starvation models have contributed to unravelling the pathogen phenotypic resistance but are too cumbersome for application to high-throughput screening (HTS) assays. In this context, non-replicating streptomycin-starved 18b (SS18b) mutant strain of M. tuberculosis provided a simple and reproducible model. This model mimics latent tuberculosis and is best suited for screening medicinally appropriate libraries. Using SS18b strain in a resazurin reduction microplate assay (REMA), high-throughput screening of ChemDiv library constituting of 30,000 compounds resulted in the identification of 470 active compounds. Clustering and scaffolding based medicinal chemistry analysis characterized these hits into 15 scaffolds. Seven most potent compounds exhibiting an MIC ≤ 1 µg/ml against SS18b were non-toxic in HepG2 cell line (selective Index ≥ 160). Our screening revealed seven novel compounds exhibiting activity against the non-replicating form of M tuberculosis. 8002-7516 was the most promising compound showing intracellular killing and could be optimized to develop a lead drug candidate.

Potential Inhibitors Against NDM-1 Type Metallo-ß-Lactamases: An Overview.

A new member of the class metallo-ß-lactamase (MBL), New Delhi metallo-beta-lactamase 1 (NDM-1) has emerged recently as a leading threat to the treatment of infections that have spread in all major Gram-negative pathogens. The enzyme inactivates antibiotics of the carbapenem family, which are a mainstay for the treatment of antibiotic-resistant bacterial infections. This review provides information about NDM-1 spatial structure, potential features of the active site, and its mechanism of action. It also enlists the inhibitors/compounds/drugs against NDM-1 in various development phases. Understanding their mode of inhibition and the structure-activity relationship would be beneficial for development, synthesis, and even increasing biological efficacy of inhibitors, making them more promising drug candidates.

Total Synthesis of Phospholipomannan of Candida albicans.

First, total synthesis of the cell surface phospholipomannan anchor [ß-Manp-(1 → 2)-ß-Manp]n-(1 → 2)-ß-Manp-(1 → 2)-α-Manp-1 → P-(O → 6)-α-Manp-(1 → 2)-Inositol-1-P-(O → 1)-phytoceramide of Candida albicans is reported. The target phospholipomannan (PLM) anchor poses synthetic challenges such as the unusual kinetically controlled (1 → 2)-ß-oligomannan domain, anomeric phosphodiester, and unique phytoceramide lipid tail linked to the glycan through a phosphate group. The synthesis of PLM anchor was accomplished using a convergent block synthetic approach using three main appropriately protected building blocks: (1 → 2)-ß-tetramannan repeats, pseudodisaccharide, and phytoceramide-1-H-phosphonate. The most challenging (1 → 2)-ß-tetramannan domain was synthesized in one pot using the preactivation method. The phytoceramide-1-H-phosphonate was synthesized through an enantioselective A3 three-component coupling reaction. Finally, the phytoceramide-1-H-phosphonate moiety was coupled with pseudodisaccharide followed by deacetylation to produce the acceptor, which on subsequent coupling with tetramannosyl-H-phosphonate provided the fully protected PLM anchor. Final deprotection was successfully achieved by Pearlman's hydrogenation.

Effect of Natural Phenolics on Pharmacokinetic Modulation of Bedaquiline in Rat to Assess the Likelihood of Potential Food-Drug Interaction.

Bedaquiline (TMC-207) is a recently approved drug for the treatment of multidrug-resistant tuberculosis (MDR-TB). Moreover, there is a present and growing concern for natural-product-mediated drug interaction, as these are inadvertently taken by patients as a dietary supplement, food additive, and medicine. In the present study, we investigated the impact of 20 plant-based natural products, typically phenolics, on in vivo oral bedaquiline pharmacokinetics, as previous studies are lacking. Three natural phenolics were identified that can significantly enhance the oral exposure of bedaquiline upon coadministration. We further investigated the possible role of all of the phytochemicals on in vitro P-glycoprotein (P-gp) induction and inhibition and CYP3A4 inhibition in a single platform as bedaquiline is the substrate for both P-gp and CYP3A4. In conclusion, curcumin, CC-I (3',5-dihydroxyflavone-7-O-ß-d-galacturonide-4'-O-ß-d-glucopyranoside), and 6-gingerol should not be coadministered with bedaquiline to avoid untoward drug interactions and, subsequently, its dose-dependent adverse effects.

A concise and sequential synthesis of the nitroimidazooxazole based drug, Delamanid and related compounds.

A concise, protection-group free and sequential route has been developed for the synthesis of the nitroimidazole based FDA-approved multi-drug resistant anti-tuberculosis drug, Delamanid and anti-leishmanial lead candidate VL-2098. The synthesis required chiral epoxides (11 and 17) as key intermediates. The chiral epoxide 11 was synthesised by sequential reaction cascades viz., allylation, selective N-arylation, Mitsunobu etherification, Sharpless asymmetric dihydroxylation and epoxidation, which do not require any special/dry reaction conditions. The steps involved towards the synthesis of epoxide also worked nicely in gram scales. After the synthesis of epoxide 11, the synthesis of Delamanid was achieved by reaction with 2-bromo-4-nitroimidazole 12 with an overall yield of 27%. Similarly, anti-leishmanial lead candidate VL-2098 was also synthesized in an overall yield of 36%.

Functionalization of Alkynes and Alkenes Using a Cascade Reaction Approach: Synthesis of ß-Keto Sulfones under Metal-free Conditions.

Here, we are reporting a multicomponent cascade reaction approach for the synthesis of ß-keto sulfones by exploiting differential reactivity pattern of substrates under open-atmosphere and metal-free conditions. The coupling partners are aryldiazonium salts, unsaturated compounds, and DABSO. The optimized conditions worked well with both alkenes and alkynes. Moreover, the reaction also works with metabisulfite for the source of sulfone. The controlled liquid chromatography-mass spectrometry and 18O-labelled experiments suggested that air is a source of the incoming oxygen atom of the keto group of ß-keto sulfones.