ABSTRACT
Sydnones are among the most well-known mesoionic compounds. Since their synthesis in 1935 by Earl and Mecknay, numerous researches have shown that the chemical behavior, physical and biological properties of sydnones make them the most useful compounds in organic chemistry. Sydnones undergo thermal 1,3-dipolar cycloaddition reaction with dipolarophiles (alkynes or alkenes) to give exclusively derivatives containing a pyrazole moiety exhibiting numerous applications, such as pharmaceuticals and agrochemicals. However, the sydnone cycloaddition reaction with alkynes requires harsh conditions, like high temperatures and long reaction times, giving poor regioselectivity to the resulting products. To overcome these constraints, new reactions named CuSAC (Copper- Catalyzed Sydnone-Alkyne Cycloaddition) and SPSAC (Strain-Promoted Sydnone- Alkyne Cycloaddition) have been developed, leading to pyrazoles with interesting constant kinetics.
Subject(s)
Alkynes , Sydnones , Humans , Alkynes/chemistry , Sydnones/chemistry , Cycloaddition Reaction , Copper/chemistryABSTRACT
Sydnones are heterocyclic compounds which display important biological activities, including their abilities to react in 1,3-dipolar additions for applications in the development of new prodrugs. Capitalizing on our preliminary work on the mechanosynthesis of sydnones, an extension of this work to two related families of molecules, diarylsydnones and iminosydnones is reported. A ball-milling approach towards the synthesis of diaryl sydnones was developed, a necessary step for the synthesis of potential sydnone-based ligands of metal complexes. A mechanochemistry-based synthesis of iminosydnones was optimized, including the preparation of active pharmaceutical ingredients (API) related to feprosidnine, linsidomine, mesocarb and molsidomine. This work demonstrated that the ball-milling procedures were efficient and time saving through avoiding purification steps, and reduced the use of organic solvents.
Subject(s)
Sydnones , Sydnones/chemistryABSTRACT
Crop pathogens reduce the yield and quality of agricultural production. The development of new fungicides will help to sustain this protection and overcome fungicide resistance. Sydnone is a kind of mesoionic, which has a wide range of biological activities. The application of sydnones in agriculture is less, and the study of these compounds will lead to the discovery of new active compounds. In this study, we designed and synthesized a series of noval sydnone mesoionic derivatives by active substructure splicing. All compounds were characterized using 1H and 13C NMR spectroscopy. Among them, trifluoromethyl compound D17 showed good bioactivity against Pseudoperonospora cubensis (EC50 = 49 mg L-1) in vivo, the activity was similar to that of the control Kresoxim-methyl (EC50 = 44 mg L-1). However, the target of these compounds should not only be tyrosinase, and the mode of action needs to be further studied. In addition, the structure-activity relationship indicated that the trifluoromethyl group was more beneficial for antifungal activity. This is the first report that fluorine-containing N(3)-benzyl sydnone compounds have good fungicidal activity. These results will provide a basis for the development of sydnone mesoionic as new lead fungicidal agents.
Subject(s)
Antifungal Agents/pharmacology , Drug Design , Fungi/drug effects , Fungicides, Industrial/pharmacology , Sydnones/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Cucurbitaceae , Dose-Response Relationship, Drug , Fungicides, Industrial/chemical synthesis , Fungicides, Industrial/chemistry , Molecular Structure , Structure-Activity Relationship , Sydnones/chemical synthesis , Sydnones/chemistryABSTRACT
Triflumezopyrim (TFM) is a new mesoionic insecticide developed by DuPont. Like other neonicotinoid insecticides, it binds to the orthosteric site of the nicotinic acetylcholine receptor (nAChR), but the binding mode has not been reported. Nicotinic acetylcholine binding proteins (nAChBPs) are ideal alternative structure for nAChRs. In this study, molecular docking, molecular dynamics (MD) simulations, binding free energy calculation, and per-residue binding free energy decomposition were used to study the binding modes of TFM and other 12 mesoionic insecticides. By comparing the binding free energy and the insecticidal activity, it was found that the sub-pocket around the benzyl group of the mesoionic insecticide is the key area for maintaining its activity, which is composed of A: Val116, A: Met124, A: Ile126, B: Trp155 and B: Val156. In order to verify the druggability of the sub-pocket, a series of iminosydnone compounds were designed and synthesized based on the structure of the sub-pocket. The lethality rate of compound 1 against Mythimna separata were 100% at 500 mg/L. Our research provides a basis for designing new mesoionic insecticides based on structure.
Subject(s)
Drug Discovery , Insecticides/pharmacology , Moths/drug effects , Pyridines/pharmacology , Pyrimidinones/pharmacology , Sydnones/pharmacology , Animals , Dose-Response Relationship, Drug , Insecticides/chemical synthesis , Insecticides/chemistry , Molecular Structure , Pyridines/chemistry , Pyrimidinones/chemistry , Structure-Activity Relationship , Sydnones/chemical synthesis , Sydnones/chemistryABSTRACT
Many novel bioorthogonal reactions have been developed for labeling, such as the strain-promoted sydnone-alkyne cycloaddition (SPSAC), but sydnone-based probes with phosphorogenicity (i. e., phosphorescence turn-on upon reaction) have not been investigated to date. Herein, we report the synthesis, characterization, and photophysical properties of rhenium(I) polypyridine complexes containing a sydnone moiety as bioorthogonal phosphorogenic probes. Their reactions with strained alkyne derivatives and the associated photophysical changes were examined. Upon SPSAC with bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN-OH), the complexes exhibited emission enhancement in the range of 8.8 to 17.3. Importantly, conjugation of the complexes with BCN-modified bovine serum albumin (BCN-BSA) led to the increase in emission enhancement to as high as 38.9 and extended lifetimes in the range of 1.80 to 4.71â µs. Additionally, the bioorthogonal ligation of one of the complexes with a morpholine derivative was shown to induce specific lysosomal labeling in live cells; colocalization studies with LysoTracker Deep Red indicated a Pearson's coefficient of 0.83.
Subject(s)
Lysosomes/chemistry , Pyridines/chemistry , Rhenium/chemistry , Sydnones/chemistry , Electrophoresis, Polyacrylamide Gel , HeLa Cells , HumansABSTRACT
We report the synthesis and use of sydnone-based profluorophores as tools for imaging applications. These new probes display exquisite reactivity towards strain promoted cycloaddition reactions with cycloalkynes allowing fast, efficient and selective labeling in biological media. Styryl-pyridinium sydnone probes were found particularly interesting for click reactions to proceed selectively inside cells.
Subject(s)
Fluorescent Dyes/chemistry , Proteins/chemistry , Sydnones/chemistry , Alkynes/chemistry , Cycloaddition Reaction , Electrophoresis, Polyacrylamide Gel , HeLa Cells , Humans , Microscopy, Confocal , Proteins/metabolismABSTRACT
The metabolic oligosaccharide engineering (MOE) strategy using unnatural sialic acids has recently enabled the visualization of the sialome in living systems. However, MOE only reports on global sialylation and dissected information regarding subsets of sialosides is missing. Described here is the synthesis and utilization of sialic acids modified with a sydnone reporter for the metabolic labeling of sialoconjugates. The positioning of the reporter on the sugar significantly altered its metabolic fate. Further in vitro enzymatic assays revealed that the 9-modified neuraminic acid is preferentially accepted by the sialyltransferase ST6Gal-I over ST3Gal-IV, leading to the favored incorporation of the reporter into linkage-specific α2,6-N-linked sialoproteins. This sydnone sugar presents the possibility of investigating the roles of specific sialosides.
Subject(s)
Antigens, CD/metabolism , N-Acetylneuraminic Acid/metabolism , Oligosaccharides/metabolism , Protein Engineering , Sialoglycoproteins/metabolism , Sialyltransferases/metabolism , Sydnones/chemistry , Humans , N-Acetylneuraminic Acid/chemistry , Substrate SpecificityABSTRACT
The first approach to pyrazole-containing helicenes via sydnone-aryne [3 + 2]-cycloaddition is described. An unprecedented regioselectivity in the cycloaddition step toward the more sterically constrained product was observed in the presence of extended aromatic scaffolds. DFT calculations enabled understanding the origin of this unexpected selectivity.
Subject(s)
Cycloaddition Reaction , Polycyclic Compounds/chemistry , Polycyclic Compounds/chemical synthesis , Sydnones/chemistry , Models, Molecular , Molecular ConformationABSTRACT
Sulfonamide derivatives have been used in pharmaceutics for decades. Here we report a new approach to release sulfonamides efficiently using a bioorthogonal reaction of sulfonyl sydnonimines and dibenzoazacyclooctyne (DIBAC). The second-order rate constant of the cycloaddition reaction can be up to 0.62 M-1 s-1, and the reactants are highly stable under physiological conditions. Most significantly, we also discovered the mutual orthogonality between the sydnonimine-DIBAC and benzonorbornadiene-tetrazine cycloaddition pairs, which can be used for selective and simultaneous liberation of sulfonamide and primary amine drugs.
Subject(s)
Azabicyclo Compounds/chemistry , Celecoxib/chemical synthesis , Doxorubicin/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Prodrugs/chemistry , Sydnones/chemistry , Azabicyclo Compounds/chemical synthesis , Celecoxib/chemistry , Click Chemistry , Cycloaddition Reaction , Cyclooxygenase 2/chemistry , Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/chemistry , Enzyme Assays , Heterocyclic Compounds, 3-Ring/chemical synthesis , Humans , Models, Chemical , Prodrugs/chemical synthesis , Quantum Theory , Sydnones/chemical synthesisABSTRACT
The combretastatins have attracted significant interest as small-molecule therapies for cancer due to their ability to function as vascular disrupting agents. We have successfully prepared a range of combretastatin analogues that are based on a novel sydnone heterocycle core, and their potential as tubulin binders has been assessed in vitro and in vivo. The most potent candidate was found to disrupt microtubules and affect cellular morphology at sub-micromolar levels. Moreover, it was found to bind reversibly to tubulin and significantly increase endothelial cell monolayer permeability, in a similar manner to combretastatin A4. Surprisingly, the compound did not exhibit efficacy in vivo, possibly due to rapid metabolism.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Stilbenes/pharmacology , Sydnones/pharmacology , Angiogenesis Inhibitors/chemistry , Animals , Cell Line, Tumor , Cell Membrane Permeability , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Human Umbilical Vein Endothelial Cells , Humans , Mice, SCID , Microtubules/drug effects , Microtubules/metabolism , Protein Binding , Stilbenes/chemistry , Structure-Activity Relationship , Sydnones/chemistry , Tubulin/metabolismABSTRACT
Sydnones are among the most popular mesoionic compounds studied so far for cycloaddition reactions. However, despite their good chemical stability and versatility, only a limited number of research groups have worked on their chemistry and use in organic synthesis. This feature article aims at providing an overview of the most recent developments in sydnone-alkyne cycloadditions, with particular attention on the strategies that allow us to achieving high regiocontrol and milder reaction conditions. The recent discovery that this dipole is able to undergo click and biorthogonal reactions with cycloalkynes may stimulate renewed interest from the scientific community. Given the high potential and flexibility of this family of mesoionics, we believe that major developments are to be expected both in terms of organic synthetic methodologies and biorthogonal chemistry applications in the field of chemical biology.
Subject(s)
Alkynes/chemistry , Sydnones/chemistry , Click Chemistry , Cycloaddition ReactionABSTRACT
A practical method for radiofluorination of anilines with [18 F]fluoride via N-arylsydnone intermediates is described. These precursors are stable, easy to handle and facilitate direct and regioselective 18 F-labeling to prepare [18 F]fluoroarenes. The value of this methodology is further highlighted by successful application to prepare an 18 F-labeled neuropeptide.
Subject(s)
Radiopharmaceuticals/chemical synthesis , Sydnones/chemistry , Fluoridation , Fluorine Radioisotopes/chemistry , Isotope Labeling , Molecular Conformation , Neuropeptides/chemistry , Positron-Emission Tomography , ThermodynamicsABSTRACT
The combretastatins are an important class of tubulin-binding agents. Of this family, a number of compounds are potent tumor vascular disrupting agents (VDAs) and have shown promise in the clinic for cancer therapy. We have developed a modular synthetic route to combretastatin analogs based on a pyrazole core through highly regioselective alkyne cycloaddition reactions of sydnones. These compounds show modest to high potency against human umbilical vein endothelial cell proliferation. Moreover, evidence is presented that these novel VDAs have the same mode of action as CA4P and bind reversibly to ß-tubulin, believed to be a key feature in avoiding toxicity. The most active compound from in vitro studies was taken forward to an in vivo model and instigated an increase in tumor cell necrosis.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Pyrazoles/pharmacology , Stilbenes/pharmacology , Sydnones/chemistry , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/chemistry , Animals , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Female , Human Umbilical Vein Endothelial Cells/cytology , Humans , Mice , Mice, SCID , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Pyrazoles/chemistry , Stilbenes/chemical synthesis , Stilbenes/chemistry , Structure-Activity RelationshipABSTRACT
Synthesis and bioactivity of novel dual acting nitric oxide releasing and reactive oxygen scavenging hybrid compound SA-2 is described. The hybrid molecule SA-2 significantly increased the superoxide dismutase enzyme level and protected the photoreceptor cells from H2O2 induced oxidative stress. Synthesis of ocular esterase sensitive aceloxy alkyl carbamate prodrug SA-4 with improved aqueous half-life is achieved to aid topical ocular formulation. This class of hybrid molecule and prodrug may have dual potential of improved IOP lowering and neuroprotection in glaucomatous optic neuropathy.
Subject(s)
Drug Design , Glaucoma/drug therapy , Optic Nerve Diseases/drug therapy , Prodrugs/therapeutic use , Sydnones/chemical synthesis , Sydnones/therapeutic use , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Glaucoma/metabolism , Glaucoma/pathology , Humans , Hydrogen Peroxide/antagonists & inhibitors , Hydrogen Peroxide/pharmacology , Intraocular Pressure/drug effects , Molecular Structure , Nitric Oxide/metabolism , Optic Nerve Diseases/metabolism , Optic Nerve Diseases/pathology , Oxidative Stress/drug effects , Prodrugs/chemical synthesis , Prodrugs/chemistry , Prodrugs/pharmacology , Reactive Oxygen Species/metabolism , Structure-Activity Relationship , Sydnones/chemistry , Sydnones/pharmacologyABSTRACT
Some new sydnonyl-substituted thiazolidine derivatives were synthesized in high yields by the modified Knoevenagel condensation of 3-aryl-4-formylsydnones with thiazolidine-2,4-dione and 2-thioxo-thiazolidine-4-one, respectively. All the synthesized thiazolidine derivatives were screened by paper-disc method to identify their antimicrobial activities against three bacteria viz. Staphylococcus aureus, Proteus vulgaris and Escherichia coli, and two fungal cultures viz. Aspergillus niger and Penicillium citrinum. The reference drugs were Norfloxacin and Griseofulvin, respectively. The screening data indicated that the tested sydnonyl-substituted thiazolidine derivatives exhibited no obvious antibacterial activity compared with the standard drug Norfloxacin. However, thiazolidine derivatives displayed significant antifungal activities against Penicillium citrinum and Aspergillus niger. Notably, all of the tested compounds showed growth inhibitory activity 1.5-4.4 times higher than that of the standard drug Griseofulvin against the two fungi.
Subject(s)
Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Thiazolidines/chemistry , Thiazolidines/pharmacology , Anti-Infective Agents/chemical synthesis , Bacteria/drug effects , Chemistry Techniques, Synthetic , Fungi/drug effects , Microbial Sensitivity Tests , Molecular Structure , Sydnones/chemistry , Thiazolidines/chemical synthesisABSTRACT
The direct arylation of the C4 position of both N-alkyl- and N-arylsydnones with aryl/heteroaryl chlorides has been realized. The reaction is quite general and allows access to a wide range of 4-substituted sydnones. Yields of more challenging substrates can be improved through the use of aryl bromides.
Subject(s)
Hydrocarbons, Chlorinated/chemistry , Pyrazoles/chemical synthesis , Sydnones/chemistry , Molecular Structure , Pyrazoles/chemistryABSTRACT
Copper-catalyzed cycloaddition of alkynes with 4-bromosydnones provides a convenient, mild, and regioselective method for the synthesis of a wide range of bromopyrazoles. The broad functional group tolerance of the cycloaddition reaction and further palladium-catalyzed cross-coupling reactions allowed the preparation of polyfunctionalized 1,4,5-pyrazoles that are otherwise difficult to obtain by conventional methods.
Subject(s)
Alkynes/chemistry , Copper/chemistry , Pyrazoles/chemical synthesis , Sydnones/chemistry , Catalysis , Cycloaddition Reaction , Molecular Structure , Pyrazoles/chemistry , StereoisomerismABSTRACT
A robust method for constructing 1,4-pyrazoles from arylglycines was developed using the copper-catalyzed sydnone-alkyne cycloaddition reaction. The procedure offers a straightforward and general route to the pyrazole heterocycle through a three-step one-pot procedure.
Subject(s)
Alkynes/chemistry , Copper/chemistry , Glycine/chemistry , Pyrazoles/chemical synthesis , Cycloaddition Reaction , Glycine/analogs & derivatives , Molecular Structure , Pyrazoles/chemistry , Sydnones/chemistryABSTRACT
A novel series of Biginelli 2-3 (a and b) and Biginelli-like compounds 4-7 (a and b) were synthesized from 3-aryl-4-formylsydnone 1 (a and b). Since the crystal structure of hyaluronidase was unavailable, the human hyaluronidase protein structure was used as template and homology modeling was performed, validated by Ramachandran plots and subjected to docking studies along with in vitro anti-inflammatory activity assessment against hyaluronidase. Compounds 2-3 (a and b) exhibited potent enzyme inhibition.