Stereoselective and controllable C3-Amination or C1,C3-di-amination of 2-nitroglycals.

Precise and selective modification of carbohydrates is a critical strategy in producing diverse carbohydrate derivatives for exploiting their functions. We disclosed a simple, efficient, and highly regioselective and stereoselective protocol to controllable amination of 2-nitroglycals under mild conditions in 5 min. A range of 3-amino-carbohydrates including 3-arylamino-2-nitro-glycals and 1,3-di-amino-carbohydrate derivatives were obtained in good to excellent yield with excellent stereoselectivity. The produced 3-amino-2-nitro-glycals can be used as a precursor for further transformation.

Design of a Spiropyran-Based Smart Adsorbent with Dual Response: Focusing on Highly Efficient Enrichment of Phosphopeptides.

Smart responsive materials have attractive application prospects due to their tunable behaviors. In this work, we design novel spiropyran (SP)-based magnetic nanoparticles (MNP-SP) with dual response to ultraviolet light and pH and apply them to the enrichment of phosphopeptides. SP is modified on the surface of magnetic nanoparticles through a simple esterification reaction, based on which an MNP-SP-MS phosphopeptide identification platform is established. The capture and release of phosphopeptides are facilely adjusted by changing external light and the pH of the solution. The smart responsive MNP-SP has fast magnetic response performance, high sensitivity (detection limit of 0.4 fmol), and good reusability (6 cycles). In addition, MNP-SP is used for the enrichment of phosphopeptides in skimmed milk, human saliva, and human serum samples, indicating that it is an ideal adsorbent for enriching low-abundance phosphopeptides in complex biological environments.

High Turnover Pd/C Catalyst for Nitro Group Reductions in Water. One-Pot Sequences and Syntheses of Pharmaceutical Intermediates.

Commercially available Pd/C can be used as a catalyst for nitro group reductions with only 0.4 mol % Pd loading. The reaction can be performed using either silane as a transfer hydrogenating agent or simply a hydrogen balloon (∼1 atm pressure). With this technology, a series of nitro compounds was reduced to the desired amines in high chemical yields. Both the catalyst and surfactant were recycled several times without loss of reactivity.

Design, synthesis, and biological evaluation of nitroisoxazole-containing spiro[pyrrolidin-oxindole] derivatives as novel glutathione peroxidase 4/mouse double minute 2 dual inhibitors that inhibit breast adenocarcinoma cell proliferation.

A series of highly active CF3-containing 3'-(nitroisoxazole)spiro[pyrrolidin-3,2'-oxindoles] were synthesized and found to be novel glutathione peroxidase 4 (GPX4)/mouse double minute 2 (MDM2) dual inhibitors. Bioactive spirooxindole and isoxazole skeletons were combined, and the resulting compounds exhibited strong activities against both targets. In particular, compound 3d displayed excellent activity in the suppression of MDM2-mediated degradation of p53, as well as levels of GPX4, in MCF-7 breast cancer cells. Moreover, 3d also exhibited inhibitory effects on MDM2 and GPX4 in MCF-7 xenograft model to trigger ferroptotic and apoptotic cell death in in vivo experiments, which was consistent with the results of in vitro experiments.

Easily accessed nitroquinolones exhibiting potent and selective anti-tubercular activity.

Nitro based DprE1 inhibitors exemplified by benzothiazinones have been reported to elicit potent anti-tubercular activity. Poor PK properties associated with benzothiazinones have inspired the discovery of alternative nitro based DprE1 inhibitors. Quinolone based antibiotics on the other hand have good PK properties. The potent anti-tubercular activity of nitro compounds and the good PK properties of the quinolones have elicited an interest in us to construct a new class of nitro containing compounds around the quinolone scaffold with the aim of identifying novel DprE1 inhibitors with potent anti-tubercular activity. Thus, we report herein the anti-tubercular activity of novel 6-nitroquinolone-3-carboxamide derivatives achieved using less than five cheap synthetic transformations. Among the 23 target compounds evaluated for anti-tubercular activity, 12 were active against Mtb─ exhibiting activity in the range of <0.244-31.865 µM. Compound 25 having a molecular weight of 399 Da and ClogP value of 2.7 is the most active (MIC90: <0.244 µM) in this series. The SAR analyses suggest that anti-tubercular activity was influenced by substituents at position N-1 (R2) and C-3 (R3) of the quinolone ring. The activity data suggest that the nature of R3 has a stronger influence on the SAR compared to R2; with a fluorobenzyl and chlorobenzyl moiety at R2 being the most favoured when R3 is an aliphatic amine. Docking study confirms that compound 25 binds to the same hydrophobic pocket as does TCA1, and other nitro based DprE1 inhibitors, with its nitro group in close proximity with Cys387 residue.

Nitro-, Cyano-, and Methylfuroxans, and Their Bis-Derivatives: From Green Primary to Melt-Cast Explosives.

In the present work, we studied in detail the thermochemistry, thermal stability, mechanical sensitivity, and detonation performance for 20 nitro-, cyano-, and methyl derivatives of 1,2,5-oxadiazole-2-oxide (furoxan), along with their bis-derivatives. For all species studied, we also determined the reliable values of the gas-phase formation enthalpies using highly accurate multilevel procedures W2-F12 and/or W1-F12 in conjunction with the atomization energy approach and isodesmic reactions with the domain-based local pair natural orbital (DLPNO) modifications of the coupled-cluster techniques. Apart from this, we proposed reliable benchmark values of the formation enthalpies of furoxan and a number of its (azo)bis-derivatives. Additionally, we reported the previously unknown crystal structure of 3-cyano-4-nitrofuroxan. Among the monocyclic compounds, 3-nitro-4-cyclopropyl and dicyano derivatives of furoxan outperformed trinitrotoluene, a benchmark melt-cast explosive, exhibited decent thermal stability (decomposition temperature >200 °C) and insensitivity to mechanical stimuli while having notable volatility and low melting points. In turn, 4,4'-azobis-dicarbamoyl furoxan is proposed as a substitute of pentaerythritol tetranitrate, a benchmark brisant high explosive. Finally, the application prospects of 3,3'-azobis-dinitro furoxan, one of the most powerful energetic materials synthesized up to date, are limited due to the tremendously high mechanical sensitivity of this compound. Overall, the investigated derivatives of furoxan comprise multipurpose green energetic materials, including primary, secondary, melt-cast, low-sensitive explosives, and an energetic liquid.

Development of Nitrolactonization Mediated by Iron(III) Nitrate Nonahydrate.

The nitrolactonization of alkenyl carboxylic acids mediated by Fe(NO3)3·9H2O has been developed. Nitrolactones were obtained in up to 93% yield by treatment of alkenyl carboxylic acids with Fe(NO3)3·9H2O. Mechanistic studies disclosed that the reaction proceeded through a radical intermediate generated from addition of NO2 to alkenyl carboxylic acids.

A Walk through Recent Nitro Chemistry Advances.

Chemistry of nitro groups and nitro compounds has long been intensively studied. Despite their long history, new reactions and methodologies are still being found today. This is due to the diverse reactivity of the nitro group. The importance of nitro chemistry will continue to increase in the future in terms of elaborate synthesis. In this article, we will take a walk through the recent advances in nitro chemistry that have been made in past decades.

Recent Advances in Synthesis and Properties of Nitrated-Pyrazoles Based Energetic Compounds.

Nitrated-pyrazole-based energetic compounds have attracted wide publicity in the field of energetic materials (EMs) due to their high heat of formation, high density, tailored thermal stability, and detonation performance. Many nitrated-pyrazole-based energetic compounds have been developed to meet the increasing demands of high power, low sensitivity, and eco-friendly environment, and they have good applications in explosives, propellants, and pyrotechnics. Continuous and growing efforts have been committed to promote the rapid development of nitrated-pyrazole-based EMs in the last decade, especially through large amounts of Chinese research. Some of the ultimate aims of nitrated-pyrazole-based materials are to develop potential candidates of castable explosives, explore novel insensitive high energy materials, search for low cost synthesis strategies, high efficiency, and green environmental protection, and further widen the applications of EMs. This review article aims to present the recent processes in the synthesis and physical and explosive performances of the nitrated-pyrazole-based Ems, including monopyrazoles with nitro, bispyrazoles with nitro, nitropyrazolo[4,3-c]pyrazoles, and their derivatives, and to comb the development trend of these compounds. This review intends to prompt fresh concepts for designing prominent high-performance nitropyrazole-based EMs.

The Cyclic Nitronate Route to Pharmaceutical Molecules: Synthesis of GSK's Potent PDE4 Inhibitor as a Case Study.

An efficient asymmetric synthesis of GlaxoSmithKline's potent PDE4 inhibitor was accomplished in eight steps from a catechol-derived nitroalkene. The key intermediate (3-acyloxymethyl-substituted 1,2-oxazine) was prepared in a straightforward manner by tandem acylation/(3,3)-sigmatropic rearrangement of the corresponding 1,2-oxazine-N-oxide. The latter was assembled by a (4 + 2)-cycloaddition between the suitably substituted nitroalkene and vinyl ether. Facile acetal epimerization at the C-6 position in 1,2-oxazine ring was observed in the course of reduction with NaBH3CN in AcOH. Density functional theory (DFT) calculations suggest that the epimerization may proceed through an unusual tricyclic oxazolo(1,2)oxazinium cation formed via double anchimeric assistance from a distant acyloxy group and the nitrogen atom of the 1,2-oxazine ring.

Stereodivergent Synthesis of Camphor-Derived Diamines and Their Application as Thiourea Organocatalysts.

A series of 18 regio- and stereo-chemically diverse chiral non-racemic 1,2-, 1,3-, and 1,4-diamines have been synthesized from commercial (1S)-(+)-ketopinic acid and (1S)-(+)-10-camphorsulfonic acid. The structures of the diamines are all based on the d-(+)-camphor scaffold and feature isomeric diversity in terms of regioisomeric attachment of the primary and the tertiary amine function and the exo/endo-isomerism. Diamines were transformed into the corresponding noncovalent bifunctional thiourea organocatalysts, which have been evaluated for catalytic activity in the conjugative addition of 1,3-dicarbonyl nucleophiles (dimethyl malonate, acetylacetone, and dibenzoylmethane) to trans-ß-nitrostyrene. The highest enantioselectivity was achieved in the reaction with acetylacetone as nucleophile using endo-1,3-diamine derived catalyst 52 (91.5:8.5 er). All new organocatalysts 48-63 have been fully characterized. The structures and the absolute configurations of eight intermediates and thiourea derivative 52 were also determined by X-ray diffraction.

Evaluation of nitrocatechol chalcone and pyrazoline derivatives as inhibitors of catechol-O-methyltransferase and monoamine oxidase.

Literature reports that chalcones inhibit the monoamine oxidase (MAO) enzymes, mostly with specificity for the MAO-B isoform, while nitrocatechol compounds are established inhibitors of catechol-O-methyltransferase (COMT). Based on this, nitrocatechol derivatives of chalcone have been proposed to represent dual-target-directed compounds that may inhibit both MAO-B and COMT. Both these enzymes play key roles in the metabolism of dopamine and levodopa, and inhibitors are thus relevant to the treatment of Parkinson's disease. The present study expands on the discovery of dual MAO-B/COMT inhibitors by synthesising additional nitrocatechol derivatives of chalcones which include heterocyclic derivatives, and converting them to the corresponding pyrazoline derivatives. The newly synthesised chalcone and pyrazoline compounds were evaluated as inhibitors of human MAO and rat COMT, and the inhibition potencies were expressed as IC50 values. A pyrazoline derivative, compound 8b, was the most potent COMT inhibitor with an IC50 value of 0.048 µM. This is more potent than the reference COMT inhibitor, entacapone, which has an IC50 value of 0.23 µM. The results indicated that the pyrazoline derivatives (IC50 = 0.048-0.21 µM) are more potent COMT inhibitors than the chalcones (IC50 = 0.14-0.29 µM). Unfortunately, the chalcone and pyrazoline derivatives were weak MAO inhibitors with IC50 values > 41.4 µM. This study concludes that the nitrocatechol derivatives investigated here are promising COMT inhibitors, while not being suitable as MAO inhibitors. Using molecular docking, potential binding modes and interactions of selected inhibitors with COMT are proposed.

Light-Driven Expansion of Spiropyran Hydrogels.

The incorporation of molecular switches in organic structures is of great interest in the chemical design of stimuli-responsive materials that mimic the complex functions of living systems. Merocyanine dyes that convert to spiropyran moieties upon exposure to visible light have been extensively studied as they can be incorporated in hydrated covalent networks that will expel water when this conversion occurs and induce a volumetric shrinkage. We report here on a sulfonate-based water-soluble photoswitch that, in contrast to the well-known systems, triggers a volumetric expansion in hydrogels upon exposure to photons. Contraction is in turn observed under dark conditions in a highly reversible manner. The novel behavior of the photoswitch incorporated in the covalent network was predicted by coarse-grained simulations of the system's chemical structure. Using pH control and polymeric structures that differ in lower critical solution temperature, we were able to develop hydrogels with highly tunable volumetric expansion. The novel molecular function of the systems developed here led to materials with the negative phototaxis observed in plants and could expand the potential use of hydrogels as sensors, soft robots, and actuators.

Nitro-Perylenediimide: An Emerging Building Block for the Synthesis of Functional Organic Materials.

Perylenediimide (PDI) is one of the most important classes of dyes and is intensively explored in the field of functional organic materials. The functionalization of this electron-deficient aromatic core is well-known to tune the outstanding optoelectronic properties of PDI derivatives. In this respect, the functionalization has been mostly addressed in bay-positions to halogenated derivatives through nucleophilic substitutions or metal-catalyzed coupling reactions. Being aware of the synthetic difficulties of obtaining the key intermediate 1-bromoPDI, we will present as an alternative in this review the potential of 1-nitroPDI: a powerful building block to access a large variety of PDI-based materials.

Silicon Microcantilever Sensors to Detect the Reversible Conformational Change of a Molecular Switch, Spiropyan.

The high sensitivity of silicon microcantilever sensors has expanded their use in areas ranging from gas sensing to bio-medical applications. Photochromic molecules also represent promising candidates for a large variety of sensing applications. In this work, the operating principles of these two sensing methods are combined in order to detect the reversible conformational change of a molecular switch, spiropyran. Thus, arrays of silicon microcantilever sensors were functionalized with spiropyran on the gold covered side and used as test microcantilevers. The microcantilever deflection response was observed, in five sequential cycles, as the transition from the spiropyran (SP) (CLOSED) to the merocyanine (MC) (OPEN) state and vice-versa when induced by UV and white light LED sources, respectively, proving the reversibility capabilities of this type of sensor. The microcantilever deflection direction was observed to be in one direction when changing to the MC state and in the opposite direction when changing back to the SP state. A tensile stress was induced in the microcantilever when the SP to MC transition took place, while a compressive stress was observed for the reverse transition. These different type of stresses are believed to be related to the spatial conformational changes induced in the photochromic molecule upon photo-isomerisation.

Recent Progress in Nitro-Promoted Direct Functionalization of Pyridones and Quinolones.

Nitro group is one of the most important functional groups in organic syntheses because its strongly electron-withdrawing ability activates the scaffold, facilitating the reaction with nucleophilic reagents or the Diels-Alder reaction. In this review, recent progress in the nitro-promoted direct functionalization of pyridones and quinolones is highlighted to complement previous reviews.

Synthesis of spiropyran with methacrylate at the benzopyran moiety and control of the water repellency and cell adhesion of its polymer film.

Stimuli-responsive materials have been actively researched over the past few decades. Among such materials, spiropyran is one of the most attractive compounds because the structure and polarity of the material are dramatically changed after photo irradiation, unlike other materials. In this work, we designed and synthesized a spiropyran derivative (SpMA) with a methacryloyl group on the nitrobenzene ring of a spiropyran skeleton. The UV spectra of the newly synthesized SpMA showed the photo-isomerization of spiropyran. The maximum absorption wavelength (λmax) of SpMA was 616 nm in n-hexane, a nonpolar solvent, although λmax of SpMA was 532 nm in methanol, a polar protic solvent, which resulted in an 84 nm blue-shift. SpMA was successfully polymerized by ruthenium (Ru)-catalyzed living radical polymerization. Poly(SpMA) (PSpMA) was then spin-coated on a PET substrate in order to control the surface properties of water repellency and cell adhesion. The water repellency was decreased approximately 10° under UV irradiation, because of the polarity change of PSpMA caused by photo-isomerization from the spiropyran (SP) type to the merocyanine (MC) type. In addition, NIH3T3 cells were spread only on 6% of the surface of the PSpMA thin film after UV irradiation compared with no UV irradiation. The polarity change of PSpMA by photo-isomerization is also believed to be the reason for this behavior. As a result, we successfully synthesized a photo-controllable cell culture scaffold.

Synthesis of novel 3-halo-3-nitroflavanones and their activities as DNA methyltransferase inhibitors in cancer cells.

The implication of DNA methylation in cancer is today clearly established. Despite that nucleoside analogues are currently used for leukaemia treatment, their low stability in physiological conditions and their lack of selectivity arise the need for the identification of non-nucleoside DNA methyltransferase inhibitors. Here, we describe the synthesis and pharmacological characterisation of a novel class of DNA methyltransferase inhibitors: the 3-halo-3-nitroflavanones. We showed that 3-bromo-3-nitroflavanones 3b and 4a have a micromolar DNMT inhibition and an increased potency in a cell reporter model. Interestingly they are significantly more stable than the reference compounds and induce a low cytotoxicity, supporting them as new candidates for the development of non-cytotoxic cell-reprogramming epi-drugs for anticancer treatment.

Bioinspired Nitroalkylation for Selective Protein Modification and Peptide Stapling.

Nitroalkanes react specifically with aldehydes, providing rapid, stable, and chemoselective protein bioconjugation. These nitroalkylated proteins mimic key post-translational modifications (PTMs) of proteins and can be used to understand the role of these PTMs in cellular processes. Demonstrated here is the substrate scope of this bioconjugation by attaching a variety of tags, such as NMR tags, fluorescent tags, affinity tags, and alkyne tags, to proteins. The structure and enzymatic activity of modified proteins remain conserved after labeling. Notably, the nitroalkane group leads to easy characterization of proteins by mass spectrometry because of its distinct fingerprint pattern. Importantly, the nitro-alkylated peptides provide a new handle for site-selective fluorination of peptides, thus installing a specific probe to study peptide-protein interactions by 19 F NMR spectroscopy. Furthermore, nitroalkane reagents can be used for the late-stage diversification of peptides and for the synthesis of peptide staples.

Pharmacologic potential of new nitro-compounds as antimicrobial agents against nosocomial pathogens: design, synthesis, and in vitro effectiveness.

Nosocomial infections are an important cause of morbi-mortality worldwide. The increase in the rate of resistance to conventional drugs in these microorganisms has stimulated the search for new therapeutic options. The nitro moiety (NO2) is an important pharmacophore of molecules with high anti-infective activity. We aimed to synthesize new nitro-derivates and to evaluate their antibacterial and anti-Candida potential in vitro. Five compounds [3-nitro-2-phenylchroman-4-ol (3); 3-nitro-2-phenyl-2H-chromene (4a); 3-nitro-2-(4-chlorophenyl)-2H-chromene (4b); 3-nitro-2-(4-fluorophenyl)-2H-chromene (4c), and 3-Nitro-2-(2,3-dichlorophenyl)-2H-chromene (4d)] were efficiently synthesized by Michael-aldol reaction of 2-hydroxybenzaldehyde with nitrostyrene, resulting in one ß-nitro-alcohol (3) and four nitro-olefins (4a-4d). The antibacterial and anti-Candida potentials were evaluated by assaying minimal inhibitory concentration (MIC), minimum fungicidal concentration (MFC), and minimum bactericidal concentration (MBC). Mono-halogenated nitro-compounds (4b and 4c) showed anti-staphylococcal activity with MIC values of 15.6-62.5 µg/mL and MBC of 62.5 µg/mL. However, the activity against Gram-negative strains was showed to be considerably lower and our data suggests that this effect was associated with the outer membrane. Furthermore, nitro-compounds 4c and 4d presented activity against Candida spp. with MIC values ranging from 7.8-31.25 µg/mL and MFC of 15.6-500 µg/mL. In addition, these compounds were able to induce damage in fungal cells increasing the release of intracellular material, which was associated with actions on the cell wall independent of quantitative changes in chitin and ß-glucan. Together, these findings show that nitro-compounds can be exploited as anti-staphylococcal and anti-Candida prototypes.