Methanesulfonyl Chloride Research Articles

The Antioxidant Transcription Factor Nrf2 Negatively Regulates Autophagy and Growth Arrest Induced by the Anticancer Redox Agent Mitoquinone

Mitoquinone (MitoQ) is a synthetically modified, redox-active ubiquinone compound that accumulates predominantly in mitochondria. We found that MitoQ is 30-fold more cytotoxic to breast cancer cells than to healthy mammary cells. MitoQ treatment led to irreversible inhibition of clonogenic growth of breast cancer cells through a combination of autophagy and apoptotic cell death mechanisms. Relatively limited cytotoxicity was seen with the parent ubiquinone coenzyme Q(10.) Inhibition of cancer cell growth by MitoQ was associated with G(1)/S cell cycle arrest and phosphorylation of the checkpoint kinases Chk1 and Chk2. The possible role of oxidative stress in MitoQ activity was investigated by measuring the products of hydroethidine oxidation. Increases in ethidium and dihydroethidium levels, markers of one-electron oxidation of hydroethidine, were observed at cytotoxic concentrations of MitoQ. Keap1, an oxidative stress sensor protein that regulates the antioxidant transcription factor Nrf2, underwent oxidation, degradation, and dissociation from Nrf2 in MitoQ-treated cells. Nrf2 protein levels, nuclear localization, and transcriptional activity also increased following MitoQ treatment. Knockdown of Nrf2 caused a 2-fold increase in autophagy and an increase in G(1) cell cycle arrest in response to MitoQ but had no apparent effect on apoptosis. The Nrf2-regulated enzyme NQO1 is partly responsible for controlling the level of autophagy. Keap1 and Nrf2 act as redox sensors for oxidative perturbations that lead to autophagy. MitoQ and similar compounds should be further evaluated for novel anticancer activity.

3- Substituted 3- Azabicyclo[3.3.1]nonan- 9- ols and Their Transformations Involving the Hydroxy Group

The reduction of 3-benzyl- and 3-tert-butoxycarbonyl-3-azabicyclo[3.3.1]nonan-9-ones with sodium tetrahydridoborate gave the corresponding alcohols as mixtures of a- and a-epimers at a ratio of 2: 3. The resulting alcohols reacted with acetyl chloride and methanesulfonyl chloride at the hydroxy group to form O-acetyl and O-methylsulfonyl derivatives. Reactions of the latter with potassium iodide and sodium azide afforded 3-substituted 9-iodo(azido)-3-azabicyclo[3.3.1]nonanes. 9-Iodo derivatives were treated with triphenylphosphine to obtain triphenylphosphonium salts which were converted into the corresponding phosphonium ylides by the action of sodium methoxide in methanol, and the ylides readily reacted with benzaldehyde according to Wittig.

Synthesis, structural chemistry and antimicrobial activity of −(−) borneol derivative

Abstract Borneol is a monoterpene that is a part of traditional Chinese and Japanese medicine. (−) borneol reacted with methanesulfonyl chloride in THF/pyridine to afford the new 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl methane sulfonate derivative in excellent yield. The product is characterized by H1NMR, C13NMR, mass spectroscopy as well as elemental analysis and its structure was identified by X-ray single crystal diffraction. The packing of 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl methanesulfonate exhibits the non-classical C-H···O hydrogen bonding in C(4) and R22(8) chain and ring motifs as structural determinants. This was also confirmed by the analysis of Hirshfeld surfaces. The 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl methane sulfonate antimicrobial activity was tested and compared with its parent (−) borneol against three different pathogens. Particularly, 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl methane sulfonate showed high sensitivity, compared to Chloramphenicol reference material, against Escherichia coli.

Crystal structure of N-[(methylsulfonyl)oxy]-N-((E)-2-(methylsulfonyl) oxy]imino-1,2-diphenylethylidene)amine, C16H16N2O6S2

C16H16N2O6S2, triclinic, P1 (no. 2), a = 5.392(2) A, b = 9.300(4) A, c = 9.420(4) A, * = 93.933(9)°, ) = 90.20(1)°, & = 106.375(9)°, V = 452.0 A, Z = 1, Rgt(F) = 0.047, wRref(F) = 0.157, T = 293 K. Source of material All reagents and solvents use in this work were commercially available and used as purchased. Methanesulfonyl chloride (0.4 g, 3.5×10mole)was dissolved in 20ml of dryTHFand 4ml of redistilled pyridine. The solution was cooled to –5 °C, then treated drop by drop with diphenylglyoxime solution (0.42 g, 1.75×10mole) dissolved in 20 ml of dry THF, during the addition the reaction temperature was kept constant for around one hour, the reaction then lefted to stir at room temperature for 12 h. 40 ml of distilled water and dichloromethane each was added to the reaction mixture, which was transferred to 200 ml separator funnel. The organic layer was separated and after evaporation by dichloromethane. White powder of 1.12 g (80 % yield) was collected. The crystals were grown by slow evaporation of solution of the compound in methanol. Discussion Oximes/dioxime and theirmetal complexes are of current interest for their rich physicochemical properties, reactivity patterns and potential applications in many important chemical processes in the areas of medicine [1], bioorganic systems [2], catalysis, electrochemical and electrooptical sensors [3,4]. The high stability of the complexes with vic-dioxime ligands has been extensively used for various purposes including model compounds for vitamin B12 or trace metal analysis [5]. The E isomer of the title compound as a kinetically favored was detected over the Z isomer due to the steric factor. The single bondC7—C7 is clearly characterized by the distance of 1.439A. The double bond of C7=N1 and C7=N1 is characterized by the distance of 1.281 A. The conjugation of the , bonding electrons in ON1=C7—C7=N1O system reduced the length of the C7—C7 bond. The molecules packing in the crystal structure (figure, bottom) is stabilized by three weak intermolecular interactions, of which oxygen O3 of the sulphonyl functions in both methylsulphonylmoietyworks as acceptor. There are two type of donors which interact with O3. The distance H8A···O3 of the methyl group is 2.611 A and the angle C8–H8A···O3 is 153.85°. The distance of the interactionC1–H1···O3 is 2.702A and the relevant angle is 137.73°. There is no intramolecular H-bond in the molecule. Z. Kristallogr. NCS 225 (2010) 611-612 / DOI 10.1524/ncrs.2010.0267 611 © by Oldenbourg Wissenschaftsverlag, Munchen

2-Aminophenols Containing Electron-Withdrawing Groups from N-Aryl Hydroxylamines

Reaction of substituted N-aryl hydroxylamines with methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride under basic conditions leads to the rearranged 2-aminophenols (45-94%). The overall reaction sequence can be performed using polymer-supported sulfonyl chloride resin allowing for the effective conversion of N-aryl hydroxylamines to the 2-aminophenols without the need for chromatography.

ChemInform Abstract: Regiospecific Synthesis of α-Alkoxy and α-Alkylthio-1- alkyl-1,2,4-triazoles from Aldehydes and Glyoxals.

Reaction between aliphatic aldehydes or glyoxals (RCOCHO) and 1,2,4-triazole followed by mesyl chloride gives α-mesylates of 1-alkyl-1,2,4-triazole, regiospecifically. Mesylate ion is readily displaced by alkoxide, aryloxide, alkylthiolate, or arylthiolate nucleophiles to give the corresponding α-functionalised 1-alkyl-1,2,4-triazoles, in good yield.

ChemInform Abstract: Facile Redox Formation of a 3-Substituted Maleimide from a 3- Substituted N-Hydroxysuccinimide.

Treatment of 3-(Phenylthio)-N-hydroxysuccinimide 1 with methanesulfonyl chloride and pyridine in dry toluene resulted in the formation of 3-(Phenylthio)maleimide 3a.

ChemInform Abstract: Beckmann Rearrangements in Bicyclo(2.2.1)heptan-2-one Oximes.

Although Beckmann rearrangement of norcamphor oxime 1 was unsatisfactory, proceeding in poor yield to give a mixture of lactam products, rearrangement of the E/Z oxime 9, or the pure E-isomer 10, upon treatment with methanesulfonyl chloride and triethylamine, gave the lactam 12 in good yield.

Synthesis and X‐ray crystal structures of chiral, nonracemic 5,6‐dihydro‐4H‐1,3,4‐oxadiazines

Abstract magnified image A series of chiral, nonracemic oxadiazines have been prepared from (1R,2S)‐ephedrine, (1R,2S)‐norephedrine, and L‐phenylalaninol. The synthesis of the Ephedra‐based oxadiazines was accomplished by a process of N‐nitrosation, reduction, acylation, and acid‐catalyzed cyclization. The trans‐ and cis‐diastereomeric oxadiazines derived from (1R,2S)‐ephedrine were analyzed by 1H NMR spectroscopy and by single crystal X‐ray crystallographic analysis. The stereochemistry of the (1R,2S)‐norephedrine–derived oxadiazines was assigned based on 1H NMR spectroscopy and by analogy with the X‐ray crystal structure of the (1R,2S)‐ephedrine–based oxadiazines. In addition, L‐phenylalaninol was used as a template to prepare a series of oxadiazines substituted at the N4‐nitrogen with an isopropyl group. This was accomplished by a reductive alkylation of L‐phenylalaninol with acetone and subsequent hydrazide formation. These hydrazides were reacted with methanesulfonyl chloride to yield the corresponding oxadiazines by a base‐mediated cyclization. J. Heterocyclic Chem., (2010).

Synthesis of 1,2- and 1,4-amino alcohols from 1,3-dienes via oxazines. Rearrangements of 1,4-amino alcohol derivatives to oxazolines

Conjugated dienes were converted to 1,2-oxazines by reaction with an acyl nitroso dienophile. The oxazines were reduced to 1,4- N-acetylamino alcohols, which were rearranged to the corresponding oxazolines upon treatment with methanesulfonyl chloride or anhydride. The oxazolines yielded 1,2- N-acetylamino alcohols upon hydrolysis. Thus either 1,4- or 1,2- N-acetylamino alcohols are available from 1,3-dienes via this methodology. Experimental and spectral data are provided for all new compounds.

Synthesis of d-camphor based γ-amino acid (1 S,3 R)-3-amino-2,2,3-trimethylcyclopentane carboxylic acid

Synthesis of a γ-amino acid derived from (1 R,3 S)-camphoric acid is described. d-(+)-Camphoric anhydride, prepared from d-(+)-camphoric acid by treatment with methanesulfonyl chloride and triethylamine, was reacted with benzyl alcohol and catalytic DMAP, and subsequently reacted in a Curtius rearrangement to afford the corresponding carbamate derivative. This derivative was converted to the desired γ-amino acid through hydrogenolysis.

Co-crystal Structure of 11-Hydroxy-2,3,9-trimethoxy-6H-chromeno[3,4-b]chromen-12-one and 11-Hydroxy-2,3,9-trimethoxy-chromeno[3,4-b]chromene-6,12-dione

A 1:1 co-crystal structure of 11-hydroxy-2,3,9-trimethoxy-6H-chromeno[3,4-b]chromen-12-one and 11-hydroxy-2,3,9-trimethoxy-chromeno[3,4-b]chromene-6,12-dione (stemonone) was crystallized from the reaction mixture of 6-deoxyclitoriacetal and methanesulfonyl chloride, and its structure was characterized by X-ray diffraction. This co-crystal crystallizes in a triclinic crystal system, space group P(−1) with unit cell parameters of a = 8.1317(3) A, b = 9.8224(4) A, c = 10.7268(3) A, α = 78.116(1)°, β = 77.463(1)°, γ = 77.140(1)°, Z = 2 and V = 804.11(3) A3. The crystal structure was solved by direct methods and refined by full-matrix least-squares on F 2 to final values of R 1 = 0.0501 and wR 2 = 0.1520. A 1:1 co-crystal structure of 11-hydroxy-2,3,9-trimethoxy-6H-chromeno[3,4-b]chromen-12-one and 11-hydroxy-2,3,9-trimethoxy-chromeno[3,4-b]chromene-6,12-dione (stemonone) is reported.

Rapid synthesis and bioactivities of 3-(nitromethylene)indolin-2-one analogues

AbstractA new synthesis method of 3-(nitromethylene)indolin-2-one analogues is described, using the Henry reaction of isatin and N-substituted isatins with nitromethane followed by dehydration of the nitroaldol adduct with mesyl chloride. The use of diethylamine (rather than DBU) as the base catalyst in a solvent-free Henry reaction gave the nitroaldol adduct in sufficient purity as to allow its direct dehydration to nitroalkene. Overall yields for this two-step synthesis are satisfactory (typically 50–77 % after chromatographic purification). 3-(Nitromethylene)indolin-2-one analogues are valued protective agents against H2O2-induced apoptosis using PC12 cells, and for their cytotoxicity against the A549 and P388 lung cancer cell lines. One compound, (E)-1-benzyl-3-(nitromethylene)indolin-2-one (VIII), exhibited potent activity in the latter assay.

Synthesis of Some Purine Nucleoside Derivatives with Expected Biological Activity

The considerable biological and medicinal activities of purine nucleoside derivatives have simulated the recent interest in the synthesis of some new purine nucleosides. The present work described the reaction of inosine (1) with triphenylphosphine which led to the formation of 5-chloro-5-deoxy inosine (2), which on reaction with methylamine and morphorine afforded the compounds (3) and (4) respectively. The benzoylation of inosine (1) with benzoylchloride led to the formation of 1-benzoyl inosine (5) followed by reaction with sodium hydroxide affording compound (6). While the treatement of inosine (1) with dichlorodimethylsilane gave the compound (7), which on reaction with ethylacrylate gave 1-etheoxycarbonylethyl-3, 5-O-(di-methylsilanediyl) ether inosine (8). Treatment of inosine (1) with methane sulfonylchloride led to the formation 3,5-dimethanesulfonylinosine (9) which reacted with bormine to give 8-bromo-3,5- dimethanesulfonylinosine (10) was allowed to react with thiourea to give 8-mercapto -3,5-dimehanesulfonylinosine (11). The biological activities of the prepared compounds were also described.

A One-Pot Synthesis of 2-Aryl-4,5-anti-diphenyloxazolines

one-pot procedure for the synthesis of oxazolines was developed. An amino alcohol was coupled with benzoyl chlorides in the presence of triethylamine to produce a β-hydroxyamide. Direct treatment with methanesulfonyl chloride forms oxazolines in good yields.

A facile, one-pot synthesis of Ephedra-based aziridines

A series of enantiomerically and diastereomerically enriched N-sulfonylaziridines have been prepared by a single-pot process from (1 R,2 S)- and (1 S,2 R)-norephedrine and (1 S,2 S)-pseudonorephedrine. The cyclization process involved N-sulfonylation of the Ephedra alkaloid followed by O-sulfonylation with methanesulfonyl chloride. The bis(sulfonyl) Ephedra derivatives were treated with either hydrazine or sodium hydroxide to afford the N-sulfonylaziridines.

Towards Convenient Precursors for α -Phosphonylated Aziridinium Ions

Mixtures of the respective 2-(N,N-dibenzylamino)-1-chloro- and 1-(N,N-dibenzylamino)-2-chlorophosphonates were obtained after mesylation of dimethyl (1R,2S)-2-(N,N-dibenzylamino)-1-hydroxy-3-methylbutylphosphonate and diethyl (1R,2S)-2-(N,N-dibenzylamino)-1-hydroxy-3-phenylpropylphosphonate with mesyl chloride in the presence of tetraethylammonium chloride. These mixtures are considered as useful precursors to α -phosphonylated aziridinium ions.

Design of Core−Shell-Type Nanoparticles Carrying Stable Radicals in the Core

Utilizing the self-assembled core-shell-type polymeric micelle technique, high-performance nanoparticles possessing stable radicals in the core and reactive groups on the periphery were prepared. The anionic ring-opening polymerization of ethylene oxide (EO) was carried out using potassium 3,3-diethoxypropanolate as an initiator, followed by mesylation with methanesulfonyl chloride to obtain acetal-poly(ethylene glycol)-methanesulfonate (acetal-PEG-Ms; 1). Compound 1 was reacted with potassium O-ethyldithiocarbonate, followed by treatment with n-propylamine to obtain heterobifunctional PEG derivatives containing both sulfanyl and acetal terminal groups (acetal-PEG-SH) (2) in a highly selective and quantitative manner. Poly(ethylene glycol)-block-poly(chloromethylstyrene) (acetal-PEG-b-PCMS) (3) was synthesized by the free-radical telomerization of chloromethylstyrene (CMS) using 2 as a telogen. The chloromethyl groups in the PCMS segment of the block copolymer (3) were quantitatively converted to 2,2,6,6-tetramethylpiperidinyloxys (TEMPOs) via the amination of 3 with 4-amino-TEMPO to obtain acetal-PEG-b-PCMS containing TEMPO moieties (4). The obtained 4 formed core-shell-type nanoparticles in aqueous media when subjected to the dialysis method: the cumulant average diameter of the nanoparticles was about 40 nm, and the nanoparticles emitted intense electron paramagnetic resonance (EPR) signals. The TEMPO radicals in the core of the nanoparticles showed reduction resistance even in the presence of 3.5 mM ascorbic acid. This means that these nanoparticles are anticipated as high-performance bionanoparticles that can be used in vivo.

Synthesis, anticancer, and anti-inflammatory activity evaluation of methanesulfonamide and amidine derivatives of 3,4-diaryl-2-imino-4-thiazolines

Condensation of 3,4-diaryl-2-imino-4-thiazoli-nes 1a-j with methanesulfonyl chloride gave methanesulfonamide derivatives 2a-j. Condensation of 2-cyanopyrazine, 4-cyanopyridine, and 2-cyanopyridine with 3,4-diaryl-2- imino-4-thiazolines 1h-m in the presence of sodium methoxide afforded amidine derivatives 3a-j. Compounds 2a-j and 3a-j were screened against various human cancer cell lines (COLO-205, HEP-2, A-549, IMR-32) and their percentage growth inhibition profile determined at 1 x 10(-5)M. The anti-inflammatory activity of these compounds was assessed using the carrageenan-induced paw edema model. Compound 2i exhibited 34.7% anti-inflammatory activity at 50 mg/kg p.o., which is comparable to standard care drug phenyl butazone (37% activity at 50 mg/kg p.o.).

Reactions of Functionalized Sulfonamides: Application to Lowering the Lipophilicity of Cytosolic Phospholipase A2α Inhibitors

The cPLA(2)alpha inhibitors we reported earlier were potent in both isolated enzyme and rat whole blood assays but have high plogD(7.4). To address these issues, reactions of electrophilic sulfonamides 9-12 were employed to incorporate various heterocyclic or heteroatom-based reagents into cPLA(2)alpha inhibitors. For example, reactions of 9 with sulfur nucleophiles such as thiophenol allowed rapid assembly of thioether analogues that were converted into the corresponding sulfoxides to afford less lipophilic derivatives. Reactions of 10 and 11 with various nitrogen nucleophiles, including aromatic heterocycles and aliphatic amines, provided an efficient way to introduce polarity into cPLA(2)alpha inhibitors. Finally, we report the first application of (2-formylphenyl)methanesulfonyl chloride, 13. Reductive amination of 2-formylphenylmethane sulfonamides allowed the introduction of various nitrogen nucleophiles. Several inhibitors obtained herein have plogD(7.4) values 3-4 units lower than previously synthesized compounds and yet maintain in vitro potency.