Fragmentation of protonated thioether conjugates of acrolein using low collision energies

The protonated mercapturic acid conjugate of acrolein, S-(3-oxopropyl)-N-acetyl-L-cysteine (I), undergoes facile retro-Michael loss of acrolein in the gas phase. To determine whether extensive loss of acrolein would impede structural characterization of acrolein-peptide adducts, fragmentation reactions of a series of conjugates, formed by 1,4-Michael addition of acrolein to peptides and cysteine derivatives, were investigated at collision cell potentials up to ?50 V using a triple quadrupole mass spectrometer. Differences in fragmentation dynamics suggest protonation at the sulfur of the N-acetylcysteine conjugate I facilitates retro-Michael elimination of acrolein with a low activation energy relative to other fragmentations. Analogous fragmentation was eliminated after borohydride reduction of the aldehyde to an alcohol. Retro-Michael fragmentation was not significant for acrolein conjugates of glutathione derivatives, suggesting that proton sequestration occurs in peptides with multiple amide linkages even when the peptide does not contain a basic amino group. An unexpected outcome of these experiments was the observation of a facile gas-phase cleavage of peptides on the N-terminal side of S-(3-oxopropyl)cysteine residues. Such fragmentation behavior may prove useful for locating cysteine residues in peptides.     

Development of approaches to fibrostatin F,N-acetyl-L-cysteinyl-containing 1,4-naphthoquinone metabolite of Streptomyces catenulae

A possibility of the synthesis of microbial metabolite Streptomyces catenulae fibrostatin F through the AcOH-catalyzed condensation of 5-hydroxy-3-hydroxymethyl-2,7-dimethoxy1,4-naphthoquinone and its related 3-chloromethyl, 3-acetoxymethyl, and 3-methoxymethyl derivatives with N-acetyl-L-cysteine and paraformaldehyde in 1,4-dioxane was studied. In these conditions, all naphthoquinones gave N-acetyl-S-[(8-hydroxy-3,6-dimethoxy-1,4-dioxonaphthalen-2-yl)methyl]-L-cysteine isomeric to the natural fibrostatin C.

     

Infrared spectra of the polymorphs of naphthazarin: Microscopy and low temperature studies

The infrared microscope spectra of theA,B, andC polymorphs of naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) can be distinguished clearly. When naphthazarin is dispersed in KBr, such a distinction can only be made when experimental precautions are taken during the preparation of the pellet. Low temperature infrared studies indicate that a phase transition takes place in naphthazarin around 110 K.     

Synthesis,Neuroprotection, and Antioxidant Activity of 1,1′-Biphenylnitrones as α-Phenyl-N-tert-butylnitrone Analogues in In Vitro Ischemia Models

Herein, we report the neuroprotective and antioxidant activity of 1,1′-biphenyl nitrones (BPNs) 1–5 as α-phenyl-N-tert-butylnitrone analogues prepared from commercially available [1,1′-biphenyl]-4-carbaldehyde and [1,1′-biphenyl]-4,4′-dicarbaldehyde. The neuroprotection of BPNs 1-5 has been measured against oligomycin A/rotenone and in an oxygen–glucose deprivation in vitro ischemia model in human neuroblastoma SH-SY5Y cells. Our results indicate that BPNs 1–5 have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone (PBN), and they are quite similar to N-acetyl-L-cysteine (NAC), which is a well-known antioxidant agent. Among the nitrones studied, homo-bis-nitrone BPHBN5, bearing two N-tert-Bu radicals at the nitrone motif, has the best neuroprotective capacity (EC₅₀ = 13.16 ± 1.65 and 25.5 ± 3.93 μM, against the reduction in metabolic activity induced by respiratory chain blockers and oxygen–glucose deprivation in an in vitro ischemia model, respectively) as well as anti-necrotic, anti-apoptotic, and antioxidant activities (EC₅₀ = 11.2 ± 3.94 μM), which were measured by its capacity to reduce superoxide production in human neuroblastoma SH-SY5Y cell cultures, followed by mononitrone BPMN3, with one N-Bn radical, and BPMN2, with only one N-tert-Bu substituent. The antioxidant activity of BPNs 1-5 has also been analyzed for their capacity to scavenge hydroxyl free radicals (82% at 100 μM), lipoxygenase inhibition, and the inhibition of lipid peroxidation (68% at 100 μM). Results showed that although the number of nitrone groups improves the neuroprotection profile of these BPNs, the final effect is also dependent on the substitutent that is being incorporated. Thus, BPNs bearing N-tert-Bu and N-Bn groups show better neuroprotective and antioxidant properties than those substituted with Me. All these results led us to propose homo-bis-nitrone BPHBN5 as the most balanced and interesting nitrone based on its neuroprotective capacity in different neuronal models of oxidative stress and in vitro ischemia as well as its antioxidant activity.     

The Fourier Transform Raman and infrared spectra of naphthazarin

The FT Raman spectra of the three naphthazarin polymorphs have been recorded for the first time and compared with the FTIR spectra of the polymorphs and of naphthazarin with deuterated hydroxyl groups. It is possible to distinguish between the polymorphs, to deduce that the room temperature static symmetry point group of naphthazarin is C_2v, to assign the ν(CH), σ(OH), γ(OH) vibrations and to confirm the absence of the ν(OH) mode.     

Chemistry of naphthazarin derivatives. Transetherification selectivity of naphthazarin methoxy derivatives

Transetherification of naphthazarin methoxy derivatives in basic conditions occurs only with primary monohydric alcohols. 1,3-Butanediol due to the assistance of the hydroxy group at the C¹ atom gives rise to a mixture of transetherification products at the primary and secondary hydroxy groups in a ratio 3: 1. The reaction with methyl α-D-glucopyranoside affords predominantly methyl 6-O-(5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-α-D-glucopyranoside, previously unknown water-soluble naphthoquinone-carbohydrate conjugate.     

Synthesis and fluorescent properties of a new photostable thiol reagent “BACM”

The 3-maleimidocoumarin BACM ( 2d ) is a new tag designed to react with thiols in biological materials to form fluorescent derivatives whose emission is in the 500 nm (green) region with good resistance to fading. The fluorescence properties of its N-acetyl-L-cysteine derivative are described. BACM itself is non-fluorescent, as is its predecessor, DACM ( 1a ). A synthesis of BACM is reported which avoids the formation of nitrocoumarin isomers obtained in the reported synthesis of DACM. The synthesis of the related 3-(4-maleimidophenyl)coumarin is also described.     

Polycyclic hydroxyquinones—VIII: Preparation of acetylhydroxynaphthazarins by photo-fries rearrangement. A convenient synthesis of spinochrome A

Several synthetic routes to mono- and dihydroxynaphthazarins bearing an acetyl side-chain have been explored. Methoxynaphthazarin1 has always been the starting material. Acylation is brought aboutvia a photo-Fries rearrangement of various adequately substituted acetoxynaphthalenes prepared in several steps from1. Further steps including oxidative demethylation, hydrolysis and ether cleavage reactions, led to the desired mono- and dihydroxysubstituted acetylnaphthazarins. A new synthesis of Spinochrome A24, a natural occurring pigment representative of this kind of naphthazarin derivatives, is described.     

Synthesis of thia-Michael-Type Adducts between Naphthoquinones and N-Acetyl-L-Cysteine and Their Biological Activity

A series of naphthoquinones, namely, 1,4-naphthoquinone, menadione, plumbagin, juglone, naphthazarin, and lawsone, were reacted with N-acetyl-L-cysteine, and except for lawsone, which did not react, the related adducts were obtained. After the tuning of the solvent and reaction conditions, the reaction products were isolated as almost pure from the complex reaction mixture via simple filtration and were fully characterized. Therefore, the aim of this work was to evaluate whether the antitumor activity of new compounds of 1,4-naphthoquinone derivatives leads to an increase in ROS in tumor cell lines of cervical carcinoma (HeLa), neuroblastoma (SH-SY5Y), and osteosarcoma (SaOS2, U2OS) and in normal dermal fibroblast (HDFa). The MTT assay was used to assay cell viability, the DCF-DA fluorescent probe to evaluate ROS induction, and cell-cycle analysis to measure the antiproliferative effect. Compounds 8, 9, and 12 showed a certain degree of cytotoxicity towards all the malignant cell lines tested, while compound 11 showed biological activity at higher IC₅₀ values. Compounds 8 and 11 induced increases in ROS generation after 1 h of exposure, while after 48 h of treatment, only 8 induced an increase in ROS formation in HeLa cells. Cell-cycle analysis showed that compound 8 caused an increase in the number of G0/G1-phase cells in the HeLa experiment, while for the U2OS and SH-SY5Y cell lines, it led to an accumulation of S-phase cells. Therefore, these novel 1,4-naphthoquinone derivatives may be useful as antitumoral agents in the treatment of different cancers.     

Cytotoxic activity of intermediates and side products of echinochrome synthesis

The cytotoxic activity of the principal intermediates and side products of echinochrome synthesis toward gametes of the sea urchin Strogylocentrotus intermedius was studied. Di-and trichloro naphthazarin derivatives with two vicinal Cl atoms were the most active. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 228–231, May–June, 2008.     

Thermogravimetric study of some divalent metal chelate polymers of dithiooxamide

The thermal properties of polymeric chelates of dithiooxamide with divalent copper, cobalt, zinc and nickel have been investigated. The order of thermal stability is Ni>Co～Zn>Cu, which is the same as that observed for previously studied naphthazarin and rhodizonic acid chelates. The procedural decomposition temperatures indicate that the dithiooxamide chelates, which are not aromatic, are about as stable as the aromatic naphthazarin and rhodizonic acid chelates. Several unsuccessful attempts were made to prepare beryllium and manganese (II) chelates.     

[4+1] Cycloaddition of N-acylimine derivatives with isocyanides: efficient synthesis of 5-aminooxazoles and 5-aminothiazoles

[4+1] Cycloaddition reaction between isocyanides and N-acylimine derivatives generated from N-acyl N,O-acetals acting as isocyanophiles has been developed. These reactions proceeded smoothly and cleanly to afford the corresponding 5-aminooxazoles in high yields. This reaction was extended to the syntheses of 5-aminothiazoles by using N-thioacyl N,O-acetals. A wide range of N-acyl N,O-acetals, N-thioacyl N,O-acetals, and isocyanides were found to be applicable to this reaction.     

The chemistry of naphthazarin derivatives

Direct oxidation of naphthazarin with manganese dioxide in conc. H₂SO₄ was found to be a simple and effective method for the synthesis of mompain. For Part 3, see Ref. 1. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1019–1021, May, 1999.     

New investigation of Vilsmeier-type reaction using pyrazolones with various amides

New investigation of Vilsmeier-type reaction was evaluated to realize the solvent effect by using pyrazolones to react with various of amides, including formamide, N-methylformamide, N-propylformamide, N-tert-butylformamide, N,N-dimethylformamide (DMF), N,N-diethylformamide (DEF), N,N-dipropylformamide (DPF), N,N-diisopropylformamide, N,N-dibutylformamide, piperidine-1-carbaldehyde, and pyrrolidine-1-carbaldehyde, in the presence of phosphorous oxychloride POCl₃. The unexpected resulting products were observed in this work according to the difference chemoseletivities of substituted amides. The plausible reactive pathways were proposed to explain the experimental result.     

Synthesis of 2-methyl-N-(2,2,2-trichloroethylidene)- and 2-methyl-N-(2,2,2-trichloroethyl)benzenesulfonamides from N,N-dichloro-2-methylbenzenesulfonamide and trichloroethylene

The reaction of N,N-dichloro-2-methylbenzenesulfonamide with trichloroethylene gave a new representative of highly electrophilic N-sulfonyl polyhaloaldehyde imines, 2-methyl-N-(2,2,2-trichloroethylidene) benzenesulfonamide. High reactivity of the product was demonstrated in the addition of water and 2-methylbenzenesulfonamide and reactions with benzene, toluene, anisole, thiophene, and 2-chlorothiophene. N,N-Dichlorobenzenesulfonamides and N,N-dichlorotrifluoromethanesulfonamide failed to react with 1,1,3,3,4,4-hexachlorobut-1-ene and 1,1,2,3,4-pentachlorobuta-1,3-diene under the conditions ensuring formation of N-(2,2,2-trichloroethylidene)arenesulfonamides from N,N-dichloroarenesulfonamides and trichloroethylene.     

Helicity of N,N′-diaryl-trans-1,2-diaminocyclohexane derivatives. Implications for molecular helicity manipulations

Derivatives of trans-1,2-diaminocyclohexane (DACH), useful as chiral ligands, scaffolds and building blocks, differ in their conformation. The conformation of N,N′-diaryl-DACH derivatives was studied by the semiempirical and DFT computational methods and by exciton-coupled circular dichroism. It was found that, contrary to M-helical N,N′-diimine, N,N′-diimide and N,N′-diamide derivatives, the aromatic residues in N,N′-diphenyl derivatives are oriented to form a P-helix for the (R,R)-DACH absolute configuration. The helicity of the bis-aryl system is modified in the case of 1-naphthyl or 2-naphthyl derivatives. Further switching of helicity has been demonstrated by either protonation or mono-N-acetylation of N,N′-diaryl DACH derivatives.     

Antibacterial activity of N-quaternary chitosan derivatives: Synthesis, characterization and structure activity relationship (SAR) investigations

Quaternary N-(2-(N,N,N-tri-alkyl ammoniumyl and 2-pyridiniumyl) acetyl) derivatives of chitosan polymer, chitooligomer, and glucosamine (monomer) were synthesized for the purpose of investigating the structure activity relationship (SAR) for the antibacterial effect. Novel methods were used in the synthesis. The final chitosan and chitooligomer derivatives could thus be obtained in two steps without prior protection of the hydroxyl groups. However, in order to obtain chitosan derivatives with the bulky N,N-dimethyl-N-dodecyl- and N,N-dimethyl-N-butyl side chains three steps were needed, starting from 3,6-O-di-tert-butyldimethylsilyl chitosan (3,6-O-di-TBDMS chitosan) as the key intermediate. The quaternary ammoniumyl acetyl derivatives of glucosamine were synthesized from glucosamine or tetra-O-acetylglucosamine. N,N,N-trimethyl chitosan (TMC) was used as reference compound for investigation of antibacterial activity. Clinical Laboratory Standard Institute (CLSI) protocols were used to determine MIC and MLC for activity against clinically important Gram-positive strains Staphylococcus aureus (ATCC 25923), and S. aureus (MRSA) (ATCC 43300), and Gram-negative strains of Escherichia coli (ATCC 25922), P. aeriginosa (ATCC 27853) and Enterococcus facialis (ATCC 29212). The MIC values for the compounds ranged from 8 to ?8192 mg/L. In general the N-(2-(N,N-dimethyl-N-dodecyl ammoniumyl) acetyl) derivatives of chitooligomer and glucosamine monomer were more active against bacteria than derivatives with shorter alkyl chains. In contrast the N-(2-(N,N-dimethyl-N-dodecyl ammoniumyl) acetyl) derivatives of chitosan were less active than derivatives with N-(2-N,N,N-trimetylammoniumyl) acetyl or N-(2-(N-pyridiniumyl) acetyl) quaternary moiety. N,N,N-trimethyl chitosan (TMC) was the most active compound in this study.     

Mass spectra of SnI2

The thermal and spectral properties of the chelates of quinizarin with copper, cobalt and nickel have been investigated. The decreasing order of thermal stability for the chelates is Ni > Co > Cu. The chelates are compared with the corresponding chelates of naphthazarin. The effect on the thermal stability of the addition of a benzene ring to naphthazarin is compared with a previous study on 2,4-dinitrosoresorcinol and 2,4-dinitroso-1,3-naphthalenediol. Several unsuccessful attempts were made to prepare a zinc chelate of this ligand.     

Reaction of ferrocenecarboxylic acid with N,N-disubstituted carbodiimides: synthesis, spectroscopic and X-ray crystallographic analysis of N,N-disubstituted N-ferrocenoylureas and identification of a one-pot coupling reagent for the formation of ferrocenecarboxamides in a non-aqueous solvent

N,N^′-dicyclohexyl-N-ferrocenoylurea 2, N,N^′-diisopropyl-N-ferrocenoylurea 3, N,N^′-di-p-tolyl-N-ferrocenoylurea 4 and N,N^′-di-tert-butyl-N-ferrocenoylurea 5 were obtained by reaction of ferrocenecarboxylic acid 1 with N,N^′-dicyclohexylcarbodiimide (DCC), N,N^′-diisopropylcarbodiimide (DIC), N,N^′-di-p-tolylcarbodiimide 10 and N,N^′-di-tert-butylcarbodiimide 11, respectively. Both N-tert-butyl-N^′-ethyl-N-ferrocenoylurea 6 and N^′-tert-butyl-N-ethyl-N-ferrocenoylurea 7 were obtained by reaction of 1 with N-tert-butyl-N^′-ethylcarbodiimide 12. In all cases a small amount of ferrocenecarboxylic anhydride 8 was formed as a by-product. All compounds were characterized by ¹H NMR, ¹³C NMR, IR and MS. Single crystal X-ray structural analyses were made of 2, 3 and 4. From the consistent results, the reaction products of 1 with carbodiimides appear different from those proposed by some earlier workers. With N-(3-dimethylaminopropyl)-N^′-ethylcarbodiimidehydrochloride 9 ferrocenoylurea was not isolated, but the main product was rather 8. The suitability of 8 as acylation reagent was applied by using 9 to obtain N-(3-triethoxysilyl)-propylferrocenecarboxamide in a one-pot reaction from 1 and 3-(triethoxysilyl)-propylamine.     

Selective N-debenzylation of amides with p-TsOH

N-Benzylamides were debenzylated efficiently with 4 equiv. of p-TsOH in refluxing toluene. Good to quantitative yields of the desired primary amides were obtained within 2-4 h from a wide variety of N-2,4-dimethoxybenzylamides. N-4-Methoxylbenzyl amides and N-benzylamides were also debenzylated cleanly. In the case of N-2,4-dimethoxylbenzylamides, selective N-debenzylation was possible in the presence of N-Fmoc, N-t-BOC or N-trityl-protection. Protected amino acid amides survived these conditions without any detectable epimerization.