N-oxide Derivatives Research Articles

Structure–activity relationship disturbed by a solvolytic process: Study on the [Cu(II)-4-nitropyridine N-oxide derivative] system

The chelate complex [CuCl2(L)] where L=2-methylamino-3-methyl-4-nitropyridine-N-oxide has been obtained and characterized, both physicochemically (by the X-ray structure analysis of the complex and the ligand, FTIR, EPR and electronic spectroscopy, and thermal analysis) and cytotoxically (MCF-7, A549, SW707, P388, Balb3T3). In solution, atypically for chelate complexes, it undergoes rapid solvolysis forming various 6- (or 5) and 4-coordinate species, depending upon the solvent. Such rapid decomposition may indicate a catalytic effect of the copper operating in the system. However, the cytotoxic activity in solution for the new copper chelate complex appeared to be a surprisingly low. Thus, before drawing any conclusions on the structure–activity relationship, one must carefully check the chemical identity of the compound(s) in both phases.

Redetermination of 4-cyanopyridineN-oxide

In the title pyridine N-oxide derivative, C6H4N2O, the 4-cyano substituent almost lies in the mean plane of the pyridine ring (r.m.s deviation of all non-H atoms = 0.004 Å). This redetermination results in a crystal structure with significantly higher precision [N—O bond length is 1.2997 (15) compared with 1.303 (5) Å in the original] than the original determination, which was recorded using the multiple-film technique and visually estimated intensities [Hardcastle et al. (1974 ▶). J. Cryst. Mol. Struct. 4, 305–311]. The crystal structure features weak C—H⋯O and C—H⋯N inter­actions, which lead to the formation of chains that inter­sect each other parallel to (001).

New Antiplasmodial Bromotyrosine Derivatives from Suberea ianthelliformisLendenfeld, 1888

Four samples of Suberea ianthelliformis were investigated and furnished five new and 13 known brominated tyrosine-derived compounds. Two of the new compounds were identified as araplysillin N20-formamide and its N-oxide derivative. Three other new compounds, araplysillins IV, V, and VI, were isolated and identified as analogs of araplysillin II. Most of these compounds exhibit moderate inhibitory activities against chloroquine-resistant and -sensitive strains of Plasmodium falciparum, and were investigated for their PFTase inhibitory properties. The chemical content of the investigated sponges is correlated with their molecular phylogeny.

A Revised Mechanism of Thermal Decay of Arylnitroso Oxides

The electronic spectra were measured and the unimolecular decay kinetics of the isomeric forms (cis and trans) of 4-methoxyphenylnitroso oxide in acetonitrile, benzene, and hexane was studied using flash photolysis. The cis form absorbed in a shorter wavelength region and was more labile than the trans form. The difference between the reactivity of the two species increased on going from hexane to acetonitrile. The temperature dependences of reaction rate constants were studied for both isomeric forms. The analysis of products of flash photolysis of 4-methoxyphenyl azide in the presence of oxygen allowed for understanding the mechanism of thermal decay of nitroso oxides. It was shown that the trans nitroso oxide is converted into cis nitroso oxide. The latter undergoes an unusual ring cleavage reaction to form 4-methoxy-6-oxohexa-2,4-dienenitrile N-oxide derivative. We conclude that the nitro- and nitrosobenzenes, which are the main products of the steady-state photolysis of aromatic azides in the presence of oxygen, are formed by the photochemical transformation of the nitroso oxides.

1,2‐Oxazine N‐Oxides as Catalyst Resting States in Michael Additions of Aldehydes to Nitro Olefins Organocatalyzed by α,α‐Diphenylprolinol Trimethylsilyl Ether

AbstractBy combining enamines, derived from aldehydes and diphenylprolinol trimethylsilyl ether (the Hayashi catalyst), with nitroethenes ((D6)benzene, 4‐Å molecular sieves, room temperature) intermediates of the corresponding catalytic Michael‐addition cycles were formed and characterized (IR, NMR, X‐ray analysis; Schemes 3–6 and Fig. 1–3). Besides cyclobutanes 2, 1,2‐oxazine N‐oxide derivatives 3–6 and 8 have been identified for the first time, some of which are very stable compounds. It may not be a lack of reactivity (between the intermediate enamines and nitro olefins) that leads to failure of the catalytic reactions (Schemes 3–5) but the high stability of catalyst resting states. The central role zwitterions play in these processes is discussed (Schemes 1 and 2).

Synthesis and cytotoxic activity of some 17-picolyl and 17-picolinylidene androstane derivatives

New 17-picolyl and 17-picolinylidene androstane derivatives, 3–10, 15, 18, 19, 22 and 23, were synthesized starting from 17α-picolyl-androst-5-en-3β,17β-diol (1) and 17(Z)-picolinylidene-androst-5-en-3β-ol (2). Reaction of 1 with m-chloroperoxybenzoic acid gives 5α,6α-epoxy N-oxide derivative 3, or, with Jones reagent, 3,6-dione derivative 4; while 17α-picolyl-androst-5-en-3β,4α,17β-triol (5) or 3β,4β,17β-triol (6) derivatives are obtainable from 1 using SeO2 in dioxane. Base-catalyzed tosyl group elimination from 7 or 9 affords AB conjugated derivatives 8 and 10. Oppenauer oxidation of 1 and 2 yields 4-en-3-one derivatives 11 and 12, which, with H2O2 in 4 M NaOH, affords 4α,5α and 4β,5β-epoxides 13, 14, 16 and 17. New 4-methoxy-3-keto derivatives 15 and 18 were obtained from 13 and 14, or, with methanol in 4 M NaOH, from 16 and 17. Reduction of 11 with NaBH4 gives 22, which was then acetylated to obtain 23. All new derivatives were screened for antitumor activity against human breast adenocarcinoma ER+, MCF-7; human breast adenocarcinoma ER-, MDA-MB-231; prostate cancer AR-, PC-3; human cervix carcinoma, HeLa; and colon cancer, HT-29 cells; as well as one human non-tumor cell line, MRC-5. Compounds 3, 5, 6, 8, 10, 18, 19 and 22 exhibited significant antitumor activity against MDA-MB-231 breast cancer cells; while 5, 6 and 10 also showed strong cytotoxicity against HT-29. Only compound 19 exhibited significant activity against MCF-7 breast cancer cells. No compounds displayed cytotoxicity against non-tumor MRC-5 cells.

Physicochemical characterization of environmental mutagens: 3-nitro-6-azabenzo[a]pyrene and its N-oxide derivative

Molecular geometries, nucleus independent chemical shifts, electronic, infrared and Raman spectra, vertical ionization energy and electron affinity, dipole moment, and electronic polarizabilities of 3-nitro-6-aza- benzo(a)pyrene and its N-oxide derivative were calculated for the gas phase using semiempirical and density functional theory. The influence of the N-oxidation on structural, elec- tronic, and spectroscopic properties is discussed. The infrared spectral region around 1,300 cm -1 involving the azabenzene N-O and the NO2 stretching vibrations is potentially useful to distinguish 3-nitro-6-azabenzo(a)pyrene from its N-oxide derivative. The calculated vertical ionization energy for 3-nitro-6-azabenzo(a)pyrene N-oxide is smaller than that of its parent compound, whereas the vertical electron affinity is higher in agreement with the experimental electrochemical reduction potentials. Both dipole moment and polarizability increase on passing from 3-nitro-6-azabenzo(a)pyrene to its N-oxide derivative, the contribution from the N-O bond formation being substantial. The electric property enhance- ments are explained through atomic charges and spectral shifts. Present results support the higher mutagenic activity for the N-oxide derivative in comparison with its parent compound. Keywords 3-Nitro-6-azabenzo(a)pyrene � 3-Nitro-6-azabenzo(a)pyrene N-oxide � Nitro-polycyclic aromatic hydrocarbons � Mutagenic activityDFT calculations

Silver-Catalyzed 2-Pyridyl Arylation of Pyridine N-Oxides with Arylboronic Acids at Room Temperature

A novel direct arylation of pyridine N-oxides with arylboronic acids through C-H functionalization has been developed. This new reaction is performed at room temperature using catalytic silver(I) nitrate in the presence of potassium persulfate and give 2-pyridyl arylation derivatives of pyridine N-oxides.

Novel N-oxide derivatives of benzyltetrahydroisoquinoline alkaloid from the tubers of Stephania viridiflavens H.S. Lo et M. Yang

An investigation on the phytochemistry of the medicinal plant Stephania viridiflavens H.S. Lo et M. Yang led to isolate two new naturally occurring benzyltetrahydroisoquinoline alkaloids, (+)-1S, 2R-laudanidine-Nβ-oxide 2 and (+)-1S, 2S-laudanidine-Nα-oxide 3, along with four known benzyltetrahydroisoquinoline alkaloids: (+)-laudanidine 1, (+)-reticuline 4, (+)-1S, 2R-reticuline-Nβ-oxide 5 and (+)-1S, 2S-reticuline-Nα-oxide 6. The structure and the stereochemistry of these compounds were determined on the basis of spectroscopic methods and also confirmed by partial synthesis. To examine putative acetycholinesterase (AChE) inhibitory or cytotoxic activities, various bioassays were performed, the N-oxide derivatives (5 and 6) demonstrated more potent cytotoxicity than the corresponding free base.

Synthesis and characterization of 5-alkoxycarbonyl-4-hydroxymethyl-5-alkyl-pyrroline N-oxide derivatives

The syntheses, analytical properties, and spin trapping behavior of four novel EMPO derivatives, namely 5-ethoxycarbonyl-4-hydroxymethyl-5-methyl-pyrroline N-oxide (EHMPO), 5-ethoxycarbonyl-5-ethyl-4-hydroxymethyl-pyrroline N-oxide (EEHPO), 4-hydroxymethyl-5-methyl-5-propoxycarbonyl-pyrroline N-oxide (HMPPO), and 4-hydroxymethyl-5-methyl-5-iso-propoxycarbonyl-pyrroline N-oxide (HMiPPO), towards different oxygen- and carbon-centered radicals are described.

Esterification via Iron-Catalyzed Activation of Triphenylphosphine with Air

Iron phthalocyanine-catalyzed oxidative activation of triphenylphosphine by molecular oxygen of air occurs, and esters and triphenylphosphine oxide are obtained in the presence of alcohols and carboxylic acids. Experimental results indicate that reactivity of esterification is dependent on acidity of the carboxylic acids and that an acyloxyphosphonium ion intermediate participates in the reaction mechanism. Addition of pyridine N-oxide derivatives accelerated the reaction, and a wide range of alcohols and carboxylic acids can be employed in this reaction.

Nickel-catalyzed Cycloaddition of Aromatic (O-Benzyl)ketoximes with Alkynes to Produce Isoquinoline and Isoquinoline N-Oxide Derivatives

Abstract A nickel-catalyzed cycloaddition of aromatic (O-benzyl)ketoximes with alkynes to afford 3,4-disubstituted isoquinoline derivatives has been developed. The reaction involves oxidative addition of N–O bond of O-benzylketoxime to Ni(0) and subsequent intermolecular C–H bond activation via elimination of benzyl alcohol. It was also found that ketoximes participate in the nickel-catalyzed reaction with alkynes to furnish isoquinoline N-oxide derivatives.

Flavin monooxygenases, FMO1 and FMO3, not cytochrome P450 isoenzymes, contribute to metabolism of anti-tumour triazoloacridinone, C-1305, in liver microsomes and HepG2 cells

5-Dimethylaminopropylamino-8-hydroxytriazoloacridinone, C-1305, being the close structural analogue of the clinically tested imidazoacridinone anti-tumour agent, C-1311, expressed high activity against experimental tumours and is expected to have more advantageous pharmacological properties than C-1311.The aim of this study was to elucidate the role of selected liver enzymes in the metabolism of C-1305.We demonstrated that the studied triazoloacridinone was transformed with rat and human liver microsomes, HepG2 hepatoma cells and with human recombinant flavin-containing monooxygenases FMO1, FMO3 but not with CYPs. Furthermore, this compound was an effective inhibitor of CYP1A2 and CYP3A4. The product of FMO catalysed metabolism was shown to be identical to the main metabolite from liver microsomes and HepG2 cells. It was identified as an N-oxide derivative and, under hypoxia, it underwent retroreduction back to C-1305, what was extremely effective with participation of CYP3A4.In summary, this work revealed that the involvement of the P450 enzymatic system in microsomal and cellular metabolism of C-1305 was negligible, whereas this agent was an inhibitor of CYP1A2 and CYP3A4. In contrast, FMO1 and FMO3 were crucial for metabolism of C-1305 by liver microsomes and in HepG2 cells, which makes C-1305 an attractive potent anti-tumour agent.

Synthesis of Quinoxaline 1,4-di-N-Oxide Analogues and Crystal Structure of 2-Carbomethoxy-3-hydroxyquinoxaline-di-N-oxide

A series of quinoxaline 1,4-di-N-oxide analogues were prepared from benzofurazan N-oxide derivatives and β-diketone ester compounds by the improved Beirut reaction. The structures of the target products were characterized by NMR, MS, IR and elemental analysis measurements, and that of 2-carbomethoxy-3-hydroxyquinoxaline- di-N-oxide was further confirmed by single-crystal X-ray diffraction. Its crystal structure belongs to the monoclinic system, space group C2/c with a = 14.4320 (12) Å, b = 10.7514 (9) Å, c = 13.2728 (11) Å, V = 1958.5 (3) Å 3, Z = 8. The X-ray crystallographic analysis reveals that quinoxaline 1,4-di-N-oxide displays acyloin-endiol tautomerism.

Synthesis and characterization of terminally functionalized and epoxidized hydroxyl-terminated polybutadiene

Pyridyl N-oxide derivatives of hydroxyl terminated polybutadiene-pyridine (HTPB-PY) were synthesized via functionalization on terminal carbon atoms of HTPB backbone by 2-chloropyridine and epoxidation of C=C bonds and N atoms using in situ generated dimethyl dioxirane (DMD). 1HNMR, 13CNMR, 14NNMR, and FT–IR spectroscopy techniques used in order to investigate the structural elucidation of products. In this synthesis method, HTPB terminal hydroxyl groups have preserved unchanged without applying any conditional controllers.

Red-Shifted Porphyrins

A high-yielding procedure for the formation of annulated porphyrins with far-red absorptions is reported from a known dione starting material. The nitrogens introduced on the exterior edge of the porphyrin structure are available for additional functionalization or metal coordination, and N-oxide derivatives are produced.

Systematic coordination chemistry and cytotoxicity of copper(II) complexes with methyl substituted 4-nitropyridine N-oxides

Three new nitrato copper(II) complexes of dimethyl substituted 4-nitropyridine N-oxide were synthesized and characterized by elemental analysis, magnetic, spectroscopic, thermal and X-ray methods, respectively. They were isolated as trans isomers, mononuclear (μ = 1.70–1.88 BM), five ( 1– 2) and four (3) coordinate species of general formula [Cu(NO 3) 2(H 2O)L 2] where L = 2,3-dimethyl-, 2,5-dimethyl-4-nitropyridine N-oxide and [Cu (NO 3) 2L 2], L = 3,5-dimethyl-4-nitropyridine N-oxide, respectively. The X-ray crystal structure of ( 1) (L = 2,3-dimethyl-4-nitropyridine N-oxide) was determined. The organic ligands, the complexes and copper hexaqua ion as a reference were tested in vitro on the cytotoxic activity against human cancer cell lines: MCF-7 (breast), SW-707 (colon) and P-388 (murine leukemia). The complexes are relatively strong cytotoxic agents towards P-388 cell line. Comparative analysis was performed for all known copper(II) complexes containing methyl derivatives of the 4-nitropyridine N-oxide on the basis of their composition, structure and cytotoxic activities. To obtain the typical structure for these species (i.e., 4-coordinate mononuclear of the type trans-[Cu(inorganic anion) 2L 2]), two methyl groups must be situated on both sides of nitrogen atom(s) (i.e., NO and NO 2) in the ligand. The biological activity was found to be strongly dependent upon the number of the methyl groups and the type of cell line. The best cytotoxic results were found for the complexes without substituents or with one methyl group. Generally, for all cell lines, the complexation increased cytotoxicity when compared with the free ligands.

The Imidazoacridinone Antitumor Drug, C-1311, Is Metabolized by Flavin Monooxygenases but Not by Cytochrome P450s

5-Diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) is an antitumor agent that is also active against autoimmune diseases. The intention of the present studies was to elucidate the role of selected liver enzymes in metabolism of C-1311 and the less active 8-methyl derivative, 5-diethylaminoethylamino-8-methoxyimidazoacridinone (C-1330). Compounds were incubated with rat liver microsomal fraction, with a set of 16 human liver protein samples, and with human recombinant isoenzymes of cytochrome P450, flavin monooxygenases (FMO), and UDP-glucuronosyltransferase (UGT). Our results showed that C-1311 and C-1330 were metabolized with human liver microsomal enzymes but not with any tested human recombinant cytochromes P450 (P450s). Two of these, CYP1A2 and CYP3A4, were inhibited by both compounds. In addition, results of C-1311 elimination from hepatic reductase-null mice, in which liver NADPH-P450 oxidoreductase has been deleted indicated that liver P450s were slightly engaged in drug transformation. In contrast, both compounds were good substrates for human recombinant FMO1 and FMO3 but not for FMO5. The product of FMO metabolism, P(FMO), which is identified as an N-oxide derivative, was identical to P3(R) of liver microsomes. P3(R) was observed even in the presence of the P450 inhibitor, 1-aminobenzotriazole, and it disappeared after heating. Therefore, FMO enzymes could be responsible for microsomal metabolism to P3(R) = P(FMO). Glucuronidation on the 8-hydroxyl group of C-1311 was observed with liver microsomes supported by UDP-glucuronic acid and with recombinant UGT1A1, but it was not the case with UGT2B7. Summing up, we showed that, whereas liver P450 isoenzymes were involved in the metabolism of C-1311 to a limited extent, FMO plays a significant role in the microsomal transformations of this compound, which is also a specific substrate of UGT1A1.

Precursors and Formation of Pyrithione and Other Pyridyl-Containing Sulfur Compounds in Drumstick Onion, Allium stipitatum

Two novel, structurally unusual cysteine derivatives were isolated from the bulbs of Allium stipitatum (Allium subg. Melanocrommyum) and shown to be S-(2-pyridyl)cysteine N-oxide and S-(2-pyridyl)glutathione N-oxide. The former compound is the first example of a naturally occurring alliinase substrate that contains an N-oxide functionality instead of the S-oxide group. In addition, S-methylcysteine S-oxide (methiin) and S-(methylthiomethyl)cysteine 4-oxide (marasmin) were found in the bulbs. Presented data suggest that the previously reported identification of S-(2-pyridyl)cysteine S-oxide was most likely erroneous. The alliinase-mediated formation of pyridyl-containing compounds following disruption of A. stipitatum bulbs was studied by a combination of HPLC-MS, HPLC-PDA, DART-MS, and NMR techniques. It was found that no pyridyl-containing thiosulfinates are present in homogenized bulbs in detectable quantities. Instead, various pyridine N-oxide derivatives are formed, including N-hydroxypyridine-2(1H)-thione (pyrithione), 2-(methyldithio)pyridine N-oxide, 2-[(methylthio)methyldithio]pyridine N-oxide, di(2-pyridyl) disulfide N-oxide, and di(2-pyridyl) disulfide N,N'-dioxide. This represents the first report of pyrithione formation as a natural product.

Studies with aza-heterocyclic N-oxides: Synthesis of some new aromatic N-oxide derivatives

Benzofuroxan derivative ( 1a ) reacts with the cyanoacetanilides ( 2a - d ) to give the benzimidazole derivatives ( 3a - d ). Benzofuroxan ( 1b ) reacts with rhodanine derivatives ( 4a , b ) in presence of sodium ethoxide to give the arylaminobenzoimidazole derivatives ( 6a , b ); while the last reaction afforded the thiazolidinone derivatives ( 8a , b ) and the o -benzoquinone dioxime derivatives ( 9a , b ) when it was repeated in the presence of sodium acetate. Moreover, a series of quinoxalinyl 1,4-di- N -oxide derivatives were prepared starting from quinoxalin-1,4-di- N -oxide derivatives ( 10a - c ). Plausible mechanisms to account for the formation of the products are discussed.