- Hypoxia-selective agents derived from 2-quinoxalinecarbonitrile 1,4-di-N- oxides. 2
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Hypoxic cells are an important target for antitumor therapy because tumors are typically characterized by such cells. Virtually all tumors which are present as solid masses contain hypoxic cells, while normal cells generally have an adequate supply of oxygen. Accordingly, antitumor agents can be made selective for tumors by virtue of high activity under hypoxic conditions. The initial purpose of this work was to determine the influence of different groups in position 3. Thus, the synthesis of some 3-NH-substituted derivatives (2a, 3a, 4a) starting from 3-amino-2-quinoxalinecarbonitrile 1,4- di-N-oxide (1a) is described. Reductive deamination of compounds 1a-k provides the 2-quinoxalinecarbonitriles 5a-k, which are more potent, while selectivity is maintained or increased in some derivatives. The compound 7- (4-nitrophenyl)-2-quinoxalinecarbonitrile 1,4-di-N-oxide (5k) is 150-fold more potent than tirapazamine (3-amino-1,2,4-benzotriazine 1,4-di-N-oxide), which has been used as a standard. Three derivatives (5g,i,k) show a hypoxic cytotoxicity ratio (HCR) ≥ 200, better than that of tirapazamine (HCR = 75) in V79 cells. Replacement of the 3-amino group by chlorine affords the potent but nonselective 3-chloro derivatives 6a-k showing similar toxicities under both aerobic and hypoxic conditions. These compounds were used as intermediates for the synthesis of a new series of water-soluble compounds derived from 3-[[(N,N-dialkylamino)alkyl]amino]-2-quinoxalinecarbonitrile 1,4-di-N-oxides 10a-i and 11a-i. The 7-chloro and the 7-trifluoromethyl derivatives 10b,f have demonstrated high potency (0.4 and 0.3 μM) and excellent selectivity (HCR = 250 and 340). Several 7-chloro analogues, 12b, 13b.1,b.2, and 14b, and the dimer 16b have been prepared and evaluated in order to determine the optimum lateral chain in position 3, which appears to be the [(N,N-dimethylamino)propyl]amino moiety.
- Monge,Martinez-Crespo,De Cerain,Palop,Narro,Senador,Marin,Sainz,Gonzalez,Hamilton,Barker
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- Reactivity and transformation of antibacterial N-oxides in the presence of manganese oxide
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Organic N-oxides are an important structural class in many pharmaceutical and industrial chemicals. Little is known about the potential transformation of organic N-oxides at the sediment-water interface. Veterinary antibacterial agents carbadox and olaquindox are examples of commonly used heterocyclic N-oxides. Investigation with various N-oxides including carbadox, olaquindox, quinoline N-oxide, and quindoxin revealed surprisingly high reactivity toward MnO2 for all of the compounds except olaquindox. Desoxycarbadox and quinoxaline, two structurally related compounds that lack an N-oxide functional group, showed much lower or no reactivity toward MnO2. Comparisons among the previous compounds indicate that N-oxide moiety is the primary reactive site to MnO2, and substitution at the α-C adjacent to the N-oxide group is critical in determining the overall reactivity. Reactions of N-oxides with MnO2 appeared to be oxidation, with generation of Mn2+ parallel to degradation of the parent organics. Product characterization confirmed that quinoline N-oxide and quindoxin transformed into 2-hydroxyquinoline and quinoxaline 2,3-diol, respectively, in reactions with MnO2. The transformation involves separate steps of N-oxide moiety deoxygenation and neighboring α-C hydroxylation as elucidated by 18O isotope experiments. All of the experimental results pointed to a mechanism that involves an N-oxide radical intermediate. This is the first study to report such transformation reactivity of organic N-oxides toward manganese oxide, offering a new degradation pathway that could be important for the fate of this group of compounds in the aquatic environment.
- Zhang, Huichun,Huang, Ching-Hua
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- Bromination of quinoxaline and derivatives: Effective synthesis of some new brominated quinoxalines
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The synthesis of brominated quinoxaline derivatives starting from several kinds of quinoxaline by different bromination strategies was studied. First the synthesis of some brominated quinoxalines was accomplished along with the development of an alternative and effective synthesis of some known compounds. A new, clean, and effective synthetic method for selective reduction of quinoxaline to 1,2,3,4-tetrahydroquinoxaline was also developed. The products obtained were characterized by means of NMR spectroscopy, elemental analyses, and mass spectrometry.
- U?ar, Sefa,E?siz, Sel?uk,Da?tan, Arif
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p. 1618 - 1632
(2017/03/08)
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- Copper-Catalyzed Direct, Regioselective Arylamination of N-Oxides: Studies to Access Conjugated π-Systems
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An efficient copper(I)-catalyzed direct regioselective arylamination of various heterocyclic N-oxides was achieved successfully under redox-neutral conditions using anthranils as arylaminating reagents. The developed protocol is simple, straightforward, and economic with a broad range substrate scope. The dual functional groups in the final molecules were utilized to construct structurally and functionally diverse nitrogen-containing organic π-conjugated systems.
- Biswas, Aniruddha,Karmakar, Ujjwal,Nandi, Shiny,Samanta, Rajarshi
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p. 8933 - 8942
(2017/09/11)
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- Catalytic N-oxidation of tertiary amines on RuO2NPs anchored graphene nanoplatelets
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Ultrafine ruthenium oxide nanoparticles (RuO2NPs) with an average diameter of 1.3 nm were anchored on graphene nanoplatelets (GNPs) using a Ru(acac)3 precursor by a very simple dry synthesis method. The resultant material (GNPs-RuO2NPs) was used as a heterogeneous catalyst for the N-oxidation of tertiary amines for the first time. The transmission electron microscopy (TEM) images of the GNPs-RuO2NPs showed the excellent attachment of RuO2NPs on GNPs. The loading of Ru in GNPs-RuO2NPs was 2.68 wt%, as confirmed by scanning electron microscope-energy dispersive spectroscopy (SEM-EDS). The X-ray photoelectron spectrum (XPS) and the X-ray diffraction pattern (XRD) of GNPs-RuO 2NPs revealed that the chemical state of Ru on GNPs was +4. After the optimization of reaction conditions for N-oxidation of triethylamine, the scope of the reaction was extended to various aliphatic, alicyclic and aromatic tertiary amines. The GNPs-RuO2NPs showed excellent catalytic activity in terms of yields even at a very low amount of Ru catalyst (0.13 mol%). The GNPs-RuO2NPs was heterogeneous in nature, chemically as well as physically, very stable and could be reused up to 5 times. The Royal Society of Chemistry 2014.
- Gopiraman, Mayakrishnan,Bang, Hyunsik,Babu, Sundaram Ganesh,Wei, Kai,Karvembu, Ramasamy,Kim, Ick Soo
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p. 2099 - 2106
(2014/06/24)
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- A new efficient route for the formation of quinoxaline N-oxides and N,N′-dioxides using HOF·CH3CN
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HOF·CH3CN, a very efficient oxygen-transfer agent made readily from fluorine and aqueous acetonitrile, was reacted with various quinoxaline derivatives to give the corresponding mono N-oxides and especially the N,N′-dioxides in very good yields under mild conditions and short reaction times.
- Carmeli, Mira,Rozen, Shlomo
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p. 5761 - 5765
(2007/10/03)
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- Thermochemical and Theoretical Study of Some Quinoxaline 1,4-Dioxides and of Pyrazine 1,4-Dioxide
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The following standard molar enthalpies of formation in the gaseous state at 298.15 K were determined from the enthalpies of combustion of the crystalline solids, and their enthalpies of sublimation and the mean (N-O) bond dissociation enthalpies were derived. ΔfHm0(g); 〈D(N-O)〉 (kJ mol-1): quinoxaline 1,4-dioxide, 227.1 ± 2.4; 255.8 ± 2.0; 2-methylquinoxaline 1,4-dioxide, 169.9 ± 7.2; 268.3 ± 4.9; 2-methyl-3-acetylquinoxaline 1,4-dioxide, 33.1 ± 5.0; 251.6 ± 4.2; 2-phenyl-3-benzoylquinoxaline 1,4-dioxide, 355.2 ± 7.1; 227.3 ± 5.4; 2-methyl-3-carbomethoxyquinoxaline 1,4-dioxide, -148.7 ± 3.2; 242.3 ± 3.9; pyrazine 1,4-dioxide, 186.5 ± 1.9; 254.0 ± 2.3; 2-methyl-5-pyrazinecarboxylic acid, -213.6 ± 1.7. Unconstrained geometry optimizations by ab initio calculations showed the effect of steric hindrance on changes in extended delocalizations and were in accord with the trends in the mean bond dissociation enthalpies.
- Acree Jr.,Powell, Joyce R.,Tucker, Sheryl A.,Ribeiro da Silva, Maria D.M.C.,Matos, M. Agostinha R.,Goncalves,Santos,Morais,Pilcher
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p. 3722 - 3726
(2007/10/03)
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- Reaction of 2,1,3-benzoxadiazole 1-oxide with ethyl 2,4-dioxo-4- phenylbutyrate. A route to 2-benzoylquinoxaline, its 1,4-dioxide, and related compounds
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The Beirut reaction of 2,1,3-benzoxadiazole 1-oxide and ethyl 2,4-dioxo-4-phenylbutryate in ethanol, or acetonitrile, catalysed by triethylamine gave first ethyl 3-benzoylquinoxaline-2-carboxylate 1,4-dioxide and then, in a slower reaction, 2-benzoylquinoxaline 1,4-dioxide. The latter was isolated in two distinct stable crystalline forms. The effects of changing the proportions of the reactants, the tertiary alkylamine used, and the temperature have been studied. Both above-mentioned 1,4-dioxides were reduced to the corresponding quinoxalines. Ethyl 3-benzoylquinoxaline-2-carboxylate 1,4-dioxide decomposed slowly to several products in ethanol in the presence of triethylamine or diethylamine and was converted by ethanolic potassium hydroxide into the potassium salt of quinoxaline-2-carboxylic acid 1,4-dioxide.
- Atfah, Adnan,Hill, John
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p. 221 - 224
(2007/10/02)
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- Quinoxaline derivatives
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The synthesis of quinoxaline and benzimidazole-N-oxides and of ester and amide derivatives of 3-hydroxy-2-quinoxalinecarboxylic acid by a novel process consisting of the reaction between a benzofuroxan and an activated methylene-containing compound under basic conditions.
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- Preparation of Some Functionalized Quinoxaline 1,4-Dioxides
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The preparation of some functionalized quinoxaline 1,4-dioxides is described from the reaction of benzofurazan oxide with 2-acetylbutyrolactone, ethyl acetopyruvate, and acetylaldehyde dimethylacetal.
- Usta, J. A.,Haddadin, M. J.,Issidorides, C. H.,Jarrar, A. A.
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p. 655 - 658
(2007/10/02)
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- REDOX TRANSFORMATIONS OF 2-FORMYLQUINOXALINE HYDRATE AND DIETHYLACETAL N,N'-DIOXIDES
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Depending on the pH of the medium, when 2-formylquinoxaline hydrate N,N'-dioxide is subjected to attack by the OH- anion, it undergoes redox transformations to give 2-carboxyquinoxaline 4-oxide or quinoline N,N'-dioxide and the formate ion.In the case of attack by the OH- anion 2-formylquinoxaline diethylacetal N,N'-dioxide undergoes only the first reaction, regardless of the pH.
- Elina, A. S.,Musatova, I. S.,Titkova, R. M.,Dubinskii, R. A.,Goizman, M. S.
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p. 861 - 863
(2007/10/02)
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- Substituted alkyl esters of quinoxaline-di-N-oxide-2-carboxylic acid
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Novel alkyl esters of quinoxaline-di-N-oxide-2-carboxylic acid substituted on the alkyl portion of the ester by hydroxy, acyloxy, N-alkyl carbamyloxy, dialkylaminoacyloxy, carboxyacyloxy, alkoxycarbonyloxy, haloacyloxy, amino and mono- and disubstituted amino, useful as antibacterial agents and in promoting growth and improving feed efficiency of animals in general.
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