Preparation of phenazine N5,N10-dioxides: Effects of benzofuroxan substituents in the outcome of their expansion reaction with phenolates

Cerecetto, Hugo; González, Mercedes; Lavaggi, María Laura; Porcal, Williams

doi:10.1590/s0103-50532005000700030

Cited by 25 publications

(12 citation statements)

References 30 publications

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“…The main scale‐up modifications were the lyophilization processes after each reactions (see Experimental Section) and that the final product was washed only with Et 2 O instead of the mixture Et 2 O/THF . In general, the expansion process when substituted‐benzofuroxans is used produces a mixture of substituted‐phenazine 5,10‐dioxide isomers depending the isomeric‐proportion on the substituent electronic effect . For this reason, the scale up preparation of 1 conducted exclusively to the corresponding 7‐fluoro‐ isomer (see Supporting Information, Figure S1).…”

Section: Resultsmentioning

confidence: 99%

“…[16] In general, the expansion process when substituted-benzofuroxans is used produces a mixture of substituted-phenazine 5,10-dioxide isomers depending the isomeric-proportion on the substituent electronic effect. [21] For this reason, the scale up preparation of 1 conducted exclusively to the corresponding 7-fluoro-isomer (see Supporting Information, Figure S1).…”

Section: Scale Up Synthesis Ofmentioning

confidence: 99%

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Selective Hypoxia‐Cytotoxin 7‐Fluoro‐2‐Aminophenazine 5,10‐Dioxide: Toward “Candidate‐to‐Drug” Stage in the Drug‐Development Pipeline

et al. 2019

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7‐Fluoro‐2‐aminophenazine 5,10‐dioxide, 1, has displayed in vitro bioreductive selective cytotoxicity, which could acts towards tumors containing hypoxic regions. In this work, we describe some preclinical studies of compound 1 confirming its in vivo antitumor activity. The synthesis of compound 1 was scaled up to 3 g improving the micro‐scale yield. Some drug‐like properties for compound 1 were theoretically‐predicted and others, i. e. aqueous‐solubility and toxicity ‐mutagenicity, in vivo chromosomal‐aberrations and ip acute LD50‐, were experimentally confirmed. Antitumoral activity was studied in mice bearing hypoxic 4T1‐breast‐tumor by assessing evolution of the tumor‐sizes, animal‐survival and bio‐chemical/hematological. Compound 1 in vivo efficacy, with the absence of systemic toxicity, was confirmed.. Results highlight the potential of 7‐fluoro‐2‐aminophenazine 5,10‐dioxide as promissory therapeutic agent for solid tumors.

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Section: Resultsmentioning

confidence: 99%

Section: Scale Up Synthesis Ofmentioning

confidence: 99%

Selective Hypoxia‐Cytotoxin 7‐Fluoro‐2‐Aminophenazine 5,10‐Dioxide: Toward “Candidate‐to‐Drug” Stage in the Drug‐Development Pipeline

et al. 2019

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“…Examples of quinoxaline-1,4-dioxides, phenazine-5,10-dioxide and benzimidazole-1,3-dioxide obtained from Beirut reaction [1][2][3][4][5] The Beirut reaction using an unsymmetrical monosubstituted or a disubstituted benzofuroxan, carrying different groups at positions 5 and 6, could in thesis, affords two regioisomers, resulting in a mixture of quinoxaline 1,4-dioxides or phenazines N,N'-dioxides or benzimidazole-1,3-dioxides. 5 This fact can be explained by the tautomeric relationship observed for benzofuroxan system that exists as a mixture of two distinct isomers, as depicted in Scheme 2. The stability of tautomers (1a/9a and 1c/9c) depends on the nature of the substituent at positions 5 and 6, in other words if the substituent is an electron releasing or electron withdrawing group.…”

Section: Figure 1 Pictures Of the Inventor And Co-inventor Of The Bementioning

confidence: 99%

Beirut Reaction and its Application in the Synthesis of Quinoxaline-N,N'-Dioxides Bioactive Compounds

Lima¹,

Amaral²

2013

Revista Virtual De Química

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Reação de Beirut e sua Aplicação na Síntese de Compostos Quinoxalina-N,N'-Dióxidos Bioativos Resumo: Descrita por Haddadin and Issidorides em 1965, a cicloadição entre benzofuroxano (i.e. óxido de benzofurazano ou 2,1,3-benzoxadiazola-1-óxido) com enaminas, cetonas insaturadas, 1,3-dinitrilas ou enolatos, produzindo quinoxalina-N,N'-dióxidos, é conhecida na literatura como reação de Beirut. A possibilidade de se obter, em etapa única, heterociclos nitrogenados aromáticos oxidados, contendo múltiplo e distinto perfil de funcionalização, tornou a reação de Beirut opção versátil para a síntese de compostos com diferentes aplicações industriais, a exemplo do carbadox, cyadox e olaquindox, disponíveis como antibióticos utilizados como promotores do crescimento em produtos de origem animal, permitindo a identificação do sistema quinoxalina-N,N'-dióxidos como importante unidade estrutural para a obtenção de compostos bioativos.

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“…[1][2][3][4][5][6][7][8][9][10][11][12][13] They have also been intensively studied from the point of view of the chemical activity. [14][15][16][17][18][19][20][21][22] In particular, a great deal of interest in recent decades has been caused by the fact that benzofuroxans exhibit a high capacity to undergo σ-complexation or covalent substitution. The action of the methoxide anion on the 4,6-dinitro7-methylbenzofuroxan (DNBF) leads only to the isolation of the anionic form DNBF -.…”

Section: Introductionmentioning

confidence: 99%

Theoretical investigation of methoxide ion reaction on the 7-methyl-4,6-dinitrobenzofuroxan

2016

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Reaction of the methoxide ion on the 7-methyl 4,6-dinitrobenzofuroxan (DNBF) 1 has been studied theoretically by means of DFT/B3LYP technique in order to interpret the kineticthermodynamic competition between the three possible compounds that are carbanion DNBF -4 and two complexed forms (2, 3) of the methoxide group in positions 5 and 7 respectively. Optimized Geometry, nbo atomic charge distribution, thermodynamic/kinetic parameters (∆ r H°T, ∆ r S°T , ∆ r G°T, ∆H*, ∆S* and ∆G*) and IRC path have been calculated for possible products and their transitional states using water as solvent. All obtained ∆ r G°T are negative, ranging from -19.16 to -42.87 kcal mol -1 , indicating the possible observation of all products but the experimenters only detected the anionic form DNBF -. Fukui indices, which were calculated by means of NBO atomic charge distribution, confirm the electrophilicity of the sites C5 and C7. Transition states barriers, ΔG* are 14.97 , 15.16 and 21.94 kcal mol -1 for the three possible products 2, 3 and 4 respectively in water. As expected, the most stable compound is the carbanion but it exhibits also the highest activation barrier. If this situation engenders formally a double kinetic-thermodynamic competition, the very weak activation energy of the two complexes in C5 and C7 makes improbable the simultaneous detection of the three expected compounds.

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Preparation of phenazine N5,N10-dioxides: Effects of benzofuroxan substituents in the outcome of their expansion reaction with phenolates

Cited by 25 publications

References 30 publications

Selective Hypoxia‐Cytotoxin 7‐Fluoro‐2‐Aminophenazine 5,10‐Dioxide: Toward “Candidate‐to‐Drug” Stage in the Drug‐Development Pipeline

Selective Hypoxia‐Cytotoxin 7‐Fluoro‐2‐Aminophenazine 5,10‐Dioxide: Toward “Candidate‐to‐Drug” Stage in the Drug‐Development Pipeline

Beirut Reaction and its Application in the Synthesis of Quinoxaline-N,N'-Dioxides Bioactive Compounds

Theoretical investigation of methoxide ion reaction on the 7-methyl-4,6-dinitrobenzofuroxan

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