Electrophilic intermediate in the reactions of a 2-(hydroxyamino)imidazole. A model for biological effects of reduced nitroimidazoles

McClelland, Robert A.; Panicucci, Rick; Rauth, Andrew M.

doi:10.1021/ja00292a053

Cited by 53 publications

(21 citation statements)

References 4 publications

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“…[141][142][143][144] The hydrolysis mechanism of Scheme 4.28 is consistent with kinetic data. 141,142 An intermediate that can be trapped by H 2 O, 142 phosphate, 143 or glutathione (GSH) 139,142 was identified as the nitrenium ion 95. The ratio k gs-/k s was estimated as 5 Â 10 5 M À1 for 95a from the variation of product yield data with [GS À ].…”

Section: Heterocyclic Nitrenium Ionssupporting

confidence: 80%

Aryl Nitrenium Ions in Aqueous Solution

Novák

Wang

2013

Nitrenes and Nitrenium Ions

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Section: Heterocyclic Nitrenium Ionssupporting

confidence: 80%

Aryl Nitrenium Ions in Aqueous Solution

Novák

Wang

2013

Nitrenes and Nitrenium Ions

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“…2-Nitroimidazoles are reductively activated to compounds that generate covalent adducts in protein and DNA (34)(35)(36) and breaks in DNA (37), and that result in depletion of the intracellular thiol glutathione (38). We have suggested that the unstable hydroxylamine may in part be responsible for these effects, since mechanistically a reactive electrophile capable of binding cellular nucleophiles can be identified for the conversion of the hydroxylamine to products such as 3 (10,21,22). In general, in these model reductions the 2-aminoimidazole, which is the product of a six-electron reduction, is not observed or is found only in small quantities.…”

Section: Discussionmentioning

confidence: 99%

“…Work in our laboratory, however, has shown that such compounds are unstable at neutral pH (6,10,19,20), with half-lives ranging from 2-15 min (21,22). The major products of their further reaction have been identified as the cis and trans 2-amino-4,5-dihydro-4,5-dihydroxyirnidazolium ions 3 (10,20,21 c R = CH2CONHCH2C6H5 (Benznidazole) tives of aldehydes and ketones. Such experiments have been found to result in the appropriate derivatives of the two-carbon dialdehyde glyoxal (7,12,17,(23)(24)(25)(26).…”

mentioning

confidence: 99%

4,5-Dihydro-4,5-dihydroxyimidazoles as products of the reduction of 2-nitroimidazoles. HPLC assay and demonstration of equilibrium transfer of glyoxal to guanine

Panicucci¹,

McClelland²

1989

Can. J. Chem.

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RICK PAN~CUCC~ and ROBERT A. MCCLELLAND. Can. J. Chem. 67, 2 128 (1 989). An HPLC method has been employed to study the electrochemical reduction (mercury cathode at -800 mV with respect to calomel electrode) of the 2-nitroimidazole benznidazole (N-benzyl-(2'-nitro-1'-imidazoy1)acetamide). The principal product of this reduction is the cyclic guanidiniurn ion 3c (protonated N-benzyl-(2'-amino-4',5'-dihydro-4',5'-dihydroxy-l'-imidazoyl)acetamide), which forms in a linear fashion as the nitroimidazole is reduced and accounts for 75% of the product upon completion of the reduction. To perform the HPLC analysis quantitatively an authentic sample of this product (isolated as cis:trans isomers) was prepared as the sulfate salt through the reaction of N-benzyl-2-guanidinoacetamide sulfate with aqueous glyoxal. The two isomers of 3c arise through the nonreductive decomposition of the 2-hydroxylaminoimidazole, which is the product of a four-electron reduction of the nitroimidazole. Analysis of high field 'H NMR spectra also showed that the two isomers of 3c were the principal products following electrochemical reduction, neutral aqueous zinc reduction, and radiation chemical reduction. Previous investigations using NMR of the reductions of misonidazole (3-methoxy-1-(2'-nitro-1'-imidazoy1)-2-propanol) and 1-methyl-2-nitroimidazole have shown that the corresponding dihydroimidazoles 3a and 36 are the major products. The agreement of these various NMR and HPLC results suggests that the formation of dihydroimidazoles 3 is a general phenomenon for model reductions of 2-nitroimidazoles in neutral aqueous solution. Previous workers have shown that 2-nitroimidazole reduction mixtures, when treated with guanine derivatives, form the adduct 4 derived from the guanine and glyoxal. This work demonstrates that this adduct is also formed when authentic samples of 3 a , 3 6 , and 3c are reacted with 2'-deoxyguanosine. A quantitative HPLC analysis, however, demonstrates that the reaction does not proceed to completion, and in fact the equilibrium for formation of 4 is unfavorable. This suggests that guanines are not useful derivatizing agents for the quantitative assay of "glyoxal-like" products formed in chemical or biological reductions of 2-nitroimidazoles.Key words: nitroimidazole, reduction of nitroimidazoles, glyoxal from nitroimidazoles.RICK PANICUCCI et ROBERT A. MCCLELLAND. Can. J. Chem. 67, 2128 (1989). On a utilisC une mtthode de CLHP pour Ctudier la rCduction Clectrochimique (cathode de mercure h -800 mV par rapport a l'tlectrode de calomel) de la 2-nitroimidazole benznidazole (N-benzyl-(2'-nitro-I '-imidazoy1)acttamide). Le produit principal de cette rCduction est l'ion guanidinium cyclique 3c (N-benzyl-(2'-amino-4',5'-dihydro-4',5'-dihydroxy-l'-imidazoyl)acCtamide protonC) qui se forme d'une faqon linCaire au fur et h mesure que le nitroimidazole est rtduit et qui forme 75% du produit ? I la fin de la riduction. Afin de rCaliser l'analyse quantitative par CLHP, on a prCparC un Cchantillon authentique de ce produit (is016 s...

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“…1 2 3 4 Such compounds have been characterized in mixtures after the reduction of the 2-nitroimidazole misonidazole (1, R = CH2CHOHCH20CH,) following treatment with the thiol glutathione (y-glutamylcysteinylglycine) (2, 3). They are also observed by reacting an isolated sample of the product of four-electron reduction, the 2-hydroxylaminoimidazole 2, with thiols such as cysteamine and glutathione (4)(5)(6). Misonidazole depletes intracellular glutathione selectively under hypoxic conditions (7), and this chemistry provides a model for the effect.…”

Section: R's S R'mentioning

confidence: 99%

“…N-Bromination, for example, results in an N-bromoimidazole 22, where loss of bromide would lead to the cation 23 and hence to 18. The cation 23 has previously been implicated as an intermediate in the aqueous decomposition of the imidazole-2-hydroxylamine 24, a reaction where 18 is also the product (4,6,23).…”

Section: No2mentioning

confidence: 99%

Preparation and reactions of bromo-2-nitro- and bromo-2-aminoimidazoles

Farah¹,

McClelland²

1993

Can. J. Chem.

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Can. J. Chem. 71,427 (1993). Treatment of 1-methyl-2-nitroimidazole with bromine in water resulted in rapid dibromination to give 4,5-dibromo-1-methyl-2-nitroimidazole. In dioxane, the bromination was slower, and could be controlled to give 4-bromo-1-methyl-2-nitroimidazole 5 and 5-bromo-1-methyl-2-nitroimidazole 6 in a 4 : 1 ratio. In an attempt to displace the bromine, the monobromo compounds were treated with cysteamine hydrochloride. In each case the nitro group was displaced instead, the 4-bromo 5 resulting in 2-[(2-aminoethyl)thio]-4-bromo-1-methylimidazole 9 as sole product, and the 5-bromo 6 giving two products identified as the monosubstituted 2-[(2-aminoethyl)thio]-5-bromo-1-methylimidazole 13 and the disubstituted 2,5-bis[2-(aminoethyl)thio]-1-methylimidazole 12. The latter product forms by further reaction of the former and was the sole material observed at long reaction times. A fraction of 12 may also originate from an initial displacement of bromine giving 5-[(2-aminoethy1)thiol-1-methyl-2-nitroimidazole 14, although this cannot be observed due to a rapid further displacement of its nitro group. The bromonitroimidazoles 5 and 6 were reduced to 4-bromo-2-amino-1-methylimidazole 25 and 5-bromo-2-amino-1-methylimidazole 26 with Zn/HCl. On reflux in water, in the presence or absence of cysteamine hydrochloride, these undergo a protodebromination resulting in the same product, 2-amino-1-methylimidazole 17. In D20 the 4-bromo isomer was demonstrated to react specifically to give 2-amino-4-deuterio-1-methylimidazole 27. Attempted preparation of the bromoaminoimidazoles 25 and 26 by bromination of 2-amino-1-methylimidazole in water resulted in the clean formation of cis and trarzs 2-amino-4,5-dihydro-4,5-dihydroxyimidazolium ions 18. SALIM F. FARAH et ROBERT A. MCCLELLAND. Can. J. Chem. 71, 427 (1993) Le traitement du 1-methyl-2-nitroimidazole avec du brome dans l'eau conduit a une dibromation rapide, avec formation du 4,5-dibromo-1-methyl-2-nitroimidazole. Dans le dioxane, la bromation est plus lente et elle peut &tre contr6lCe pour conduire a la formation des 4-bromo-(5) et 5-bromo-(6) 1-methyl-2-nitroimidazoles, dans un rapport de 4 : 1. Dans un effort pour deplacer le brome, on a trait6 les composCs monobromes avec de chlorhydrate de la cystkinamine. Dans chaque cas, c'est plut6t le groupe nitro qui a Ct C deplace; le derive 4-brome (5) conduit uniquement au 2-[(2-aminoCthy1)thiol-4-bromo-1-methylimidazole (9) alors que le compose 5-bromC (6) fournit deux produits identifies comme le 2-[(2-aminotthy1)thiol-5-bromo-1-methylimidazole (13) monosubstituC et le 2,5-bis-[2-(aminoCthy1)thiol-1-methylimidazole (12) disubstitue. Ce dernier compose se forme par reaction ulterieure du premier; il est le seul produit a se former aprits des temps de reactions prolonges. Une partie du compose 12 peut aussi provenir d'un deplacement initial du brome conduisant au 5-[(2-aminoethyl)thio]-1-methyl-2-imidazole (14); toutefois, on ne peut pas observer sa formation a cause de la substitution rapide du groupe nitro. On...

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Electrophilic intermediate in the reactions of a 2-(hydroxyamino)imidazole. A model for biological effects of reduced nitroimidazoles

Cited by 53 publications

References 4 publications

Aryl Nitrenium Ions in Aqueous Solution

Aryl Nitrenium Ions in Aqueous Solution

4,5-Dihydro-4,5-dihydroxyimidazoles as products of the reduction of 2-nitroimidazoles. HPLC assay and demonstration of equilibrium transfer of glyoxal to guanine

Preparation and reactions of bromo-2-nitro- and bromo-2-aminoimidazoles

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