Oxygenase model reactions.  1.  Intra- and extradiol oxygenations of 3,5-di-tert-butylcatechol catalyzed by (bipyridine)(pyridine)iron(III) complex

Funabiki, Takuzo; Mizoguchi, Akira; Sugimoto, T.; Tada, Satoru; Tsuji, Minori; Sakamoto, Hirotoshi; Yoshida, Satohiro

doi:10.1021/ja00271a022

Cited by 159 publications

(86 citation statements)

References 3 publications

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“…The formation of M5 could be initiated from M2, followed by spontaneous enzymatic dehydration and ring cyclization. Funabiki et al (1986) demonstrated several oxygenase model reactions using 3,5-ditert-butylcatechol as a probe compound. The studied compound was oxygenated with insertion of molecular oxygen to give intra-and extradiol oxygenation intermediates, which further produced pyrone products through eliminating a carbonyl group.…”

Section: Miao Et Almentioning

confidence: 99%

Identification of the in Vitro Metabolites of 3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; β-Lapachone) in Whole Blood

Miao¹,

Song²,

Savage³

et al. 2008

Drug Metab Dispos

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ABSTRACT:3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; ␤-lapachone) showed promising anticancer activity in phase I clinical trials as monotherapy and in combination with cytotoxic drugs. ARQ 501 is currently in multiple phase II clinical trials. In vitro incubation in fresh whole blood at 37°C revealed that ARQ 501 is stable in plasma but disappears rapidly in whole blood. Our data showed that extensive metabolism in red blood cells (RBCs) was mainly responsible for the rapid disappearance of ARQ 501 in whole blood. By comparison, covalent binding of ARQ 501 and/or its metabolites to whole blood components was a minor contributor to the disappearance of this compound. Sequestration of intact ARQ 501 in RBCs was not observed. Cross-species metabolite profiles from incubating [ 14 C]ARQ 501 in freshly drawn blood were characterized using a liquid chromatography-mass spectrometry-accurate radioactivity counter. The results show that ARQ 501 was metabolized more rapidly in mouse and rat blood than in dog, monkey, and human blood, with qualitatively similar metabolite profiles. Six metabolites were identified in human blood using ultra-high performance liquid chromatography/time-of-flight mass spectrometry, and the postulated structure of five metabolites was confirmed using synthetic standards. We conclude that the primary metabolic pathway of ARQ 501 in human blood involved oxidation of the two adjacent carbonyl groups to produce dicarboxylic and monocarboxylic metabolites, elimination of a carbonyl group to form a ring-contracted metabolite, and lactonization to produce two metabolites with a pyrone ring to form a ring-contracted metabolite. Metabolism by RBCs may play a role in clearance of ARQ 501 from the blood compartment in cancer patients.

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Section: Miao Et Almentioning

confidence: 99%

Identification of the in Vitro Metabolites of 3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; β-Lapachone) in Whole Blood

Miao¹,

Song²,

Savage³

et al. 2008

Drug Metab Dispos

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“…The phenomenon of thermal spin crossover was also observed for a set of close analogues of the above compound, both in the solid state [5,6] as well as in solution. [7] As far as the intradiol cleavage activity is concerned, Que and co-workers [8] and others [9,10] have shown that there is a strong correlation between the reactivity in the presence of dioxygen and the radical character of the catecholate substrate as a ligand. The analysis of the intersite interaction was based on the comparison of the energies of the corresponding ligand-to-metal charge-transfer (LMCT) transitions localized in the NIR-visible range.…”

Section: Introductionmentioning

confidence: 99%

Photoexcitation and Relaxation Dynamics of Catecholato–Iron(III) Spin‐Crossover Complexes

et al. 2006

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“…35 Recent growing interest has been shifted towards the extradiol-cleaving catechol dioxygenase and their model complexes and several small molecule analogues [36][37][38][39][40][41][42][43][44] have been isolated and studied to get insight into the reaction mechanism of catechol cleavage. Earlier Funabiki et al 37 reported the first model by using FeCl 2 /FeCl 3 with pyridine/bipyridine mixture. Later Die et al 38 found that [Fe(TACN)(DBC)Cl] (TACN = 1,4,7-triazacyclononane), upon exposure to molecular oxygen, yielded 35% of the extradiol product substituted 2-pyrones.…”

Section: Introductionmentioning

confidence: 99%

Mononuclear non-heme iron(III) complexes of linear and tripodal tridentate ligands as functional models for catechol dioxygenases: Effect of N-alkyl substitution on regioselectivity and reaction rate

Palaniandavar

Visvaganesan

2011

J Chem Sci

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Catechol dioxygenases are responsible for the last step in the biodegradation of aromatic molecules in the environment. The iron(II) active site in the extradiol-cleaving enzymes cleaves the C-C bond adjacent to the hydroxyl group, while the iron(III) active site in the intradiol-cleaving enzymes cleaves the C-C bond in between two hydroxyl groups. A series of mononuclear iron(III) complexes of the type [Fe(L)Cl 3 ], where L is the linear N -alkyl substituted bis(pyrid-2-ylmethyl)amine, N -alkyl substituted N -(pyrid-2-ylmethyl)ethylenediamine, linear tridentate 3N ligands containing imidazolyl moieties and tripodal ligands containing pyrazolyl moieties have been isolated and studied as structural and functional models for catechol dioxygenase enzymes. All the complexes catalyse the cleavage of catechols using molecular oxygen to afford both intra-and extradiol cleavage products. The rate of oxygenation depends on the solvent and the Lewis acidity of iron(III) center as modified by the sterically demanding N -alkyl groups. Also, our studies reveal that stereo-electronic factors like the Lewis acidity of the iron(III) center and the steric demand of ligands, as regulated by the N -alkyl substituents, determine the regioselectivity and the rate of dioxygenation. In sharp contrast to all these complexes, the pyrazole-containing tripodal ligand complexes yield mainly the oxidized product benzoquinone.

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Oxygenase model reactions. 1. Intra- and extradiol oxygenations of 3,5-di-tert-butylcatechol catalyzed by (bipyridine)(pyridine)iron(III) complex

Cited by 159 publications

References 3 publications

Identification of the in Vitro Metabolites of 3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; β-Lapachone) in Whole Blood

Identification of the in Vitro Metabolites of 3,4-Dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ARQ 501; β-Lapachone) in Whole Blood

Photoexcitation and Relaxation Dynamics of Catecholato–Iron(III) Spin‐Crossover Complexes

Mononuclear non-heme iron(III) complexes of linear and tripodal tridentate ligands as functional models for catechol dioxygenases: Effect of N-alkyl substitution on regioselectivity and reaction rate

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