Dye-sensitized photooxygenation of tyrptophan: 3a-Hydroperoxypyrroloindole as a labile precursor of formylkynurenine.

Nakagawa, Masako; Kato, Shiro; Kataoka, Sho; Kodato, Shinichi; Watanabe, Hideyuki; Okajima, Hideo; Hino, Tohru; Witkop, Bernhard

doi:10.1248/cpb.29.1013

Cited by 58 publications

(84 citation statements)

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“…(20) The compound was isolated as a mixture of two diastereoisomers in a ratio of 2:1, and the structure confirmed by NMR analysis (see SI). Both isomers have a cis- 5,5-ring junction with the major isomer having a cis -relationship between the hydroxyl and carboxylic acid groups (these assignments were confirmed by NOE experiments).…”

Section: Resultsmentioning

confidence: 89%

The Mechanism of Formation ofN-Formylkynurenine by Heme Dioxygenases

et al. 2011

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Heme dioxygenases catalyze the oxidation of l-tryptophan to N-formylkynurenine (NFK), the first and rate-limiting step in tryptophan catabolism. Although recent progress has been made on early stages in the mechanism, there is currently no experimental data on the mechanism of product (NFK) formation. In this work, we have used mass spectrometry to examine product formation in a number of dioxygenases. In addition to NFK formation (m/z = 237), the data identify a species (m/z = 221) that is consistent with insertion of a single atom of oxygen into the substrate during O2-driven turnover. The fragmentation pattern for this m/z = 221 species is consistent with a cyclic amino acetal structure; independent chemical synthesis of the 3a-hydroxypyrroloindole-2-carboxylic acid compound is in agreement with this assignment. Labeling experiments with 18O2 confirm the origin of the oxygen atom as arising from O2-dependent turnover. These data suggest that the dioxygenases use a ring-opening mechanism during NFK formation, rather than Criegee or dioxetane mechanisms as previously proposed.

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Section: Resultsmentioning

confidence: 89%

The Mechanism of Formation ofN-Formylkynurenine by Heme Dioxygenases

et al. 2011

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“…Significant variations of the reaction pathways and product distribution in dependence of the pH of the reaction were observed [40][41]. 2 Wenkert had postulated that the pyrroloquinoline moiety of the natural product and clinically relevant anti-leucemia drug camptothecin (99) is biosynthetically formed by oxidation of a corresponding carboline derivative and subsequent Camps reaction [42].…”

Section: Oxidation With Singlett Oxygenmentioning

confidence: 99%

The Witkop-Winterfeldt-Oxidation of Indoles

Mentel¹,

Breinbauer

2007

COC

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In the early 1950s Witkop described in a series of papers that oxidation of indoles with a variety of oxidation reagents leads to the formation of quinolones. The mechanism of this reaction involves the oxidative cleavage of the 2,3-double bond of the indole moiety (Witkop-oxidation) followed by a Camps-cyclization forming the quinolone ring. Winterfeldt identified conditions which allow a one pot Witkop-oxidation/Camps-cyclization sequence and applied this strategy for the synthesis of pyrrolo[2,3-c]quinolones starting from 1,2,3,4-tetrahydro--carbolines. This review gives a comprehensive description of all described examples of this reaction including a definition of scope and limitations and a discussion of the mechanism of this transformation.

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“…Later, Agozzino et al (2003) showed that this structure was not correct, because it was not compatible with the 13 C-NMR and that the metabolite had structure 4. Chemical oxidation of tryptophan to the tricyclic product 6 can be achieved by various methods, including oxidation with peroxoacetic acid (Savige W 1975), by photooxidation followed by reduction (Nakagawa et al, 1981), by horseradish peroxidase (Nguyen et al, 1986a), or electrochemically (Nguyen et al, 1986b), and its 13 C-NMR has been described (Yang et al, 2003). Furthermore, the tricyclic moiety is quite common in natural products, e.g., brevianamide E (13), which belongs, together with the paraherquamides, to an unusual class of prenylated indole-derived alkaloids produced by Penicillium sp.…”

Section: Discussionmentioning

confidence: 99%

Biocatalytic Synthesis and Structure Elucidation of Cyclized Metabolites of the Deacetylase Inhibitor Panobinostat (LBH589)

Fredenhagen

Kittelmann²,

Oberer³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Panobinostat (LBH589) is a novel pan-deacetylase inhibitor that is currently being evaluated in phase III clinical trials for treatment of Hodgkin's lymphoma and multiple myeloma. Under catalysis of recombinant human CYP3A4 and CYP2D6 coexpressed with human cytochrome P450 reductase in Escherichia coli JM109, five metabolites of panobinostat were produced via whole-cell biotransformation. The structures of the metabolites were elucidated with the spectroscopic methods mass spectrometry (MS) and NMR and revealed an oxidative cyclization of the ethyl-amino group to the methylindole moiety. The MS 2 spectrum of the cyclized metabolite showed a base peak, where the closed ring is reopened and that, taken as sole base for structure proposals, would have lead to wrong conclusions. The metabolites were substantially less potent deacetylase inhibitors than the parent compound.

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Dye-sensitized photooxygenation of tyrptophan: 3a-Hydroperoxypyrroloindole as a labile precursor of formylkynurenine.

Cited by 58 publications

References 1 publication

The Mechanism of Formation ofN-Formylkynurenine by Heme Dioxygenases

The Mechanism of Formation ofN-Formylkynurenine by Heme Dioxygenases

The Witkop-Winterfeldt-Oxidation of Indoles

Biocatalytic Synthesis and Structure Elucidation of Cyclized Metabolites of the Deacetylase Inhibitor Panobinostat (LBH589)

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