Biomimetic synthesis of the IDO inhibitors exiguamine A and B

Volgraf, Matthew; Lumb, Jean‐Philip; Brastianos, Harry C.; Carr, Gavin; Chung, Marco K.W.; Münzel, Martin; Mauk, A. Grant; Andersen, Raymond J.; Trauner, Dirk

doi:10.1038/nchembio.107

Cited by 61 publications

(40 citation statements)

References 19 publications

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“…We define a natural product as a compound that is present within or in the immediate vicinity of the producing organism. As such, many compounds that are spontaneously formed from reactive intermediates, for instance via cascade reactions [29][30][31][32][33][34] , can indeed be classified as natural products. Our hypothetical starting material O-Methyl bipinnatin J (7), however, has been suspected to be an isolation artefact as methanolysis of bipinnatin J (1) and of kallolide (2) is a very facile process 18 .…”

Section: Discussionmentioning

confidence: 99%

Photochemical formation of intricarene

et al. 2014

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Sunlight is the ultimate driver of biosynthesis but photochemical steps late in biosynthetic pathways are very rare. They appear to play a role in the formation of certain furanocembranoids isolated from Caribbean corals. One of these compounds, intricarene, has been suspected to arise from an intramolecular 1,3-dipolar cycloaddition involving an oxidopyrylium. Here we show, by a combination of experiments and theory, that the oxidopyrylium forms under photochemical conditions and that its cycloaddition occurs via a triplet state. The formation of a complex by-product can be rationalized by another photochemical step that involves a conical intersection. Our work raises the question whether intricarene is biosynthesized in the natural habitat of the corals or is an artefact formed during workup. It also demonstrates that the determination of exact irradiation spectra, in combination with quantum chemical calculations, enables the rationalization of complex reaction pathways that involve multiple excited states.

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Section: Discussionmentioning

confidence: 99%

Photochemical formation of intricarene

et al. 2014

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“…Until recently, the majority of IDO inhibitors showed enzyme affinities in the micromolar range and were derived from metabolites of tryptophan (eg, 1-MT) and b-carbolines (Rohrig et al, 2010). Nevertheless, more potent (nanomolar range) IDO inhibitors have been identified in extracts from marine invertebrates and screening of the NCI Diversity Set Library (Volgraf et al, 2008;Rohrig et al, 2010;Di Pucchio et al, 2010). In addition, elaboration of the crystal structure of human IDO has paved the way for the in silico design of new IDO inhibitors (Rohrig et al, 2010).…”

Section: Neurotransmitter Targetsmentioning

confidence: 99%

Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior

Haroon

Raison

Miller

2011

Neuropsychopharmacol

822

596

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The potential contribution of chronic inflammation to the development of neuropsychiatric disorders such as major depression has received increasing attention. Elevated biomarkers of inflammation, including inflammatory cytokines and acute-phase proteins, have been found in depressed patients, and administration of inflammatory stimuli has been associated with the development of depressive symptoms. Data also have demonstrated that inflammatory cytokines can interact with multiple pathways known to be involved in the development of depression, including monoamine metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits relevant to mood regulation. Further understanding of mechanisms by which cytokines alter behavior have revealed a host of pharmacologic targets that may be unique to the impact of inflammation on behavior and may be especially relevant to the treatment and prevention of depression in patients with evidence of increased inflammation. Such targets include the inflammatory signaling pathways cyclooxygenase, p38 mitogen-activated protein kinase, and nuclear factor-kB, as well as the metabolic enzyme, indoleamine-2,3-dioxygenase, which breaks down tryptophan into kynurenine. Other targets include the cytokines themselves in addition to chemokines, which attract inflammatory cells from the periphery to the brain. Psychosocial stress, diet, obesity, a leaky gut, and an imbalance between regulatory and pro-inflammatory T cells also contribute to inflammation and may serve as a focus for preventative strategies relevant to both the development of depression and its recurrence. Taken together, identification of mechanisms by which cytokines influence behavior may reveal a panoply of personalized treatment options that target the unique contributions of the immune system to depression.

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“…[3] In der Natur kommen die Exiguamine als Racemate vor und enthalten als Schlüsselelement ein spirobicyclisches N,O-Acetal. Die Variecolortide (1 a-c) haben daher als kürzlich entdeckte Familie racemischer N,O-Acetale unser Interesse geweckt.…”

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Kompakte Totalsynthese von Variecolortid A und B durch eine ungewöhnliche Hetero‐Diels‐Alder‐Reaktion

2010

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Besondere Alkaloide aus Pilzen, die Variecolortide, scheinen eine Kombination aus bestimmten Anthrachinonen und Diketopiperazinen zu sein. Eine neue, kompakte Totalsynthese der Variecolortide A und B ergibt die natürlichen Racemate in beinahe schutzgruppenfreier und hoch konvergenter Weise. Sie verläuft über eine Hetero‐Diels‐Alder‐Reaktion eines 1,4‐Anthrachinons mit einem Didehydrodiketopiperazin zum Aufbau des spirocyclischen Kerns.

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Biomimetic synthesis of the IDO inhibitors exiguamine A and B

Cited by 61 publications

References 19 publications

Photochemical formation of intricarene

Photochemical formation of intricarene

Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior

Kompakte Totalsynthese von Variecolortid A und B durch eine ungewöhnliche Hetero‐Diels‐Alder‐Reaktion

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