Chemistry of Pyrazino[2,1‐b]quinazoline‐3,6‐diones

Avendaño, Carmen; Menéndez, J. Carlos

doi:10.1002/chin.200328283

Cited by 1 publication

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“…The hydroxyindole reaction products produced by HbpA are reported to be unstable and spontaneously oxidize and dimerize to form pigments (44). Analogously, the presumed oxy-FQF intermediates 1 and 2 were not isolated during the course of experimentation; rather, the compounds isolated were from spontaneous reaction with water (3) or dimerization (4). With regard to modification of a pendant indole group as part of a more complex natural product, the oxidation at indole C2 of a bisindolepyrrolidone by VioC has been reported in the biosynthesis of violacein (45).…”

Section: Discussionmentioning

confidence: 99%

“…Filamentous fungi are prolific producers of bioactive secondary metabolites, including potent mycotoxins such as aflatoxin, ochratoxin, gliotoxin, and cyclopiazonic acid , and molecules of important therapeutic value such as the antibiotic cephalosporins/penicillins, immunosuppressant cyclosporins, and cholesterol-lowering statins. One class of fungal natural products consists of the quinazoline alkaloids , , a subclass of which are the fumiquinazolines (FQs) which possess a pyrazino[2,1- b ]quinazoline-3,6-dione core scaffold derived from condensation of anthranilic acid (Ant) with two additional amino acids (Figure S1 of the Supporting Information) .…”

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confidence: 99%

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Enzymatic Processing of Fumiquinazoline F: A Tandem Oxidative-Acylation Strategy for the Generation of Multicyclic Scaffolds in Fungal Indole Alkaloid Biosynthesis

2010

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Aspergillus fumigatus Af293 is a known producer of quinazoline natural products including the antitumor fumiquinazolines, of which the simplest member is fumiquinazoline F (FQF) with a 6-6-6 tricyclic core derived from anthranilic acid, tryptophan, and alanine. FQF is the proposed biological precursor to fumiquinazoline A (FQA) where the pendant indole side chain has been modified via oxidative coupling of an additional molecule of alanine, yielding a fused 6-5-5 imidazoindolone. We recently identified fungal anthranilate-activating non-ribosomal peptide synthetase (NRPS) domains through bioinformatics approaches. One domain previously identified is part of the trimodular NRPS Af12080, which we predict is responsible for FQF formation. We now show that two adjacent A. fumigatus ORFs, a monomodular NRPS Af12050 and a flavoprotein Af12060, are necessary and sufficient to convert FQF to FQA. Af12060 oxidizes the 2',3'-double bond of the indole side chain of FQF, and the three-domain NRPS Af12050 activates L-Ala as the adenylate, installs it as the pantetheinyl thioester on its carrier protein domain and acylates the oxidized indole for subsequent intramolecular cyclization to create the 6-5-5 imidazolindolone of FQA. This work provides experimental validation of the fumiquinazoline biosynthetic cluster of A. fumigatus A293, and describes an oxidative annulation biosynthetic strategy likely shared among several classes of polycyclic fungal alkaloids.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%