Stereoselective Synthesis of Tilivalline<sup>1</sup>

Nagasaka, Tatsuo; Koseki, Yuji

doi:10.1021/jo972158g

Cited by 26 publications

(14 citation statements)

References 18 publications

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“…CID spectra from the [M + H + ] + ion included fragments characteristic of tilivalline at m/z = 316.1454, 219.109, 199.1237, and 136.040 (Figure S3). The proton NMR spectrum (Figure S4) from a culture isolate, while weak due to the small amount of material, was also consistent with that reported for tilivalline [42]. Consistent with previous reports, tilivalline (1 µg/ml) induced cell abnormalities and death in HEp-2 cells (Figure 5).…”

Section: Resultssupporting

confidence: 90%

Cytotoxic and Pathogenic Properties of Klebsiella oxytoca Isolated from Laboratory Animals

et al. 2014

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Klebsiella oxytoca is an opportunistic pathogen implicated in various clinical diseases in animals and humans. Studies suggest that in humans K. oxytoca exerts its pathogenicity in part through a cytotoxin. However, cytotoxin production in animal isolates of K. oxytoca and its pathogenic properties have not been characterized. Furthermore, neither the identity of the toxin nor a complete repertoire of genes involved in K. oxytoca pathogenesis have been fully elucidated. Here, we showed that several animal isolates of K. oxytoca, including the clinical isolates, produced secreted products in bacterial culture supernatant that display cytotoxicity on HEp-2 and HeLa cells, indicating the ability to produce cytotoxin. Cytotoxin production appears to be regulated by the environment, and soy based product was found to have a strong toxin induction property. The toxin was identified, by liquid chromatography-mass spectrometry and NMR spectroscopy, as low molecular weight heat labile benzodiazepine, tilivalline, previously shown to cause cytotoxicity in several cell lines, including mouse L1210 leukemic cells. Genome sequencing and analyses of a cytotoxin positive K. oxytoca strain isolated from an abscess of a mouse, identified genes previously shown to promote pathogenesis in other enteric bacterial pathogens including ecotin, several genes encoding for type IV and type VI secretion systems, and proteins that show sequence similarity to known bacterial toxins including cholera toxin. To our knowledge, these results demonstrate for the first time, that animal isolates of K. oxytoca, produces a cytotoxin, and that cytotoxin production is under strict environmental regulation. We also confirmed tilivalline as the cytotoxin present in animal K. oxytoca strains. These findings, along with the discovery of a repertoire of genes with virulence potential, provide important insights into the pathogenesis of K. oxytoca. As a novel diagnostic tool, tilivalline may serve as a biomarker for K oxytoca-induced cytotoxicity in humans and animals through detection in various samples from food to diseased samples using LC-MS/MS. Induction of K. oxytoca cytotoxin by consumption of soy may be in part involved in the pathogenesis of gastrointestinal disease.

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Section: Resultssupporting

confidence: 90%

Cytotoxic and Pathogenic Properties of Klebsiella oxytoca Isolated from Laboratory Animals

et al. 2014

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“…eapokensis could serve as a starting point for biotechnologically produced PBDs with varying substitution in PBD A-ring, as demonstrated for tomaymycin [ 21 ] and sibiromycin [ 37 , 43 ]. Furthermore, enzyme catalyzed PBD synthesis is stereoselective and avoids the use of toxic chemicals in contrast to chemical PBD synthesis [ 44 ]. Substituted PBDs for their part, can serve as monomeric [ 45 ] or dimeric [ 46 ] building blocks for antibody payloads in antineoplastic chemotherapeutics due to their cytotoxic properties.…”

Section: Discussionmentioning

confidence: 99%

The benzodiazepine-like natural product tilivalline is produced by the entomopathogenic bacterium Xenorhabdus eapokensis

Wolff

Bode

2018

PLoS ONE

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The pyrrolobenzodiazepine tilivalline (1) was originally identified in the human gut pathobiont Klebsiella oxytoca, the causative agent of antibiotic-associated hemorrhagic colitis. Here we show the identification of tilivalline and analogs thereof in the entomopathogenic bacterium Xenorhabdus eapokensis as well as the identification of its biosynthesis gene cluster encoding a bimodular non-ribosomal peptide synthetase. Heterologous expression of both genes in E. coli resulted in the production of 1 and from mutasynthesis and precursor directed biosynthesis 11 new tilivalline analogs were identified in X. eapokensis. These results allowed the prediction of the tilivalline biosynthesis being similar to that in K. oxytoca.

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“…In the other hand, Nagasaka (44) reported isomeric mixture of benzoxazinediones from the reaction of non-symmetric phthalic anhydrides with TMSA. We observed this same effect for phthalic anhydrides substituted in 3-or 4-position ( Table 3) due to that the azide nucleophilic attack can take place on either of the anhydride carbonyls.…”

Section: Resultsmentioning

confidence: 99%

Microwave-assisted synthesis of benzoxazinediones under solvent-free conditions

Sarmiento-Sánchez

Ochoa-Terán

Picos-Corrales

et al. 2016

Green Chemistry Letters and Reviews

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Benzoxazinediones exhibit potential as versatile synthons in the synthesis of wide variety of heterocyclic compounds with biological activity. In this work, an efficient and eco-friendly onestep synthesis of benzoxazine-2,4-diones from phthalic anhydrides derivatives and trimethylsilyl azide using the microwave technique was developed and compared with conventional heating. Microwave irradiation plays a critical role in driving the reaction and providing access to products and/or regioisomers not available from conventional heating. Thus, the regioselectivity of the reaction may be modulated by the irradiation time. Depending on the method employed the benzoxazinediones were isolated with yields in the range of 30-90%.

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Stereoselective Synthesis of Tilivalline¹

Cited by 26 publications

References 18 publications

Cytotoxic and Pathogenic Properties of Klebsiella oxytoca Isolated from Laboratory Animals

Cytotoxic and Pathogenic Properties of Klebsiella oxytoca Isolated from Laboratory Animals

The benzodiazepine-like natural product tilivalline is produced by the entomopathogenic bacterium Xenorhabdus eapokensis

Microwave-assisted synthesis of benzoxazinediones under solvent-free conditions

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Stereoselective Synthesis of Tilivalline1

Cited by 26 publications

References 18 publications

Cytotoxic and Pathogenic Properties of Klebsiella oxytoca Isolated from Laboratory Animals

Cytotoxic and Pathogenic Properties of Klebsiella oxytoca Isolated from Laboratory Animals

The benzodiazepine-like natural product tilivalline is produced by the entomopathogenic bacterium Xenorhabdus eapokensis

Microwave-assisted synthesis of benzoxazinediones under solvent-free conditions

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Product

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Stereoselective Synthesis of Tilivalline¹