The Chemical Screening Approach

Grabley, Susanne; Thiericke, Ralf; Zeeck, Axel

doi:10.1007/978-3-642-60250-4_8

Cited by 27 publications

(25 citation statements)

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“…In the culture broth of Actinomyces sp. (strain Lu 9419), which was isolated from the intestines of a rose chafer (Cetonia aureata) we identified two novel aminocarba sugars, which were named cetoniacytone A (1) and B (2). Carba sugars and aminocarba sugars are widespread metabolites produced especially by actinomycetes.…”

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Structure and Biosynthesis of Cetoniacytone A, a Cytotoxic Aminocarba Sugar Produced by an Endosymbiontic Actinomyces.

et al. 2002

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Cetoniacytone A (1) and some related minor components (2, 6, 7) were produced by Actinomyces sp. (strain Lu 9419), which was isolated from the intestines of a rose chafer (Cetonia aureata). The structures of the novel metabolites were established by detailed spectroscopic analysis. The absolute configuration of 1 was determined by X-ray analysis and derivatisation with chiral acids. 1 exhibits a significant cytotoxicity against selected tumor cell lines. The biosynthesis of 1 was studied by feeding 13C labelled precursors. The results suggest that the characteristic p-C7N skeleton of the aminocarba sugar is formed via the pentose phosphate pathway by cyclisation of a heptulose phosphate intermediate.In the course of our screening program for new secondary metabolites2) we investigated endosymbionts, which were isolated from several members of Crustacea (wood-lice), Myriapoda (millipedes) and Hexapoda (insects)3). In the culture broth of Actinomyces sp. (strain Lu 9419), which was isolated from the intestines of a rose chafer (Cetonia aureata) we identified two novel aminocarba sugars, which were named cetoniacytone A (1) and B (2). Carba sugars and aminocarba sugars are widespread metabolites produced especially by actinomycetes. Many of their natural derivatives are biologically active, well known examples are validamycin A4) and acarbose5), both containing valienamine (3). Structurally related to the cetoniacytones are epoxyquinomicin C (4) and D (5), which were isolated from the culture broth of an Amycolatopsis sp6), They possess anti-arthritic effects on type II collagen-induced arthritis in mice7) and inhibited the histidine decarboxylase in rat embryos8).Different biosynthetic pathways leading to carbocyclic Additionally we report the structures of three novel minor components, cetoniacytone B (2) and two aromatic analogues (6, 7). Fermentation and IsolationActinomyces sp. (strain Lu 9419) was cultivated in shaking flasks, using oatmeal medium with sodium acetate described metabolites were only found in the culture filtrate, which was separated from the mycelium by centrifugation. The filtrate was passed through Amberlite(R) XAD-2, from which the metabolites were eluated with methanol. The evaporation residue was separated by successive column chromatography on silica gel and Sephadex LH-20 leading to 10-15mg/liter of cetoniacytone A (1). Besides 4.8mg/liter of 1a cultivation in absence of sodium acetate yielded 5.6mg/liter of cetoniacytone B (2). Addition of glucose (1g/liter) after 48 hours, when the production of 1 has just started, increased the yield of 1 to 20.25mg/liter. However, addition of glucose at the beginning of the fermentation had no influence on the yield of 1. A scale-up using a 50-liter stirring fermenter yielded 85mg of 1 and allowed the isolation of minor components: 34mg of 2, 5-dihydroxy-4-hydroxymethylacetanilide (6), 4.1mg of 2, 5-dihydroxy-4-methoxymethylacetanilide (7) and 9.4mg of 2-acetamido-phenol. All compounds are detectable on silica gel TLC-plates with UV light at 254nm ...

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Structure and Biosynthesis of Cetoniacytone A, a Cytotoxic Aminocarba Sugar Produced by an Endosymbiontic Actinomyces.

et al. 2002

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“…A detailed screening of the secondary metabolite pattern produced by different athropod associated strains of the species Streptomyces anulatus resulted in the isolation and structure elucidation of the endophenazines A-D (2,(4)(5)(6). The structures were assigned by spectroscopic methods and chemical transformations.…”

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Biosynthetic Capacities of Actinomysetes. No.27. Endophenazines A-D, New Phenazine Antibiotics from the Athropod Associated Endosymbiont Streptomyces anulatus. II. Structure Elucidation.

et al. 2002

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A detailed screening of the secondary metabolite pattern produced by different athropod associated strains of the species Streptomyces anulatus resulted in the isolation and structure elucidation of the endophenazines A-D (2, 4-6). The structures were assigned by spectroscopic methods and chemical transformations. 4 represents a chromophoric system based on a phenazin-7-one, 5 and 6 are new 5,10-dihydrophenazine derivatives.In the course of our screening for bioactive compounds from endosymbiontic microorganisms we investigated athropod associated microorganisms by analyzing their metabolite pattern. The extracts of Streptomyces anulatus (strains 9663, 9843, 9958 and 10099) were applied to our chemical screening programme2). HPTLC analysis resulted in five substances utilising their colour, UV absorption and colourization by Ehrlich's reagent. The substances were identified as phenazine derivatives.In the previous paper the taxonomy of Streptomyces anulatus as well as the fermentation, isolation and biological activities of the endophenazines have been described1). In this part we present the structure elucidation of these antibiotics mainly done by NMR analysis. Structure ElucidationPhenazine-1-carboxylic acid (1), isolated from the culture filtrate of the strain 9663, was identified by comparison of its spectroscopic data with the data given in the literature3,4). The UV spectrum of endophenazine A (2) is very similar to that of 1, indicating a further phenazine derivative. The 1H NMR spectrum shows six aromatic protons, their coupling pattern points to a 1,6-or 1,9-disubstituted phenazine skeleton. From the molecular formula (C13H8N2O2) and the data obtained from the NMR spectra a carboxyl and a C5-prenyl group can be derived as substituents. Due to a NOE between the acidic proton of the carboxyl and the methine group of the prenyl residue, the regiochemistry of the substituents was unambiguously

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“…Treatment of 249 with three primary amines (R 1 NH 2 ) yielded carbamates 250. For the incorporation of the second element of diversity (R 2 ) onto the spiroketal scaffold, the terminal olefin of 250 was previously converted to acid in three steps by osmylation, oxidative cleavage using Pb(OAc) 4 , and chlorite oxidation. The second diversity step was then accomplished using amide bond formation.…”

Section: Other Natural Productsmentioning

confidence: 99%

“…[1][2][3][4][5] Despite changing strategies in natural product research, in which concern sample selection and collection, isolation techniques, structure elucidation, biological evaluation, semisynthesis, dereplication, biosynthesis, as well as optimisation of downstream processing, 6,7 the rate of discovery of truly novel natural product drugs has actually decreased. 8 Reasons for this fact are related to high costs and time consuming of conventional programs in natural products, 9,10 which led to the exploitation of modern high-throughput screening and combinatorial strategies by the pharmaceutical industry, to generate new lead structures.…”

Section: Introductionmentioning

confidence: 99%

Natural Product‐Like Combinatorial Libraries

Abreu

Branco

2004

ChemInform

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A química combinatorial emergiu ao longo dos últimos anos como uma importante ferramenta na pesquisa de moléculas pioneiras para a modelagem de novos fármacos. Nesta perspectiva, a diversidade estrutural e a vasta gama de propriedades biológicas exibidas pelos metabolitos secundários, constituem um desafio à implementação de estratégias combinatórias na síntese e derivatização de produtos naturais. Este artigo ilustra a aplicação das técnicas combinatórias no desenho e formação de bibliotecas baseadas em produtos naturais de diversa origem biossintética, e seus análogos estruturais.Combinatorial chemistry has emerged over the last few years as an important tool for drug discovery and lead optimisation. In this approach, the molecular diversity and range of biological properties displayed by secondary metabolites constitutes a challenge to combinatorial strategies for natural products synthesis and derivatization. This article surveys the application of combinatorial techniques to the design of "natural product-looking" libraries covering a wide range of structural diversities.

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The Chemical Screening Approach

Cited by 27 publications

References 120 publications

Structure and Biosynthesis of Cetoniacytone A, a Cytotoxic Aminocarba Sugar Produced by an Endosymbiontic Actinomyces.

Structure and Biosynthesis of Cetoniacytone A, a Cytotoxic Aminocarba Sugar Produced by an Endosymbiontic Actinomyces.

Biosynthetic Capacities of Actinomysetes. No.27. Endophenazines A-D, New Phenazine Antibiotics from the Athropod Associated Endosymbiont Streptomyces anulatus. II. Structure Elucidation.

Natural Product‐Like Combinatorial Libraries

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