A γ-Lactone Form Nafuredin, Nafuredin-γ, also Inhibits Helminth Complex I

Shiomi, Kazuro; Ui, Hideaki; Suzuki, Hideaki; Hatano, Hiroko; Nagamitsu, Tohru; Takano, Daisuke; Miyadera, Haruo; Yamashita, Tetsuo; Kita, Kiyoshi; Miyoshi, Hideto; Harder, Achim; Tomoda, Hiroshi; Ōmura, Satoshi

doi:10.1038/ja.2005.5

Cited by 45 publications

(24 citation statements)

References 14 publications

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“…1 A total synthetic study of 1 subsequently identified a novel and structurally simpler γ-lactone compound, nafuredin-γ (2), which was generated from 1 under mild basic conditions. [4][5][6] Moreover, the nematode complex I inhibitory activity of 2 was identical to that of 1. Therefore, nafuredin (1) and nafuredin-γ (2) holds promise as a selective antiparasitic agent.…”

Section: Introductionmentioning

confidence: 74%

“…(( (2E,6E,10E) 7,11,6,10, sulfonyl)benzene (14) To a solution of geranyl geraniol (43.1 mg, 0.148 mmol) in Et 2 O (3.0 ml) at 0°C was added PBr 3 (7 μl, 0.0742 mmol). After stirring for 2 h at 0°C, the resulting mixture was quenched with cold water and the aqueous phase was extracted with a 1:1 Et 2 O:hexane mixture.…”

Section: (R)-5-methyl-1-((s)-2-methyltetrahydrofuran-2-yl)hex-4-en-1-mentioning

confidence: 99%

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Development of a new air-stable structure-simplified nafuredin-γ analog as a potent and selective nematode complex I inhibitor

et al. 2017

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Nafuredin-γ, obtained from natural nafuredin, has demonstrated a potent and selective inhibitory activity against nematode complex I. However, nafuredin-γ is unstable in air since its conjugated dienes are oxygen-labile. The instability in air was naturally solved by the synthesis of structure-simplified nafuredin-γ analogs without conjugated dienes. However, these modified analogs showed lower complex I inhibitory activities. Therefore, new air-stable structure-simplified nafuredin-γ analogs were designed and synthesized herein. Among all analogs synthesized, the one bearing a unique 1-azabicyclo[3.1.0]hexane scaffold showed the highest inhibitory activity (IC 50 = 170 nM) while presenting high selectivity against nematode complex I.

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Section: Introductionmentioning

confidence: 74%

Section: (R)-5-methyl-1-((s)-2-methyltetrahydrofuran-2-yl)hex-4-en-1-mentioning

confidence: 99%

Development of a new air-stable structure-simplified nafuredin-γ analog as a potent and selective nematode complex I inhibitor

et al. 2017

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“…as an inhibitor of acyl-CoA: cholesterol acyl transferase (ACAT) [14]. There is a closer structural resemblance, at least in size, if not in oxidation state to nafuredin-g , a degradation product of another fungal metabolite from Aspergillus niger FT-0554, and shown to selectively inhibit helminth NADH-fumarate reductase [15]. Perhaps the closest structural relatives are the aurafurons A, EB and ZB isolated from the myxobacteria Stigmatella aurantiaca and Archangium gephyra [16].…”

Section: Resultsmentioning

confidence: 99%

Isolation and Identification of Three New 5-Alkenyl-3,3(2H)-furanones from Two Streptomyces species using a Genomic Screening Approach

et al. 2006

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Analyses of biosynthetic gene clusters derived from Streptomyces aculeolatus NRRL 18422 and Streptomyces sp. Eco86 indicated that both microorganisms have similar type I polyketide synthase (PKS) gene clusters with relatively few genes encoding post-PKS elaborative enzymes. However both gene clusters included a sequence coding for a relatively uncommon oxidative enzyme related to Baeyer-Villiger, flavin-type monooxygenases. Screening of culture extracts for compounds with the predicted physicochemical properties of the end products from these loci, led to the isolation of three 5-alkenyl-3,3(2H)-furanones, one (E-837, 1) from the former and two (E-492, 2, E-975, 3) from the latter strain. The structures, confirmed by spectral analyses including MS, and 1D and 2D NMR experiments, were in accord with those predicted by genomic analyses. Baeyer-Villiger type oxidation is postulated to be involved in the formation of the furanone moieties in these molecules. All three new compounds were tested for their electron transport inhibitory activities. They had IC 50 values of 1ϳ4 mg/ml against Ascaris suum NADH-fumarate reductase and 1ϳ12 mg/ml against bovine heart NADH oxidase.Keywords Streptomyces aculeolatus, Streptomyces sp., E-837, E-492, E-975, Baeyer-Villiger monooxygenase IntroductionNatural products play an important role in drug discovery and have been used for the treatment of various diseases for decades. They constitute a leading source of novel molecules for the development of new drug candidates to treat life threatening infections and other human disorders [1]. To identify such potential drug candidates from nature, different methods have been developed and routinely used in natural product discovery laboratories. The genomics of secondary metabolite biosynthesis has recently evolved to the point where analysis of the genome of an organism can define its secondary metabolic capabilities. A genome scanning technique has been developed in our laboratories to greatly reduce the amount of sequencing required to define this capability [2,3]. This approach not only ascertains the potential of a producing organism, but it provides the scientist with a handle to identify, isolate and structurally define a specific metabolite. We have demonstrated this approach in the isolation and structural determination of an antifungal agent, ECO-02301 from Streptomyces aizunensis [4].In our continuing effort to find novel secondary metabolites from actinomycetes, we observed that two different streptomycetes, Streptomyces aculeolatus NRRL 18422 (a producer of the semi-naphthaquinone antibiotic, [5] and Streptomyces sp. Eco86 (a proprietary Ecopia strain) had similar gene clusters for type I polyketides with relatively few post-polyketide elaborative enzymes, but including an uncommon Baeyer-Villiger type monooxygenase. Analyses of these gene clusters led us to conclude that these microorganisms produce members of a group of very closely related secondary metabolites. Here, we report the isolation and identification of...

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“…NFRD activity was measured as described previously [24]. The other enzyme assays were performed as described previously [4].…”

Section: Biological Studiesmentioning

confidence: 99%

Paecilaminol, a New NADH-Fumarate Reductase Inhibitor, Produced by Paecilomyces sp. FKI-0550

Shiomi

Suzuki

et al. 2006

J Antibiot

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A γ-Lactone Form Nafuredin, Nafuredin-γ, also Inhibits Helminth Complex I

Cited by 45 publications

References 14 publications

Development of a new air-stable structure-simplified nafuredin-γ analog as a potent and selective nematode complex I inhibitor

Development of a new air-stable structure-simplified nafuredin-γ analog as a potent and selective nematode complex I inhibitor

Isolation and Identification of Three New 5-Alkenyl-3,3(2H)-furanones from Two Streptomyces species using a Genomic Screening Approach

Paecilaminol, a New NADH-Fumarate Reductase Inhibitor, Produced by Paecilomyces sp. FKI-0550

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