Total Synthesis of Nafuredin, a Selective NADH-fumarate Reductase Inhibitor

Takano, Daisuke; Nagamitsu, Tohru; Ui, Hideaki; Shiomi, Kazuro; Yamaguchi, Yuuichi; Masuma, Rokuro; Kuwajima, Isao; Ōmura, Satoshi

doi:10.1021/ol010089t

Cited by 55 publications

(31 citation statements)

References 19 publications

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“…Thus, complex II is indispensable for the survival of anaerobic parasitic eukaryotes and, therefore, is regarded as a good chemotherapeutic target for novel antihelmintics. In the course of screening microbial broths for inhibitors of the NADH-fumarate pathway, we isolated a previously uncharacterized compound, nafuredin (20,21). We determined that nafuredin is a selective inhibitor of helminth complex I (NADH-quinone oxidoreductase), and was an effective antihelmintic in animal trials (22).…”

mentioning

confidence: 99%

Atpenins, potent and specific inhibitors of mitochondrial complex II (succinate-ubiquinone oxidoreductase)

Miyadera

Shiomi²,

Ui³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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242

192

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Enzymes in the mitochondrial respiratory chain are involved in various physiological events in addition to their essential role in the production of ATP by oxidative phosphorylation. The use of specific and potent inhibitors of complex I (NADH-ubiquinone reductase) and complex III (ubiquinol-cytochrome c reductase), such as rotenone and antimycin, respectively, has allowed determination of the role of these enzymes in physiological processes. However, unlike complexes I, III, and IV (cytochrome c oxidase), there are few potent and specific inhibitors of complex II (succinate-ubiquinone reductase) that have been described. In this article, we report that atpenins potently and specifically inhibit the succinate-ubiquinone reductase activity of mitochondrial complex II. Therefore, atpenins may be useful tools for clarifying the biochemical and structural properties of complex II, as well as for determining its physiological roles in mammalian tissues. T he use of specific and potent inhibitors of respiration has enabled the investigation of how the respiratory enzymes function in physiological processes. However, unlike other enzyme complexes in the respiratory chain, there has been a lack of potent and specific inhibitors of complex II [succinateubiquinone reductase (SQR)]. Although carboxin (5,6-dihydro-2-methyl-N-phenyl-1,4-oxathiin-3-carboxamide), TTFA [4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedione], and HQNO (2-heptyl-4-hydroxyquinoline N-oxide) have long been known as complex II inhibitors and have been used extensively to elucidate the structure-function relationships of complex II, rather higher concentration is required for the inhibition (1). This result has hampered the study of the structure-function relationship of the complex II enzyme, as well as its roles in physiological processes.Complex II catalyzes the oxidation of succinate in the inner membrane of mitochondria and in the cytoplasmic membrane of bacteria (1-3). In addition to its function as a dehydrogenase in the respiratory system, complex II plays an important role in the tricarboxylic acid cycle. Mitochondrial complex II is an integral membrane protein consisting of four subunits (Fig. 1). The largest subunit is the 70-kDa, FAD-containing flavoprotein subunit (Fp). The dehydrogenase catalytic portion of complex II is formed by Fp and an Ϸ30-kDa iron-sulfur protein subunit (Ip) containing three different types of iron-sulfur clusters. The small hydrophobic subunits, SDHC or CybL (Ϸ15 kDa) and SDHD or CybS (Ϸ13 kDa), anchor the catalytic portion to the membrane and are also required for electron transfer to quinones. In contrast to mitochondrial complex IIs, some bacterial complex IIs contain only one larger hydrophobic polypeptide as a membrane anchor (see ref. 4 for reviews).In addition to its essential role in energy production, various recent findings suggest that mutant variants of complex II are involved in causing diverse physiological disorders. For instance, a mutation in the CybL subunit in Caenorhabditis elegans (mev-1 mutant) resu...

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mentioning

confidence: 99%

Atpenins, potent and specific inhibitors of mitochondrial complex II (succinate-ubiquinone oxidoreductase)

Miyadera

Shiomi²,

Ui³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

242

192

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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%

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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“…Alongside the high yields (up to 100%) of alkenes 62 the process is characterized by a high streoselectivity. Therefore compounds 61 were recently extensively used in Julia olefination instead of aryl and hetaryl sulfones [5,54] for stereoselective prepara-tion of naturally occurring compounds containing in their structure a fragment of trans-1,2-disubstituted alkene, for instance, Hennoxazole A [55], Herboxidiene [56], Thiazinotrienomycin E [57], Cylindrocyclophanes A and F [58], Zampanolide [59], Ambruticin [60], Laulimalide [61], Nafuredin [62], Callystatin A [63], Plakortone D [64], Brefeldin A [65], Lasonolide A [66,67], Amphidino-lide A [68], Zampanolide, Dactylolide…”

Section: N-tert-butyl-5-(2-bromophenyl)tetrazolementioning

confidence: 99%

Organometallic Tetrazole Derivatives: Preparation and Application to Organic Synthesis

2005

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Total Synthesis of Nafuredin, a Selective NADH-fumarate Reductase Inhibitor

Cited by 55 publications

References 19 publications

Atpenins, potent and specific inhibitors of mitochondrial complex II (succinate-ubiquinone oxidoreductase)

Atpenins, potent and specific inhibitors of mitochondrial complex II (succinate-ubiquinone oxidoreductase)

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

Organometallic Tetrazole Derivatives: Preparation and Application to Organic Synthesis

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