Abstract
A new NADH-fumarate reductase inhibitor, verticipyrone, was isolated from the cultured broth of a fungus, Verticillium sp. FKI-1083. The structure was established as (E)-2-methoxy-3,5-dimethyl-6-(3-methyl-2-undecenyl)-4H-pyran-4-one. Verticipyrone exhibited an IC50 value of 0.88 nM against NADH-fumarate reductase of Ascaris suum. Verticipyrone inhibited both Ascaris and bovine heart complex I, and its synthetic analogue, 8,9-dihydro-8-hydroxyverticipyrone, showed good selectivity against Ascaris complex I.
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References
Komuniecki R, Tielens AGM . Carbohydrate and energy metabolism in parasitic helminths. In: Marr JJ, et al. (eds). Molecular Medical Parasitology. Academic Press, London, pp. 339–358 ( 2003)
Kita K, Nihei C, Tomitsuka E . Parasite mitochondria as drug target: diversity and dynamic changes during the life cycle. Curr Med Chem 10: 2535–2548 ( 2003)
Ōmura S, Miyadera H, Ui H, Shiomi K, Yamaguchi Y, Masuma R, Nagamitsu T, Takano D, Sunazuka T, Harder A, Kölbl H, Namikoshi M, Miyoshi H, Sakamoto K, Kita K . An anthelmintic compound, nafuredin, shows selective inhibition of complex I in helminth mitochondria. Proc Natl Acad Sci USA 98: 60–62 ( 2001)
Ui H, Shiomi K, Yamaguchi Y, Masuma R, Nagamitsu T, Takano D, Sunazuka T, Namikoshi M, Ōmura S . Nafuredin, a novel inhibitor of NADH-fumarate reductase, produced by Aspergillus niger FT-0554. J Antibiot 54: 234–238 ( 2001)
Miyadera H, Shiomi K, Ui H, Yamaguchi Y, Masuma R, Tomoda H, Miyoshi H, Osanai A, Kita K, Ōmura S . Atpenins, potent and specific inhibitors of mitochondrial complex II (succinate-ubiquinone oxidoreductase). Proc Natl Acad Sci USA 100: 473–477 ( 2003)
Ui H, Shiomi K, Suzuki H, Hatano H, Morimoto H, Yamaguchi Y, Masuma R, Sakamoto K, Kita K, Miyoshi H, Tomoda H, Tanaka H, Ōmura S . Paecilaminol, a new NADH-fumarate reductase inhibitor, produced by Paecilomyces sp. FKI-0550. J Antibiot 59: 591–596 ( 2006)
Ōmura S, Shiomi K, Masuma R . Novel substance FKI-1083 and process for producing the same. PCT Int Appl, WO/2003/050104, June 19 ( 2003)
Yano K, Yokoi K, Sato J, Oono J, Kouda T, Ogawa Y, Nakashima T . Actinopyrones A, B and C, new physiologically active substances. I. Producing organism, fermentation, isolation and biological properties. J Antibiot 39: 32–37 ( 1986)
Yano K, Yokoi K, Sato J, Oono J, Kouda T, Ogawa Y, Nakashima T . Actinopyrones A, B and C, new physiologically active substances. II. Physico-chemical properties and chemical structures. J Antibiot 39: 38–43 ( 1986)
Maeda K . Chemical studies on antibiotic substances, IV. A crystalline toxic substance of Streptomyces thioluteus producing aureothricin. J Antibiot A 6: 137–138 ( 1953)
Hirata Y, Nakata H, Yamada K, Okuhara K, Naito T . The structure of aureothin, a nitro compound obtained from Streptomyces thioluteus. Tetrahedron 14: 252–274 ( 1961)
Friedrich T, Van Heek P, Leif H, Ohnishi T, Forche E, Kunze B, Jansen R, Trowitzsch-Kienast W, Höfle G, Reichenbach H, Weiss H . Two binding sites of inhibitors in NADH: ubiquinone oxidoreductase (complex I). Relationship of one site with the ubiquinone-binding site of bacterial glucose: ubiquinone oxidoreductase. Eur J Biochem 219: 691–698 ( 1994)
Cassinelli G, Grein A, Orezzi P, Pennella P, Sanfilippo A . New antibiotics produced by Streptoverticillium orinoci, n. sp. Arch Mikrobiol 55: 358–368 ( 1967)
Cardani C, Ghiringhelli D, Selva A, Arcamone F, Camerino B, Cassinelli G . The structure of neoaureothin. Chim Ind 52: 793–794 ( 1970)
Kakinuma K, Hanson CA, Rinehart KL Jr . Spectinabilin, a new nitro-containing metabolite isolated from Streptomyces spectinabilis. Tetrahedron 32: 217–222 ( 1976)
Graber MA, Gerwick WH . Kalkipyrone, a toxic γ-pyrone from an assemblage of the marine cyanobacteria Lyngbya majuscula and Tolypothrix sp. J Nat Prod 61: 677–680 ( 1998)
Zdero C, Bohlmann F, King RM, Robinson H . Pyrone derivatives from Podolepis hieracioides and sesquiterpene acids from Cassinia longifolia. Phytochemistry 26: 187–190 ( 1987)
Jaensch M, Jakupovic J, King RM, Robinson H . Pyrones and other constituents from Podolepis species. Phytochemistry 28: 3497–3501 ( 1989)
Kanazawa T, Ohkawa Y, Kuda T, Minobe Y, Tani T, Nishizawa M . γ-Pyrones from Gonystylus keitheii, as new inhibitors of parathyroid hormone (PTH)-induced Ca release from neonatal mouse calvaria. Chem Pharm Bull 45: 1046–1051 ( 1997)
Barlow L, Pattenden G . Synthesis of poly-Z-isomers of 2,6,11,15-tetramethylhexadeca-2,6,8,10,14-pentaene, a C20 analogue of phytoene. Re-examination of the stereochemistry of a new isomer of phytoene from Rhodospirillum rubrum. J Chem Soc Perkin Trans I 1976: 1029–1034 ( 1976)
Shimamura H, Sunazuka T, Izuhara T, Hirose T, Shiomi K, Ōmura S . Total synthesis of verticipyrone, and biological evaluation of its synthetic analogues. Org Lett (in press)
Enomoto Y, Shiomi K, Matsumoto A, Takahashi Y, Iwai Y, Harder A, Kölbl H, Woodruff HB, Ōmura S . Isolation of a new antibiotic oligomycin G produced by Streptomyces sp. WK-6150. J Antibiot 54: 308–313 ( 2001)
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Ui, H., Shiomi, K., Suzuki, H. et al. Verticipyrone, a New NADH-fumarate Reductase Inhibitor, Produced by Verticillium sp. FKI-1083. J Antibiot 59, 785–790 (2006). https://doi.org/10.1038/ja.2006.103
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DOI: https://doi.org/10.1038/ja.2006.103
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