53(P-10) 糸状菌由来新規NADH-fumarate reductase阻害剤nafuredinの単離、構造、生物活性(ポスター発表の部)

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NADH-fumarate reductase is a terminal electron transport system of anaerobic energy metabolism found in many anaerobic organisms such as helminths. This electron transport system is used to generate ATP in the absence of oxygen and allows helminths to live in the microaerobic environment. So an inhibitor of NADH-fumarate reductase is expected to be a selective anthelmintic. In the course of our screening for the inhibitors, we found a novel compound, nafuredin. It was produced by a fungus Aspergillus niger FT-0554 isolated from a marine sponge. Nafuredin was isolated from the mycelia of the cultured broth of the strain FT-0554 by solvent extraction, silica gel chromatography, and precipitation in n-hexane. Nafuredin was a white powder, and its molecular formula was established as C_<22>H_<32>O_4 by high resolution FAB-MS. The NMR analysis of nafuredin revealed its structure as (2R^*, 3S^*, 4S^*, 5R^*, 6E,8E,12E,14E)-3,4-epoxy-2-hydroxy-4,10,12,16-tetramethyl-6,8,12,14-octadecatetraeno-5-lactone. The incorporation study of ^<13>C-labeled acetates and methionine suggested that nafuredin is biosynthesized from a nonaketide and four methionines. Nafuredin inhibited NADH-fumarate reductase (complexes I+II) from adult Ascaris suum (pig roundworm) at IC_<50>, value of 12 nM. The target of nafuredin was revealed as complex I (IC_<50>=24 nM), while nafuredin showed very weak inhibition against rat liver complex I. The kinetic analysis showed that the inhibition was noncompetitive with NADH and competitive with rhodoquinone. Furthermore, nafuredin inhibited complex I in L2 larvae of A. suum, which possess aerobic energy metabolism as in mammals, at the same concentration range (IC_<50>=8.9 nM). Nafuredin also showed anthelmintic activity against Haemonchus contortus (wireworm) in in vivo trials with sheep (2 mg/kg, p.o.). This study suggests that mitochondrial complex I is a promising target for chemotherapy, and nafuredin is a potential lead compound as an anthelmintic isolated from microorganisms.
天然有機化合物討論会の論文
2001-09-01

53(P-10) 糸状菌由来新規NADH-fumarate reductase阻害剤nafuredinの単離、構造、生物活性(ポスター発表の部)

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