Nafuredin, a Novel Inhibitor of NADH-fumarate Reductase, Produced by Aspergillus niger FT-0554.

Abstract

A novel compound, nafuredin, was isolated as an inhibitor of anaerobic electron transport (NADH-fumarate reductase). It was obtained from culture broth of Aspergillus niger FT-0554 isolated from a marine sponge. The structure was elucidated as an epoxy-<5-lactone with an attached methylated olefinic side chain on the basis of spectral analysis. NADH-fumarate reductase (NFRD)is a terminal electron transport system involved in a unique energy metabolic pathway found in many anaerobic organisms such as helminth1~3). This electron transport system is used to generate ATP in the absence of oxygen, which is different from an aerobic system4^. It allows helminths to live in a microaerobic lumen with the host inside. Thus an inhibitor of NFRD is expected to be a selective anthelmintic. Though several compoundswere reported to have NFRDinhibiting activity5'6), they are weak or nonspecific inhibitors. In the course of our screening for NFRD inhibitors, we found a novel compound, nafuredin (1, Fig. 1), from the culture broth ofA. niger FT-0554 isolated from a marine sponge. Compound 1 inhibited NFRDofAscaris suum (pig roundworm) at nM concentrations, while it showed very weak inhibition against a mammalianenzyme. Details of the inhibition and in vivo studies were described previously7). In this paper we describe the fermentation, isolation, structure elucidation, and biosynthesis of 1.

Verticipyrone, a New NADH-fumarate Reductase Inhibitor, Produced by Verticillium sp. FKI-1083

“…During our screening for inhibitors of NFRD using Ascaris suum (roundworm) mitochondria, we obtained nafuredin, atpenins, and paecilaminol from cultured broth of fungi. Nafuredin is a selective inhibitor of helminth complex I which showed anthelmintic activity in vivo [3,4]. Atpenins are the most potent complex II inhibitors, useful as tools for biochemical studies, though the inhibition is non-selective between helminths and mammals [5].…”

“…FKI-1083 [7]. The structure of 1 contains 2-methoxy-3,5-dimethyl-gpyrone similar to that of actinopyrone A (3) [8,9], aureothin (4) [10ϳ12], neoaureothin (spectinabilin, 5)…”

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

“…During our screening for inhibitors of NFRD using Ascaris suum (roundworm) mitochondria, we obtained both nafuredin and atpenins. Nafuredin is a selective inhibitor of helminth complex I which showed anthelmintic activity in vivo [4,5]. Atpenins are complex II inhibitors, and the inhibition is non-selective between helminths and mammals [6].…”

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

“…Therefore, we have screened NFRD inhibitors using mitochondria of Ascaris suum (pig roundworm), and obtained a novel inhibitor, nafuredin (1), from the cultured broth of Aspergillus niger FT-0554 isolated from a marine sponge [6,7]. Compound 1 inhibited NFRD of A. suum at nanomolar levels, while it showed very weak inhibition to the mammalian enzyme [6].…”

“…Thus, 1 is a new potential lead compound as a novel anthelmintic. Its structure is an epoxy-d-lactone with a methylated olefinic side chain [7]. The absolute configuration of 1 was elucidated by comparing ozonolysis products of 1 and their corresponding synthetic compounds [8], and total synthesis of 1 has been also achieved [9].…”