Dioxopiperazine Alkaloids Produced by the Marine Mangrove Derived Endophytic Fungus Eurotium rubrum

Abstract

Cultivation of the fungal strain Eurotium rubrum, an endophytic fungus that was isolated from the inner tissue of stems of the mangrove plant Hibiscus tiliaceus, resulted in the isolation of two new dioxopiperazine derivatives, namely, dehydrovariecolorin L (1) and dehydroechinulin (2), together with eight known dioxopiperazine compounds including variecolorin L (3), echinulin (4), isoechinulin A (5), dihydroxyisoechinulin A (6), preechinulin (7), neoechinulin A (8), neoechinulin E (9), and cryptoechinuline D (10). The structures of the isolated compounds were determined by extensive analysis of their spectroscopic data as well as by comparison with literature. Compounds 1, 2, 9, and 10 were investigated for their a,a-diphenyl-b-picrylhydrazyl (DPPH) radical-scavenging activity. In addition, the new compounds, 1 and 2, were evaluated for their cytotoxic activity against the P-388, HL-60, and A549 cell lines.Introduction. -A number of tryptophan-derived alkaloids, characterized by a reversed isoprenic chain in the C(2) position of the indole and a 2,5-dioxopiperazine moiety, have been isolated from the genus Aspergillus [1 -5]. These metabolites are of interest because of their activity in various pharmacological assay systems [6]. The genus Eurotium is the teleomorphs of Aspergillus, and is also a common source of tryptophan-derived alkaloids, i.e., echinulins and neoechinulins [7].This article describes the isolation, structure elucidation, and biological activity of two new dioxopiperazine derivatives (1 and 2) from the endophytic fungal strain Eurotium rubrum which was isolated from the inner tissue of stems of the marine mangrove plant Hibiscus tiliaceus. In addition, eight known dioxopiperazine derivatives, including variecolorin L (3) [8], echinulin (4) [9], isoechinulin A (5) [10], dihydroxyisoechinulin A (6) [4], preechinulin (7) [11], neoechinulin A (8) [12], neoechinulin E (9) [12], and cryptoechinuline D (10) [13], were also isolated and identified. It deserves to be mentioned that just at the time when we started to prepare this manuscript, compound 3 was reported as a new metabolite of Aspergillus variecolor B-17, a halotolerant fungal strain isolated from a sediment collection of a salt field in inner Mongolia, China [8].

A survey of xerophilic Aspergillus from indoor environment, including descriptions of two new section Aspergillus species producing eurotium-like sexual states

“…Echinulin was first discovered in A. brunneus (= E. echinulatum) by Quilico and Panizzi (1943). It was subsequently detected in many more section Aspergillus species (Ali et al 1989;Almeida et al 2010;Greco et al 2015;Li et al 2008b;Slack et al 2009;Smetanina et al 2007;Vesonder et al 1988) and shown to be toxic to animal cells (Ali et al 1989;Umeda et al 1974), while swine and mice respectively refused feed and water containing echinulin (Vesonder et al 1988). The presence of echinulin in the environment is not well documented however.…”

“…Species of section Aspergillus produce many extrolites exhibiting a wide range of biological activities (Frisvad and Larsen 2015a;Gomes et al 2012;Kanokmedhakul et al 2011;Li et al 2008a;Li et al 2008b;Slack et al 2009;Smetanina et al 2007). Most notably, compounds from A. chevalieri were shown to be active against Plasmodium falciparum (malaria), Mycobacterium tuberculosis and cancer cell lines (Kanokmedhakul et al 2011), an antitumor compound was reported from A. cristatus (Almeida et al 2010), while many compounds are known to be antioxidants.…”

Synthetic and Structure-Activity Relationship Studies on Bioactive Natural Products

“…Bridelia ferruginea (Euphorbiaceae), 45) Eurotium sp., [46][47][48][49] Penicillium griseofulvum, 50) and the aerial parts of Plumbago zeylanica.…”

The in vitro anticancer activity of the crude extract of the sponge-associated fungus Eurotium cristatum and its secondary metabolites

“…[11][12][13][14][15][16][17][18] Compound 1 has been previously isolated from the endophytic fungus Chaetomium globosum which was isolated from the inner tissue of the marine red alga Polysiphonia urceolata [17] and later from the liquid culture of the endophytic fungus Eurotium rubrum, [12] while physcion (2) was previously reported from Eurotium repens, the marine fungus isolated from the marine sponge Suberites donuncula. [11] Interestingly, the dioxopiperazine alkaloid echinulin (3) seems to be a chemical marker of this genus, having been isolated from all the Eurotium species investigated so far.…”