Biosynthetic studies of novel polyketides from the marine sponge-derived fungus Stachylidium sp. 293K04.

The marilones and marilines are a new family of polyketide metabolites recently isolated from the marine-derived fungus Stachylidium sp. 293K04. They are characterized by a phthalide and phthalimidine skeleton, respectively. From a series of feeding experiments using 13C-labeled precursors we could outline the biogenetic origin of the basic carbon skeleton of marilone A and mariline B. Results established the tetraketide nature of the phthalide/phthalimidine nucleus including the involvement of a methylated acetate starter unit in polyketide biosynthesis, which is unique amongst fungal metabolites.

Insights into the Biosynthetic Origin of 3-(3-Furyl)alanine in Stachylidium sp. 293 K04 Tetrapeptides.

The marine-sponge-derived fungus Stachylidium sp. 293 K04 produces the N-methylated peptides endolide A (1) and endolide B (2), showing affinity for the vasopressin receptor 1A and serotonin receptor 5HT2B, respectively. Both peptides feature the rare amino acid 3-(3-furyl)alanine. Isotope labeling experiments, employing several 13C-enriched precursors, revealed that this unprecedented heterocyclic amino acid moiety in endolide A (1) is synthesized from a cyclic intermediate of the shikimate pathway, but not from phenylalanine. Two new tetrapeptide analogues, endolides C and D (3 and 4), were characterized, as well as the previously described hirsutide (5).

Endolides A and B, Vasopressin and Serotonin-Receptor Interacting N-Methylated Peptides from the Sponge-Derived Fungus Stachylidium sp.

The marine-derived fungus Stachylidium sp. was isolated from the sponge Callyspongia sp. cf. C. flammea. Culture on a biomalt medium supplemented with sea salt led to the isolation of two new, most unusual N-methylated peptides, i.e., the tetrapeptides endolide A and B (1 and 2). Both of these contain the very rare amino acid 3-(3-furyl)-alanine. In radioligand binding assays endolide A (1) showed affinity to the vasopressin receptor 1A with a Ki of 7.04 µM, whereas endolide B (2) exhibited no affinity to the latter receptor, but was selective toward the serotonin receptor 5HT2b with a Ki of 0.77 µM.

GPR18 Inhibiting Amauromine and the Novel Triterpene Glycoside Auxarthonoside from the Sponge-Derived Fungus Auxarthron reticulatum.

The marine sponge-derived fungus Auxarthron reticulatum produces the cannabinoid receptor antagonist amauromine (1). Recultivation of the fungus to obtain further amounts for more detailed pharmacological evaluation of 1 additionally yielded the novel triterpene glycoside auxarthonoside (2), bearing, in nature, a rather rare sugar moiety, i.e., N-acetyl-6-methoxy-glucosamine. Amauromine (1), which inhibited cannabinoid CB1 receptors (Ki 0.178 µM) also showed antagonistic activity at the cannabinoid-like orphan receptor GPR18 (IC50 3.74 µM). The diketopiperazine 1 may thus serve as a lead structure for the development of more potent and selective GPR18 antagonists, which are required to study the orphan receptor's potential as a new drug target. Despite the execution of many biological assays, to date, no bioactivity could be found for auxarthonoside (2).

Phenalenones: insight into the biosynthesis of polyketides from the marine alga-derived fungus Coniothyrium cereale.

The marine alga-derived fungus Coniothyrium cereale is a prolific producer of phenalenones. These polyketides were shown to possess antimicrobial effects and inhibitory activity towards the protease human leucocyte elastase (HLE). The current study focused on the biosynthesis of eight different structural types of phenalenones, comprising the natural products rousselianone A' (1), coniosclerodin (3), cereolactam (12), cereoaldomine (15), and trypethelone (16). Solid agar cultures of C. cereale were used to follow up the incorporation of [1-(13)C] labeled acetate into these metabolites. Taking the respective mechanisms of polyketide metabolism into account, the labeling pattern was interpreted, thus providing a hypothesis for the biosynthetic formation of the phenalenones. The polyketide skeleton of the phenanthrene-based compound cereolactam is proposed to be formed through degradation of a heptaketide by loss of two carbon atoms.

New bicyclo-spartinols from the marine-derived fungus Phaeosphaeria spartinae.

Investigation of the marine-derived fungus Phaeosphaeria spartinae, an endophyte of the marine alga Ceramium sp., led to the isolation of the unprecedented polyketides 1 and 2. The structures of these compounds were established from extensive spectroscopic analyses.