Identification of a Potent and Selective Cannabinoid CB₁ Receptor Antagonist from <i>Auxarthron reticulatum</i>

The fungus <i>Auxarthron reticulatum</i> derived from the marine sponge <i>Ircinia variabilis</i> produced the diketopiperazine alkaloid amauromine (<b>1</b>) and the quinolinone methyl-penicinoline (<b>2</b>). Compound <b>2</b> is identical to the reported methyl-marinamide, whose structure is herewith revised. In radioligand binding studies at human cannabinoid CB₁ and CB₂ receptors recombinantly expressed in Chinese hamster ovary (CHO) cells, amauromine (<b>1</b>) was found to exhibit high affinity and selectivity for the CB₁ receptor (<i>K</i>_i = 178 nM). The compound was shown to be a neutral CB₁ antagonist with a <i>K</i>_b value of 66.6 nM determined in cAMP assays. Compound <b>2</b> exhibited only weak or no effects at CB receptors. To the best of our knowledge, compound <b>1</b> is the first fungal natural product that shows affinity for cannabinoid CB₁ receptors. Because of its high antagonistic potency and selectivity, it may have potential for use as a drug and/or serve as a lead structure for drug development

Polyketide Skeletons from the Marine Alga-Derived Fungus Coniothyrium cereale

The fungus Coniothyrium cereale was isolated from the Baltic Sea alga Enteromorpha sp. Upon cultivation in saline medium, C. cereale produced the structurally unprecedented isoindole pseudoalkaloid conioimide (1) and the polyketide cereoanhydride (2). Because of the very limited amount of compounds isolated, the structures of 1 and 2 were established from extensive NMR spectroscopic and mass spectrometric analyses, and in the case of 1, the structural analysis was completed by NMR shielding calculations. Conioimide and cereoanhydride represent new structural types of polyketides. Experiments with 13C-labeled acetate proved the polyketide nature of the major and known C. cereale metabolite (–)-trypethelone (3), which is proposed to be the precursor of cereoanhydride. Conioimide has prominent and selective inhibitory activity towards the protease human leukocyte elastase (HLE), an enzyme involved in many inflammatory diseases, with an IC50 (half maximal inhibitory concentration) value of 0.2 μg mL–1