Unprecedented Polyketides from a Marine Sponge-Associated <i>Stachylidium</i> sp.

From the marine sponge-derived fungus <i>Stachylidium</i> sp. six novel phthalide-related compounds, cyclomarinone (<b>1</b>), maristachones A–E (<b>2</b>–<b>5</b>), and marilactone (<b>6</b>), were isolated. The structure of compound <b>1</b> comprises a hydroxycyclopentenone ring instead of the furanone ring characteristic for phthalides and represents a new carbon arrangement within polyketides. In the epimeric compounds <b>5a</b> and <b>5b</b> the phthalide (=isobenzofuranone) nucleus is modified to an isobenzofuran ring with ketal and acetal functionalities. Biosynthetically the structural skeletons of cyclomarinone (<b>1</b>) and maristachones A (<b>2</b>), C (<b>4</b>), D (<b>5a</b>), and E (<b>5b</b>) are most unusual due to the presence of an additional carbon atom when compared to the basic polyketide skeleton. This special biosynthetic feature also holds true for the likewise isolated polyketide marilactone (<b>6</b>)

Insights into the Biosynthetic Origin of 3‑(3-Furyl)alanine in <i>Stachylidium</i> sp. 293 K04 Tetrapeptides

The marine-sponge-derived fungus <i>Stachylidium</i> sp. 293 K04 produces the <i>N</i>-methylated peptides endolide A (<b>1</b>) and endolide B (<b>2</b>), showing affinity for the vasopressin receptor 1A and serotonin receptor 5HT_2B, 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 (<b>1</b>) is synthesized from a cyclic intermediate of the shikimate pathway, but not from phenylalanine. Two new tetrapeptide analogues, endolides C and D (<b>3</b> and <b>4</b>), were characterized, as well as the previously described hirsutide (<b>5</b>)

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

The marine-derived fungus <i>Stachylidium</i> sp. was isolated from the sponge <i>Callyspongia</i> sp. cf. <i>C. flammea.</i> Culture on a biomalt medium supplemented with sea salt led to the isolation of two new, most unusual <i>N</i>-methylated peptides, i.e., the tetrapeptides endolide A and B (<b>1</b> and <b>2</b>). Both of these contain the very rare amino acid 3-(3-furyl)-alanine. In radioligand binding assays endolide A (<b>1</b>) showed affinity to the vasopressin receptor 1A with a <i>K</i>_i of 7.04 μM, whereas endolide B (<b>2</b>) exhibited no affinity to the latter receptor, but was selective toward the serotonin receptor 5HT_2b with a <i>K</i>_i of 0.77 μM

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

Indoloditerpenes from a Marine-Derived Fungal Strain of <i>Dichotomomyces cejpii</i> with Antagonistic Activity at GPR18 and Cannabinoid Receptors

A marine-derived strain of <i>Dichotomomyces cejpii</i> produces the new compounds emindole SB beta-mannoside (<b>1</b>) and 27-<i>O</i>-methylasporyzin C (<b>2</b>), as well as the known indoloditerpenes JBIR-03 (<b>3</b>) and emindole SB (<b>4</b>). Indole derivative <b>1</b> was found to be a CB₂ antagonist, while <b>2</b> was identified as the first selective GPR18 antagonist with an indole structure. Compound <b>4</b> was found to be a nonselective CB₁/CB₂ antagonist. The new natural indole derivatives may serve as lead structures for the development of GPR18- and CB receptor-blocking drugs

Corallorazines from the Myxobacterium <i>Corallococcus coralloides</i>

The myxobacterium <i>Corallococcus coralloides</i> is the producer of the antibiotic compound corallopyronin A, which is currently in preclinical evaluation. To obtain suitable amounts of this antibiotic, the production strain <i>C. coralloides</i> B035 was cultured in large volumes, which in the addition to the isolation of the target molecule facilitates the detection of additional metabolites of this myxobacterial strain (corallorazines A–C). Corallorazine A is a new structural type of dipeptide composed of a dehydroalanine and a glycine moiety that are linked via a semiaminal bond, thus forming a piperazine ring. The latter is further connected via an amide bond to an unusual aliphatic acyl chain

Applying Molecular Networking for the Detection of Natural Sources and Analogues of the Selective Gq Protein Inhibitor FR900359

The cyclic depsipeptide FR900359 (FR), isolated from the traditional Chinese medicine plant <i>Ardisia crenata</i>, is a potent Gq protein inhibitor and thus a valuable tool to study Gq-mediated signaling of G protein-coupled receptors. Two new FR analogues (<b>3</b> and <b>4</b>) were isolated from <i>A. crenata</i> together with the known analogues <b>1</b> and <b>2</b>. The structures of compounds <b>3</b> and <b>4</b> were established by NMR spectroscopic data and MS-based molecular networking followed by in-depth LCMS² analysis. The latter approach led to the annotation of further FR analogues <b>5</b>–<b>9</b>. Comparative bioactivity tests of compounds <b>1</b>–<b>4</b> along with the parent molecule FR showed high-affinity binding to Gq proteins in the low nanomolar range (IC₅₀ = 2.3–16.8 nM) for all analogues as well as equipotent inhibition of Gq signaling, which gives important SAR insights into this valuable natural product. Additionally, FR was detected from leaves of five other <i>Ardisia</i> species, among them the non-nodulated leaves of <i>Ardisia lucida</i>, implying a much broader distribution of FR than originally anticipated

Insights into Structure–Activity Relationships of Bacterial RNA Polymerase Inhibiting Corallopyronin Derivatives

The new compound precorallopyronin A is a stable precursor in the biosynthesis of the antibiotic corallopyronin A. This natural product was isolated from the producer strain <i>Corallococcus coralloides</i> B035. Together with various semisynthetically obtained corallopyronin A derivatives its antibacterial effects were evaluated. In combination with an X-ray crystallization model limitations of derivatization possibilities were revealed. The antibiotic potential of the novel precorallopyronin A is comparable to that of the structurally more complex corallopyronin A, which highlights that the additional chiral center is not essential for activity