Journal of Natural Products 最新文献

Spectroscopy-guided isolation of extracts of the Tongan marine sponge Hyattella cf. intestinalis (Lamarck, 1814) has resulted in the reisolation of the labdane diterpenoid luakuliide A (1) and one new congener, luakulialactam A (2). In addition to establishing the absolute configuration of 1, synthetic modifications to the luakuliide framework at key positions has created a set of six derivatives (3-8) which were used to interrogate a structure-activity relationship relating to the immunomodulatory effects of luakuliide A. This revealed that compounds 4, 5, and 6, bearing substituted furan motifs, show potent activity in primary macrophages by inhibiting pro-inflammatory cytokine production, while upregulating cellular metabolism and anti-inflammatory IL-10 production at nanomolar concentrations. This is an activity profile consistent with macrophages modulated toward an anti-inflammatory phenotype associated with wound-healing and resolution of inflammation.

Six undescribed macrocyclic compounds, including diarylhexanoids (1 and 2), a diarylhexanoid glucoside (3), diarylheptanoids (4 and 5), and an aceroside (6), were isolated from the roots of Myrica nana Cheval., along with 11 known analogues (7-17). The structures were elucidated by spectroscopic analysis, as well as by calculated optical rotatory dispersion and derivatization reactions. Metabolites 1-3, with a rare macrocyclic diarylhexane skeleton, differ from the familiar macrocyclic diarylheptanoids. The spasmolytic activity of the isolated compounds was evaluated on acetylcholine-induced contraction of isolated rat ileum. All isolated compounds exhibited significant spasmolytic activities with an EC₅₀ ranging from 1.4 to 5.1 μM. The spasmolytic mechanism of action of compound 1 could be related to the NO production, blockade of muscarinic receptors, K⁺ efflux, and cytosolic calcium reduction.

The common milkweed Asclepias syriaca is widespread in North America and produces cardenolide toxins that deter herbivores by targeting the transmembrane enzyme Na⁺/K⁺-ATPase. In 1979, Nobel Laureate Tadeus Reichstein elucidated the structure of novel cardenolides isolated from A. syriaca roots and proposed structures for several other cardenolides that could not be confirmed. In this study, we investigate the cardenolide composition of A. syriaca seeds, focusing on their abundance and in vitro inhibitory potency on the sensitive porcine Na⁺/K⁺-ATPase and that of the highly resistant large milkweed bug, Oncopeltus fasciatus. We identify five previously unreported cardenolides (1-5), three of which are predominantly found in seeds, in addition to the known syrioside (6), aspecioside (7), and the 2-thiazoline ring-containing cardenolide labriformin (8). Glucopyranosyl-allomethylosyl-12-deoxy aspecioside (5) is distinguished by lack of oxidation at C-12, and compounds 2, 3, 6, and 8 contain a rare 1,4-dioxane motif. Inhibitory efficacy of the isolated cardenolides for sensitive and resistant enzymes appears to be correlated. Finally, we confirmed the structure of compound 2, originally proposed by Tadeus Reichstein, and are pleased to share his original 1979 handwritten manuscript.

Eighteen cyclopenta[b]benzopyran derivatives (1-5 and 11-23) and 10 limonoids (6-10 and 24-28) were identified from Aglaia edulis, including 10 undescribed compounds (1-10), all of which were identified by analysis of spectroscopic data, electronic circular dichroism calculations, and X-ray crystallography studies. Nine compounds displayed significant cytotoxic activity against three cancer cells, with IC₅₀ values of 3-900 nM. Sixteen compounds demonstrated potent antiviral activity on the dengue virus, with selectivity index values between 13.0 and 532.6. A mechanism of action investigation revealed that compound 11 may function as an eIF4E activator, which could suppress the expression of the E protein, thereby conferring significant activity against the dengue virus.

The similar structures of natural compounds and the absence of NMR data for commercial products raise the risk of misidentification. This work reports a case in which purchased samples labeled as "berbamine" from 14 suppliers are oxyacanthine (1). The NMR data of all purchased samples were consistent. The X-ray crystallography characterization of one sample revealed it to be 1. The NMR data of 1 were fully assigned for the first time. Berbamine (2) was isolated from the roots of Berberis sieboldii Miq. The NMR data of 2 were assigned, and its crystal structure was reported for the first time. The authors intend to raise awareness and support the academic/industrial community through a study of this misidentification case.

Hericium erinaceus is an edible and medicinal mushroom. Previously, we found hericenones C-H from the fruiting bodies and erinacines A-I from the mycelia of the fungus. These compounds stimulated nerve growth factor (NGF) synthesis both in vitro and in vivo; some have been suggested to be effective in the prevention and treatment of dementia. Recently, the total synthesis of hericenones C-H and their derivatives (1-4) was reported by one of the authors. We considered that the chemical synthetic route would also be reasonable as a biosynthetic pathway of the compounds. Based on the hypothesis, we investigated the endogenous existence of synthetic intermediates and products of the chemical synthesis in the fruiting bodies. The n-hexane-soluble part of the fruiting bodies of H. erinaceus was fractionated, and all the fractions were subjected to a product ion scan and multiple reaction monitoring (MRM) analysis by LC-MS/MS and compared to the authentic synthesized compounds. The analysis indicated the endogenous existence of 1-4 and the dehydrated form of 2 or 3. The dehydrated form was elucidated to be (Z)-5 by chemical synthesis, and a plausible biosynthetic pathway was proposed.

Nonenzymatic reactions, though critical in natural product biosynthesis, are significantly challenging to control. Adding 3% NaI to the culture medium of Penicillium janczewskii significantly increased pseurotin D (1) production and decreased pseurotin A (2) production. Previously, 1 and 2 were suggested to be produced via a nonenzymatic reaction, where the epoxide at C-10 undergoes S_N2 (2) or S_N2' (1) reactions. We confirmed that 1 was isolated as a 1:1 mixture of C-13 epimers by spectral elucidation via CP3 analysis aided by selective excitation NMR methods, which supported that 1 was produced through a nonenzymatic S_N2' reaction. We propose that NaI increased the ratio of 1 by causing steric hindrance at the C-11 position of the transient intermediate, which makes C-13 more preferred in the S_N2/S_N2' competition.

Cannabicyclol ((±)-CBL), a minor phytocannabinoid, is largely unexplored, with its biological activity previously undocumented. We studied its conversion from cannabichromene (CBC) using various acidic catalysts. Montmorillonite (K30) in chloroform at room temperature had the highest yield (60%) with minimal byproducts. Key reaction conditions, such as solvent, temperature, and time, significantly impacted the yield. The structure of (±)-CBL was confirmed via X-ray crystallography. Stability studies showed that (±)-CBL and its MCT oil dilution remain stable at 25-40 °C for three months. Radioligand binding assays revealed high affinity of CBL for the 5-HT_1A receptor but weak interaction with CB₁ and CB₂ receptors. At 10 μM and 1 μM, (±)-CBL inhibited [³H]-8-hydroxy-DPAT binding to 5-HT_1A by 75% and 20%, respectively. Functional assays showed that (±)-CBL acts as a weak agonist at high concentrations but a potent positive allosteric modulator of serotonin-induced activation at low concentrations. At 4 μM, (±)-CBL increased serotonin-induced β-arrestin recruitment from 20% to 80%. This unique modulatory profile highlights the potential of (±)-CBL in drug discovery targeting serotonin receptors.

Microcystins, a large family of nonribosomal cyclic heptapeptides known for their hepatotoxicity, are among the best-studied cyanobacterial toxins. Recently, they have been discussed as leads for the development of anticancer drug substances. Their main mode-of-action is inhibition of the eukaryotic serine/threonine protein phosphatases 1 and 2A. Unlike many cytotoxins that can cross cell membranes by passive diffusion, microcystins depend on active uptake via organic anion transporting polypeptides 1B1 or 1B3. Both phosphatase inhibition and transportability strongly depend on the structure of the individual microcystin. Here, we present how chemical modification of positions 2 and 4 of the microcystin core structure can alter these two properties. Aiming to reduce transportability and increase phosphatase inhibition, we used pharmacophore modeling to investigate the phosphatase inhibition potential of microcystins derivatized with small molecules containing a variety of functional groups. The respective derivatives were synthesized using click chemistry. We discovered that some derivatized microcystins can address a yet undescribed subpocket of the protein phosphatase 1. The derivatized microcystins were tested for phosphatase 1 inhibition and cytotoxicity on transporter-expressing cell lines, revealing that target inhibition and transportability of microcystins can independently be influenced by the physicochemical properties, especially of the residue located in position 2 of the microcystin. Derivatization with small acids or amino acids resulted in microcystins with a favorable ratio of inhibition to transportability, making these derivatives potentially suitable for drug development.