Journal of Natural Products 最新文献

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.

The parasite Trypanosoma cruzi is the causative agent of Chagas disease, a neglected tropical disease that affects the lives of millions of indigenous people in Latin America. As medications to treat Chagas disease are limited to the application of benznidazole and nifurtimox, which are not ideal treatments for the chronic stage of the disease, the search for new antichagasic drug candidates is an important need. Ecdysone has previously been shown to interfere with the life cycle of T. cruzi. Here, we report the biological profiling and subsequent semisynthetic structure optimization of 47 ecdysteroids against T. cruzi with the aim of identifying selective trypanocidal ecdysteroids. Two moderately trypanocidal pharmacophores were identified: ecdysteroids containing a 6-tert-butyl oxime ether and a cinnamic ester moiety. These functional groups were combined into the structures of four new semisynthetic ecdysteroids (44-47), among which 44 exerted potent and selective trypanocidal activity (IC₅₀ < 2 μM). Cellular infection assays showed that ecdysteroid 44 potently and efficiently inhibited amastigote replication as determined by trypomastigote release after cellular infection with an IC₅₀ of 2.7 ± 0.1 μM. The compound was similarly potent to benznidazole (IC₅₀ = 3.8 ± 0.7 μM) and more than 5-fold more cytotoxic toward T. cruzi over RAW264.7 host macrophages. Overall, the ecdysteroid cinnamate ester 44 is a novel trypanocidal lead structure that needs to be further characterized in follow-up studies.

Seven new nitrogen-containing heptacyclic oligophenalenone dimers, talauromides A-G (1-7), together with known compounds bacillisporins A and B (8 and 9), talaromycesones C and B (10 and 11), duclauxin (12) and lamellicolic anhydride (13), were isolated from the soil derived-fungus Talaromyces stipitatus BMC-16. Their chemical structures were determined based on spectroscopic analysis data. The absolute configurations were elucidated by chemical approaches and the comparison of CD spectra with related compounds. Compounds 3, 8 and 11 exhibited inhibitory activity on the Wnt/β-catenin signaling pathway in zebrafish embryos at a concentration of 20 μM.

Penicamins A-L (1-12), 12 highly oxygenated novel diterpenes, were obtained from the fungus Penicillium camemberti JSB-7212. Compounds 1-12 share the same 7/6/5 tricyclic skeleton as valparane-type diterpenes but differ in the absolute configurations at C-7, C-11, and C-14, as well as in the oxidation levels at C-6 and C-8, which were determined through extensive spectroscopic data interpretation. Stereochemical assignments of compounds 1, 2, and 4-12 were established by single-crystal X-ray diffraction, and the absolute configuration of 3 was determined by analysis of the NOESY data and biogenetic consideration. Compounds 2 and 3 were immunosuppressive against lipopolysaccharide (LPS)-induced B cells, with IC₅₀ values of 3.0 and 7.9 μM, respectively. They also moderately suppressed concanavalin A (ConA)-induced T cell proliferation, with IC₅₀ values of 19 and 20 μM, respectively.

In search of a more comprehensive structure-activity relationship (SAR) regarding the inhibitory effect of cytochalasin B (2) on actin polymerization, a virtual docking of 2 onto monomeric actin was conducted. This led to the identification of potentially important functional groups of 2 (i.e., the NH group of the isoindolone core (N-2) and the hydroxy groups at C-7 and C-20) involved in interactions with the residual amino acids of the binding pocket of actin. Chemical modifications of 2 at positions C-7, N-2, and C-20 led to derivatives 3-6, which were analyzed for their bioactivities. Compounds 3-5 exhibited reduced or no cytotoxicity in murine L929 fibroblasts compared to that of 2. Moreover, short- and long-term treatments of human osteosarcoma cells (U-2OS) with 3-6 affected the actin network to a variable extent, partially accompanied by the induction of multinucleation. Derivatives displaying acetylation at C-20 and N-2 were subjected to slow intracellular conversion to highly cytotoxic 2. Together, this study highlights the importance of the hydroxy group at C-7 and the NH function at N-2 for the potency of 2 on the inhibition of actin polymerization.

Vancomycin-resistant Enterococcus (VRE) is an important nosocomial opportunistic pathogen that is associated with multidrug resistance. Here, we demonstrate that morellic acid inhibits VRE by restoring its sensitivity to vancomycin and ampicillin with low drug resistance and efficient biofilm clearance effects. Morellic acid binds to inner membrane phospholipids, such as phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and cardiolipin (CL) of VRE, such that the fluidity and proton-motive force (PMF) interfere with the damaged inner membrane, causing intracellular reactive oxygen species (ROS) accumulation and bacterial death. Transcriptional analyses supported this effect on inner membrane-related pathways such as fatty acid biosynthesis and glycerophospholipid metabolism. Moreover, morellic acid significantly eliminated residual bacteria in the spleen, liver, kidneys, and abdominal effusion in mice. Our findings indicate the potential applications of morellic acid as an antibacterial agent or adjuvant for treating VRE infections.

Hybridized spirobisnaphthalene derivatives, triantaspirols A-C (1-3) and paraphaeolactones C1 and C2 (4 and 5), were identified from the culture broth of the fungus Paraphaeosphaeria sp. KT4192. The NMR spectra of 2 and 3, as well as 4 and 5, closely resembled each other, indicating that these were pairs of diastereomers. Although this NMR spectral resemblance made it challenging to distinguish their relative configurations, detailed analysis of the electronic circular dichroism (ECD) spectra and NOE correlations allowed us to deduce them. The CP3 metric with the DFT-based NMR chemical shifts was found to distinguish configurations of diastereomers in a highly sensitive and accurate manner that DP4 could not account for because of the very close chemical shift differences in the experimental NMR spectra. The reliability of this method was assessed using 23 published examples which could not be distinguished by DP4 protocol.

Breviane spiroditerpenoids are a small group of structurally interesting and complex meroterpenoids. This work focused on an endophytic fungus Penicillium bialowiezense ZBWPQ-27 that was isolated from a medicinal plant Euphorbia neriifolia, leading to the isolation of 15 breviane spiroditerpenoids with four types of polycyclic systems (1-6 and 9-17), and two new carotane sesquiterpenoids (7 and 8). The structures including absolute configurations of the new compounds 1-8 were elucidated by spectroscopic data analysis and electronic circular dichroism (ECD) calculations. In addition, the misassigned NMR data of several resonances of the 5-methyl-TAL motif (E ring) in those of known brevianes (9-15) were corrected by spectroscopic data analysis. Biological tests revealed that brevianes with the type A ring system (6/6/6/5/6) showed moderate to significant immunosuppressive activities, and compound 11 displayed the most potent inhibitory activities against concanavalin A (ConA)-induced T cell proliferation (IC₅₀ 4.1 ± 0.2 μM) and lipopolysaccharide (LPS)-induced B cell proliferation (IC₅₀ 4.6 ± 0.2 μM), with good SI values of 28 ± 2 and 25 ± 4, respectively.

Prorocentrin-5 (1) was isolated from the benthic marine dinoflagellate Prorocentrum lima. A combination of NMR spectroscopy, quantum chemical calculations, and chemical reactions was then employed to elucidate its molecular structure, including the configurations of all stereogenic centers. In cytotoxicity assays, prorocentin-5 exhibited potent activity against the HCT-116 and Neuro2a cell lines, with IC₅₀ values of 4.4 and 2.8 μM, respectively. Furthermore, 1 increased the apoptotic cell population and induced cell cycle arrest, leading to the accumulation of cells in the S or G2/M phase and an accompanying decrease in the G0/G1 phase in HCT-116, Neuro2a, and HepG2 cells.

The marine alkaloid erebusinone is a secondary metabolite isolated from the Antarctic sponge Isodictya erinacea. Initial biological assays have shown that erebusinone increases amphipod mortality, probably by inhibition of the biosynthesis of molting hormone (ecdysone). Herein, we report the first total synthesis of the proposed structure of erebusinone and a structural revision.