Two new sesterterpenoids from Atractylodes japonica Koidz. ex Kitam.

Two new sesterterpenoids, atractylodes japonica terpenoid acid I (1) and atractylodes japonica terpenoid aldehyde I (2), were isolated from the rhizomes of Atractylodes japonica Koidz. ex Kitam together with ten known compounds (3-12). Their structures were elucidated on the basis of comprehensive spectroscopic analysis (1D/2D NMR, HRESIMS and IR). In addition, all of these isolated compounds were evaluated for their cytotoxic activities against human gastric cancer cell MGC-803 and human hepatocellular cancer cell HepG-2. Most of them exhibited moderate to weak inhibitory effects with IC50 values in the range of 25.15-88.85 µM except for 9-12.

Bipoladien A, a Sesterterpenoid Containing an Undescribed 5/8/5/7 Carbon Skeleton from Bipolaris maydis.

Bipoladiens A-E (1-5), five new ophiobolin-derived sesterterpenoids, and a known compound 6 (bipolaricin R) were isolated from the cultures of the phytopathogenic fungus Bipolaris maydis. Their structures and absolute configurations were elucidated based on comprehensive spectroscopic analyses, HRESIMS, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analyses. Notably, compound 1 has an undescribed tetracyclic 5/8/5/7 fused carbon skeleton, and compound 2 possesses a rare multicyclic caged ring system. The biosynthetic pathway of 1 was proposed starting from 6 via a series of oxidation and cyclization reactions. Compound 6 showed excellent antiproliferation and apoptosis induction effects against A549 cell line. Additionally, compounds 5 and 6 exhibited noticeable antimicrobial ability against Bacillus cereus, Staphylococcus aureus, and Staphylococcus epidermidis. These findings not only developed the chemical and bioactivities diversities of ophiobolin-sesterterpenoid but also provided an idea to boost the application of natural products in the control of food pathogens.

LC-MS/MS-Guided Molecular Networking for Targeted Discovery of Undescribed and Bioactive Ophiobolins from Bipolaris eleusines.

An integrated purification procedure through the LC-MS/MS-based molecular networking strategy combined with bioactive evaluation was first ushered for discovering bioactive ophiobolins from Bipolaris eleusines. Ophiobolins were mainly dispersed in five clusters, which were classified based on different ring systems and functional groups. Nine undescribed ophiobolins (1-6 and 9-11) and an undescribed natural product (8) along with two known analogs (7 and 12) were isolated in target. The undescribed structures were characterized by HR-ESI-MS, NMR spectra, and X-ray diffraction experiments. Compounds 3-12 exhibited strong phytotoxic effects on green foxtails by producing visible lesions, and compounds 1-10 and 12 displayed different levels of cytotoxic activities against cancer cell lines B16, Hep G2, and MCF-7, from which the possible structure-activity relationships were then suggested. The results have supported that bioactivity-guided molecular networking is an efficient strategy to expedite the discovery of undescribed bioactive natural products.

Antiplasmodial Asperterpenoids from Two Aspergillus oryzae Transformants with Heterologous Expression of Sesterterpene Genes.

The synthetic biology approach enables efficient and directional mining of target compounds during drug discovery. Ten new asperterpenoids (6-15) and five known analogues (1-5), possessing a rare 5/7/3/6/5 skeleton, were obtained from two Aspergillus oryzae transformants with heterologous expression of a terpene cyclase gene AstC with one or two P450 genes AstB/A under the guidance of molecular networking. Their planar structures were determined by 1D and 2D NMR and HR-ESI-MS. The absolute configurations of compounds 6 and 9-13 were determined by single crystal X-ray diffraction, and those of compounds 7-8 and 14-15 were compared with the ECD of known compounds. Seven of all the compounds are the first asperterpenoid oxidation products at C-17 or at C-25. In bioassay, compounds 1-2, 4-5, and 6-8 displayed moderate to strong eliminating activities against chloroquine-sensitive strain (P.f.3D7) with EC50 values ranging from 2.1 to 19.3 µM. The structure-activity relationship (SAR) was discussed, which showed that substituents at C-3, C-11, C-17, C-18, and C-23 of asperterpenoids significantly affected anti-plasma parasite activity.

Scalarane Sesterterpenoids Isolated from the Marine Sponge Hyrtios erectus and their Cytotoxicity.

Eighteen scalarane sesterterpenoids (1-18), including eight new derivatives (1-8), were isolated from the sponge Hyrtios erectus (family Thorectidae), the extract of which showed cytotoxicity against the HeLa and MCF-7 cell lines. Of the new derivatives, six compounds (1-6) were found to contain a γ-hydroxybutenolide moiety capable of reversible stereoinversion at the hydroxylated carbon center. Under the influence of other adjacent functional groups, each derivative exhibited a different stereochemical behavior, which was fully deduced by ROESY experiments. All the isolated compounds were examined for their cytotoxicity by MTS assay using staurosporine as a positive control (IC50 0.18 and 0.13 µΜ against HeLa and MCF-7 cells, respectively), and they were found to show weak growth inhibitory activities against HeLa and MCF-7 cells, with a minimal IC50 value of 20.0 µΜ. The compounds containing a γ-hydroxybutenolide moiety (1-3, 10, 12) showed cytotoxicity, with IC50 values ranging from 24.3 to 29.9 µΜ, and the most potent derivative was heteronemin (16). Although the cytotoxicities of isolated compounds were insufficient to discuss the structure-activity relationship, this research could contribute to expanding the structural diversity of scalaranes and understanding the stereochemical behavior of γ-hydroxybutenolides.

A Stereoselective Photoinduced Cycloisomerization Inspired by Ophiobolin A.

A stereoselective synthetic entry point to the 5-8-5 carbocyclic core of the ophiobolins was developed. This strategy exploits the chiral tertiary alcohol of ophiobolin A to guide assmebly of the 5-8-5 scaffold in a single step via a photoinitiated cycloisomerization. Mechanistic insights into the origin of stereocontrol in this reaction are described, as are efforts to elaborate the resultant fused 5-8-5 ring system to the pharmacophore of ophiobolin A.

Discovery of Ircinianin Lactones B and C-Two New Cyclic Sesterterpenes from the Marine Sponge Ircinia wistarii.

Two new ircinianin-type sesterterpenoids, ircinianin lactone B and ircinianin lactone C (7 and 8), together with five known entities from the ircinianin compound family (1, 3-6) were isolated from the marine sponge Ircinia wistarii. Ircinianin lactones B and C (7 and 8) represent new ircinianin terpenoids with a modified oxidation pattern. Despite their labile nature, the structures could be established using a combination of spectroscopic data, including HRESIMS and 1D/2D NMR techniques, as well as computational chemistry and quantum-mechanical calculations. In a broad screening approach for biological activity, the class-defining compound ircinianin (1) showed moderate antiprotozoal activity against Plasmodium falciparum (IC50 25.4 µM) and Leishmania donovani (IC50 16.6 µM).

Identification of Anthelmintic Bishomoscalarane Sesterterpenes from the Australian Marine Sponge Phyllospongia bergquistae and Structure Revision of Phyllolactones A-D.

High-throughput screening of the NatureBank marine extract library (7616 samples) identified an extract derived from the Australian marine sponge Phyllospongia bergquistae with activity against Hemonchus contortus (barber's pole worm), an economically important parasitic nematode. Bioassay-guided fractionation of the CH2Cl2/MeOH extract from P. bergquistae led to the purification of four known bishomoscalarane sesterterpenes, phyllolactones A-D (1-4). The absolute configurations of phyllolactones B (2) and C (3) were determined by single-crystal X-ray diffraction analysis; literature and data analyses revealed the need for these chemical structures to be revised. Compounds 2-4 induced a lethal, skinny (Ski) phenotype in larvae of H. contortus at concentrations between 5.3 and 10.1 µM. These data indicate that the bishomoscalarane sesterterpene structure class warrants further investigation for nematocidal or nematostatic activity.

Bioactive Scalarane-Type Sesterterpenoids from Marine Sources.

Scalarane-type sesterterpenoids have received considerable attention in the scientific literature due to their diverse carbon skeletons and various biological activities and pharmacological properties. Among all these derivatives are commonly isolated from marine sponges and are occasionally derived from shell-less mollusks, such as nudibranchs. This review comprehensively discusses the marine-derived natural sources that give rise to these scalarane-type sesterterpenoids, providing the names, their chemical structures, biological properties, with emphasis on anticancer activity and literature references related to these metabolites. A critical summary of the 221 compounds generated from January 2010 up to December 2021 for their potential as anticancer agents is presented.

The Biosynthesis and Transport of Ophiobolins in Aspergillus ustus 094102.

Ophiobolins are a group of sesterterpenoids with a 5-8-5 tricyclic skeleton. They exhibit a significant cytotoxicity and present potential medicinal prospects. However, the biosynthesis and transport mechanisms of these valuable compounds have not been fully resolved. Herein, based on a transcriptome analysis, gene inactivation, heterologous expression and feeding experiments, we fully explain the biosynthesis pathway of ophiobolin K in Aspergillus ustus 094102, especially proved to be an unclustered oxidase OblCAu that catalyzes dehydrogenation at the site of C16 and C17 of both ophiobolin F and ophiobolin C. We also find that the intermediate ophiobolin C and final product ophiobolin K could be transported into a space between the cell wall and membrane by OblDAu to avoid the inhibiting of cell growth, which is proved by a fluorescence observation of the subcellular localization and cytotoxicity tests. This study completely resolves the biosynthesis mechanism of ophiobolins in strain A. ustus 094102. At the same time, it is revealed that the burden of strain growth caused by the excessive accumulation and toxicity of secondary metabolites is closely related to compartmentalized biosynthesis.

Design and synthesis of marine sesterterpene analogues as novel estrogen receptor α degraders for breast cancer treatment.

Targeted protein degradation using small molecules is an intriguing strategy for drug development. The marine sesterterpene compound MHO7 had been reported to be a potential ERα degradation agent. In order to further improve its biological activity, two series of novel MHO7 derivatives with long side chains were designed and identified as novel selective estrogen receptor down-regulators (SERDs). The growth inhibition activity of the novel SERD compounds were significantly affected by the type and length of the side chain. Most of the derivatives were significantly more potent than MHO7 against both drug-sensitive and drug-resistant breast cancer cells. Among them, compound 16a, with IC50 values of 0.41 µM against MCF-7 cell lines and 9.6-fold stronger than MHO7, was the most potential molecule. A whole-genome transcriptomic analysis of MCF-7 cells revealed that the mechanism of 16a against MCF-7 cell was similar with that of MHO7. The estrogen signaling pathway was the most affected among the disturbed genes, but the ERα degradation activity of 16a was observed higher than that of MHO7. Other effects of 16a were confirmed similar with MHO7, which means that the basic mechanisms of the derivatives are the same with the ophiobolin backbone, i.e. the degradation of ERα is mediated via proteasome-mediated process, the induction of apoptosis and the cell cycle arrest at the G1 phase. Meanwhile, a decrease of mitochondrial membrane potential and an increase of cellular ROS were also detected. Based on these results, as a novel modified ophiobolin derived compound, 16a may warrant further exploitation as a promising SERD candidate agent for the treatment of breast cancer.

Scalarane Sesterterpenoids with Antibacterial and Anti-Proliferative Activities from the Mushroom Neonothopanus nambi.

Seven undescribed scalarane sesterterpenoids, nambiscalaranes B-H (1-7), together with two known compounds, nambiscalarane (8) and aurisin A (9) were isolated from the cultured mycelium of the luminescent mushroom Neonothopanus nambi. Their structures were elucidated by thorough analysis of their 1D and 2D NMR spectroscopic data. The absolute configurations of 1-8 were determined by electronic circular dichroism (ECD) calculations and optical rotation measurements. The isolated sesterterpenoids were evaluated against A549, HT29, HeLa, and HCT-116 cancer cell lines, and against five bacterial strains. Compounds 3, 5, and 7 showed strong cytotoxicity against HCT-116 cell line, with IC50 values ranging from 13.41 to 16.53 µM, and showed no cytotoxicity towards Vero cells. Moreover, compound 8 inhibited the growth of Bacillus subtilis with a MIC value of 8 µg/mL, which was equivalent to the MIC value of the standard kanamycin.

Isolation of Scalarane-Type Sesterterpenoids from the Marine Sponge Dysidea sp. and Stereochemical Reassignment of 12-epi-Phyllactone D/E.

The chemical investigation of the marine sponge Dysidea sp., which was collected from Bohol province in the Philippines, resulted in the identification of 15 new scalarane-type sesterterpenoids (1-14, 16), together with 15 known compounds. The chemical structures of the new compounds were elucidated based on NMR spectroscopy and HRMS. The structure of 12-epi-phyllactone D/E (15) isolated during this study was originally identified in 2007. However, careful inspection of our experimental 13C NMR spectrum revealed considerable discrepancies with the reported data at C-9, C-12, C-14, and C-23, leading to the correction of the reported compound to the C-12 epimer of 15, phyllactone D/E. The biological properties of compounds 1-16 were evaluated using the MDA-MB-231 cancer cell line. Compound 7, which bears a pentenone E-ring, exhibits significant cytotoxicity with a GI50 value of 4.21 µM.

Scalarane-Type Sesterterpenoids from the Marine Sponge Lendenfeldia sp. Alleviate Inflammation in Human Neutrophils.

Sponge-derived scalaranes are remarkable sesterterpenoids previously found to exhibit profound inhibitory effects against neutrophilic inflammation. In our current work, we constructed the metabolomic profile of marine sponge Lendenfeldia sp. for the first time using a tandem mass spectrometry (MS/MS) molecular networking approach. The results highlighted the rich chemical diversity of these scalaranes, motivating us to conduct further research to discover novel scalaranes targeting neutrophilic inflammation. MS- and NMR-assisted isolation and elucidation led to the discovery of seven new homoscalaranes, lendenfeldaranes K-Q (1-7), characterized by methylation at C-24, together with five known derivatives, lendenfeldarane B (8), 25-nor-24-methyl-12,24-dioxoscalar-16-en-22-oic acid (9), 24-methyl-12,24,25-trioxoscalar-16-en-22-oic acid (10), felixin B (11), and 23-hydroxy-20-methyldeoxoscalarin (12). Scalaranes 1-4 and 6-12 were assayed against superoxide anion generation and elastase release, which represented the neutrophilic inflammatory responses of respiratory burst and degranulation, respectively. The results indicated that 1-3 and 6-12 exhibited potential anti-inflammatory activities (IC50 for superoxide anion scavenging: 0.87~6.57 µM; IC50 for elastase release: 1.12~6.97 µM).

Activity of the yeast vacuolar TRP channel TRPY1 is inhibited by Ca2+-calmodulin binding.

Transient receptor potential (TRP) cation channels, which are conserved across mammals, flies, fish, sea squirts, worms, and fungi, essentially contribute to cellular Ca2+ signaling. The activity of the unique TRP channel in yeast, TRP yeast channel 1 (TRPY1), relies on the vacuolar and cytoplasmic Ca2+ concentration. However, the mechanism(s) of Ca2+-dependent regulation of TRPY1 and possible contribution(s) of Ca2+-binding proteins are yet not well understood. Our results demonstrate a Ca2+-dependent binding of yeast calmodulin (CaM) to TRPY1. TRPY1 activity was increased in the cmd1-6 yeast strain, carrying a non-Ca2+-binding CaM mutant, compared with the parent strain expressing wt CaM (Cmd1). Expression of Cmd1 in cmd1-6 yeast rescued the wt phenotype. In addition, in human embryonic kidney 293 cells, hypertonic shock-induced TRPY1-dependent Ca2+ influx and Ca2+ release were increased by the CaM antagonist ophiobolin A. We found that coexpression of mammalian CaM impeded the activity of TRPY1 by reinforcing effects of endogenous CaM. Finally, inhibition of TRPY1 by Ca2+-CaM required the cytoplasmic amino acid stretch E33-Y92. In summary, our results show that TRPY1 is under inhibitory control of Ca2+-CaM and that mammalian CaM can replace yeast CaM for this inhibition. These findings add TRPY1 to the innumerable cellular proteins, which include a variety of ion channels, that use CaM as a constitutive or dissociable Ca2+-sensing subunit, and contribute to a better understanding of the modulatory mechanisms of Ca2+-CaM.

The Configuration-Dependent Anti-Leukemic Effect of Manoalide Stereoisomers: Reignite Research Interest in these Sponge-Derived Sesterterpenoids.

Manoalide was studied as a potential anti-inflammatory agent for the last forty years and more than 200 publications and 180 patents were reported on this compound. However, the configurations at positions 24 and 25 and configuration-dependent bioactivity were not yet studied. In the current report, ten manoalide-like sesterterpenoids were isolated from Luffariella sp. (1-10). These stereoisomers were identified and separated for the first time since 1980 and their configurations at positions 24 and 25 were determined by analyzing their spectroscopic spectra. The configuration-dependent anti-proliferative activity of manoalide derivatives was examined by evaluating their effect on four leukemic cancer cell lines (Molt 4, K562, Sup-T1, and U937). The 24R,25S-isomers exhibited the most potent activity (IC50 0.50-7.67 µM). The anti-proliferative mechanism of action of 24R,25S-manoalide (7) was further studied on Molt 4 cells. Compound 7 exhibited apoptotic activity on Molt 4 cells through the disruption of mitochondrial membrane potential (MMP) and the generation of intracellular reactive oxygen species (ROS). It also inhibited the activity of human topoisomerase I and II. The apoptotic-inducing effect of 7 was further supported by the in vivo experiment by suppressing the volume of xenograft tumor growth (66.11%) compared with the control.

Antibiofilm Activity of Phorbaketals from the Marine Sponge Phorbas sp. against Staphylococcus aureus.

Biofilm formation by Staphylococcus aureus plays a critical role in the persistence of chronic infections due to its tolerance against antimicrobial agents. Here, we investigated the antibiofilm efficacy of six phorbaketals: phorbaketal A (1), phorbaketal A acetate (2), phorbaketal B (3), phorbaketal B acetate (4), phorbaketal C (5), and phorbaketal C acetate (6), isolated from the Korean marine sponge Phorbas sp. Of these six compounds, 3 and 5 were found to be effective inhibitors of biofilm formation by two S. aureus strains, which included a methicillin-resistant S. aureus. In addition, 3 also inhibited the production of staphyloxanthin, which protects microbes from reactive oxygen species generated by neutrophils and macrophages. Transcriptional analyses showed that 3 and 5 inhibited the expression of the biofilm-related hemolysin gene hla and the nuclease gene nuc1.

The untapped potential of plant sesterterpenoids: chemistry, biological activities and biosynthesis.

Covering: 1969 up to 2021Sesterterpenoids, biosynthetically derived from the precursor, namely geranylfarnesyl diphosphate (GFDP) are amongst the rarest of all isoprenoids with approximately 1300 compounds known. Most sesterterpenoids originate from marine organisms (especially sponges), while only about 15% of these compounds are isolated from several families of plants such as Lamiaceae, Gentianaceae, and Nartheciaceae. Many plant sesterterpenoids possess highly oxygenated and complex cyclic skeletons and exhibit remarkable biological activities involving cytotoxic, anti-inflammatory, antimicrobial, and antifeedant properties. Thus, due to their intrinsic chemical complexity and intriguing biological profiles, plant sesterterpenoids have attracted continuing interest from both chemists and biologists. However, the biosynthesis and distribution of sesterterpenoids in the plant kingdom still remain elusive, although substantial progress has been achieved in recent years. This review provides an overall coverage of sesterterpenoids originating from plant sources, followed by a classification of their chemical skeletons, which summarizes the distribution, chemistry, biological activities, biosynthesis and evolution of plant sesterterpenoids, aiming at strengthening the research efforts toward the untapped great potential of these unique natural product resources.

Epithelial-mesenchymal transition sensitizes breast cancer cells to cell death via the fungus-derived sesterterpenoid ophiobolin A.

The epithelial-mesenchymal transition (EMT) imparts properties of cancer stem-like cells, including resistance to frequently used chemotherapies, necessitating the identification of molecules that induce cell death specifically in stem-like cells with EMT properties. Herein, we demonstrate that breast cancer cells enriched for EMT features are more sensitive to cytotoxicity induced by ophiobolin A (OpA), a sesterterpenoid natural product. Using a model of experimentally induced EMT in human mammary epithelial (HMLE) cells, we show that EMT is both necessary and sufficient for OpA sensitivity. Moreover prolonged, sub-cytotoxic exposure to OpA is sufficient to suppress EMT-imparted CSC features including sphere formation and resistance to doxorubicin. In vivo growth of CSC-rich mammary cell tumors, is suppressed by OpA treatment. These data identify a driver of EMT-driven cytotoxicity with significant potential for use either in combination with standard chemotherapy or for tumors enriched for EMT features.

Bioactive sesterterpenoids from the fungus Penicillium roqueforti YJ-14.

Seven previously undescribed sesterterpenes were characterized from Penicillium roqueforti YJ-14 by solid fermentation. Their structures were initially investigated in detail by spectroscopic analyses and HR-ESI-MS and were further confirmed by X-crystallography. In in vitro bioassays, compounds 1, 5 and 7 showed cytotoxic activity against the MCF-7 breast cancer cell line with IC50 values of 7.98 ±â€¯0.93, 6.42 ±â€¯0.41 and 7.32 ±â€¯0.18 µM, respectively. Compounds 5 and 7 displayed significant cytotoxicity against the A549 lung cancer cell line (IC50 values of 4.83 ±â€¯0.22 µM and 4.58 ±â€¯0.85 µM, respectively). In addition, compound 5 showed an obvious inhibitory effect on nitric oxide production in LPS-activated RAW264.7 macrophages with an IC50 value of 9.53 ±â€¯0.16 µM.