Sesquiterpene Quinones Research Articles

Divergent total synthesis of sesquiterpene (hydro)quinone meroterpenoids dysideanones A and E–G

The first total synthesis of marine sesquiterpene (hydro)quinone meroterpenoids dysideanones A and E–G (1 and 4–6) has been accomplished in an enantioselective and divergent way. The sesquiterpene fragment and the aromatic moiety were efficiently connected via a site-selective and diastereoselective intermolecular alkylation of Wieland–Miescher ketone derivative 9 and benzyl bromide 10. The core 6/6/6/6-fused backbone of dysideanones was efficiently constructed through an intramolecular radical cyclization reaction. Dysideanone G (6) was easily prepared on a gram-scale and dysideanones A, E, and F (1, 4, and 5) were divergently transformed from dysideanone G (6) in one or two steps

Total synthesis of 1,2,11,12E-tetradehydrohardwickiic acid

Clerodane diterpenoids are a large class of natural products found in various species and exhibit a wide range of biological activities. trans-Clerodanes, which feature a trans-decalin core structure, are the most common subfamily of clerodane diterpenoids. Previously, we have developed a tail-to-head cyclization strategy via a titanium(III) catalyzed alkyne terminated radical polyene cyclization to synthesis C18 non-oxidized trans-clerodanes and sesquiterpene (hydro)quinones with a similar trans-decalin skeleton. In this communication, we reported the first asymmetric total synthesis of 1,2,11,12E-tetradehydrohardwickiic acid, a C18 oxidized trans-clerodane, through the product of titanium(III) catalyzed tail-to-head polyene cyclization of the derivative of farnesol. A hydroxyl group directed hydrogenation of alkene, an E-selective hydrobromination of terminal alkyne, and a Suzuki coupling were the key steps of the synthesis.

Pseudoceranoids A-J, Sesquiterpene-Based Meroterpenoids with Cytotoxicity from the Sponge Pseudoceratina purpurea.

Pseudoceranoid A (1), a rare merosesquiterpene featuring a rearranged 4,9-friedodrimane-type core with a crotonolactone moiety, two new rearranged 4,9-friedodrimane-type sesquiterpene cyclopentanones (2 and 3), and three new rearranged 4,9-friedodrimane-type sesquiterpene hydroquinones (4-6), along with two new drimane-type sesquiterpene derivatives (7 and 8), as well as two new 4,9-friedodrimane-type sesquiterpene quinones (9 and 10), were isolated from the South China Sea sponge Pseudoceratina purpurea. The structures of compounds were established by analysis of spectroscopic data, as well as by single-crystal X-ray diffraction, DP4+ probability analyses, and calculated electronic circular dichroism. Compound 4 showed weak cytotoxicity against K562, H69AR, and MDAMB-231 cell lines with IC50 values of 3.01, 7.74, and 9.82 μM, respectively. Compound 5 exhibited cytotoxicity against the H69AR cell line with an IC50 value of 2.85 μM.

High variability of perezone content in rhizomes of Acourtia cordata wild plants, environmental factors related, and proteomic analysis.

With the aim of exploring the source of the high variability observed in the production of perezone, in Acourtia cordata wild plants, we analyze the influence of soil parameters and phenotypic characteristics on its perezone content. Perezone is a sesquiterpene quinone responsible for several pharmacological effects and the A. cordata plants are the natural source of this metabolite. The chemistry of perezone has been widely studied, however, no studies exist related to its production under natural conditions, nor to its biosynthesis and the environmental factors that affect the yield of this compound in wild plants. We also used a proteomic approach to detect differentially expressed proteins in wild plant rhizomes and compare the profiles of high vs. low perezone-producing plants. Our results show that in perezone-producing rhizomes, the presence of high concentrations of this compound could result from a positive response to the effects of some edaphic factors, such as total phosphorus (Pt), total nitrogen (Nt), ammonium (NH4), and organic matter (O. M.), but could also be due to a negative response to the soil pH value. Additionally, we identified 616 differentially expressed proteins between high and low perezone producers. According to the functional annotation of this comparison, the upregulated proteins were grouped in valine biosynthesis, breakdown of leucine and isoleucine, and secondary metabolism such as terpenoid biosynthesis. Downregulated proteins were grouped in basal metabolism processes, such as pyruvate and purine metabolism and glycolysis/gluconeogenesis. Our results suggest that soil parameters can impact the content of perezone in wild plants. Furthermore, we used proteomic resources to obtain data on the pathways expressed when A. cordata plants produce high and low concentrations of perezone. These data may be useful to further explore the possible relationship between perezone production and abiotic or biotic factors and the molecular mechanisms related to high and low perezone production.

Assessment of antidiabetic activity of three Phenylspirodrimanes from fungus Stachybotrys chartarum MUT 3308 by ADME, QSAR, molecular docking and molecular dynamics simulation studies against protein tyrosine phosphatase 1B (PTP1B)

Phenylspirodrimanes (PSD) are the sesquiterpene quinone type meroterpenoids found in nature. PSDs are found to exhibit inhibitory activity against immunocomplex diseases, and tyrosine kinase receptors. Three of the different PSDs C1, C2, and C3 that have been reported to be isolated from the sponge-associated fungus Stachybotrys chartarum MUT 3308 are selected for studying their possible inhibitory effect against type 2 diabetes mellitus. Mechanistically, blocking protein tyrosine phosphatase 1B (PTP1B) helps to reduce the insulin resistance induction caused by the high expression of PTP1B. The QSAR, ADME, toxicity (T) study was carried out to predict the pharmacokinetic properties and the biological activities of the PSDs. PASS prediction web tool was used to find and select the target proteins 1NNY, and 2HNP. According to the molecular docking simulations, C1 and C2 showed better binding affinity of −8.5 kcal/mol, and −8.1 kcal/mol respectively against 1NNY compared to the control ligand. RMSD, RMSF, Rg, and SASA analysis revealed that both C1, and C2 showed better stability, minor conformational changes, and minor fluctuation upon binding to PTP1B. Protein contact analysis was carried out to validate the residues that are in contact with the ligands according to molecular docking studies. Overall, C1, and C2 could be proposed as novel natural hits to be developed and small modifications of these PSDs could result in inducing the binding affinity significantly, although experimental validation is required for further evaluation of the work. Communicated by Ramaswamy H. Sarma

Practical and Scalable Total Syntheses of (+)-Dysidavarones A–C

AbstractA practical and scalable enantioselective total syntheses of the marine anticancer sesquiterpene quinone meroterpenoids (+)-dysidavarones A–C has been accomplished. The central bridged bicyclo[3.3.1]nonane structure of dysidavarones was efficiently established by a one-pot intermolecular diastereoselective alkylation and intramolecular α-arylation of a Wieland–Miescher ketone derivative with a substituted benzylic bromide, without protection of the more-reactive C(4) carbonyl group. (+)-Dysidavarones A and ‘E’ were prepared on a 150-mg scale, demonstrating the efficiency and reliability of our synthetic route and providing sufficient amounts of the dysidavarones for further bioactivity evaluation.

Divergent total synthesis of marine meroterpenoids (+)-dysidavarones A–C

Here, we report a concise and divergent enantioselective total synthesis of marine sesquiterpene quinone meroterpenoids (+)-dysidavarones A–C (1–3) using predysidavarone 6 as a key common intermediate. The highly strained and bridged eight-membered carbocycle of predysidavarone 6 was constructed by a one-pot intermolecular alkylation and intramolecular arylation of Wieland–Miescher ketone derivative 11 and benzyl bromide 12. The total synthesis of (+)-dysidavarones A–C (1–3) was achieved from predysidavarone 6 in a divergent manner by a late-stage introduction of the ethoxy group, which reveals the possible source of the ethoxy group within (+)-dysidavarones A–C (1–3) and provides a late-stage modifiable route for the synthesis of dysidavarone analogs for further anti-cancer activity evaluation.

Evidence of Insulin-Sensitizing and Mimetic Activity of the Sesquiterpene Quinone Avarone, a Protein Tyrosine Phosphatase 1B and Aldose Reductase Dual Targeting Agent from the Marine Sponge Dysidea avara.

Type 2 diabetes mellitus (T2DM) is a complex disease characterized by impaired glucose homeostasis and serious long-term complications. First-line therapeutic options for T2DM treatment are monodrug therapies, often replaced by multidrug therapies to ensure that non-responding patients maintain target glycemia levels. The use of multitarget drugs instead of mono- or multidrug therapies has been emerging as a main strategy to treat multifactorial diseases, including T2DM. Therefore, modern drug discovery in its early stages aims to identify potential modulators for multiple targets; for this purpose, exploration of the chemical space of natural products represents a powerful tool. Our study demonstrates that avarone, a sesquiterpene quinone obtained from the sponge Dysidea avara, is capable of inhibiting in vitro PTP1B, the main negative regulator of the insulin receptor, while it improves insulin sensitivity, and mitochondria activity in C2C12 cells. We observe that when avarone is administered alone, it acts as an insulin-mimetic agent. In addition, we show that avarone acts as a tight binding inhibitor of aldose reductase (AKR1B1), the enzyme involved in the development of diabetic complications. Overall, avarone could be proposed as a novel natural hit to be developed as a multitarget drug for diabetes and its pathological complications.

Modular total syntheses of trans-clerodanes and sesquiterpene (hydro)quinones via tail-to-head cyclization and reductive coupling strategies

The trans-clerodanes and sesquiterpene (hydro)quinones are a growing class of natural products that exhibit a wide range of biological activities. Although they are different types of natural products, some of them feature the same trans-decalin core structure. Here, we report the total syntheses of two members of trans-clerodanes, five members of sesquiterpene (hydro)quinones as well as the proposed structure of dysidavarone D via a modular synthetic route. A bioinspired tail-to-head cyclization strategy was developed to syntheses of the trans-decalin architectures by using two diastereochemically complementary radical polyene cyclization reactions catalyzed by Ti(III) and mediated by Mn(III), respectively. The different types of side chains were introduced by challenging nickel catalyzed reductive couplings of sterically hindered alkyl halides. The synthesis of the proposed dysidavarone D proved a wrong structural assignment of the natural product.

Dysideanones F-G and dysiherbols D-E, unusual sesquiterpene quinones with rearranged skeletons from the marine sponge Dysidea avara.

Four new sesquiterpene quinone meroterpenoids, dysideanones F-G (1-2) and dysiherbols D-E (3-4), were isolated from the marine sponge Dysidea avara collected from the South China Sea. The new structures were elucidated by extensive analysis of spectroscopic data including HR-MS and 1D and 2D NMR spectra, and their absolute configurations were assigned by single-crystal X-ray diffraction and ECD calculations. Anti-inflammatory evaluation showed that dysiherbols D-E (3-4) exhibited moderate inhibitory activity on TNF-α-induced NF-κB activation in human HEK-293T cells with IC50 values of 10.2 and 8.6 μmol·L-1, respectively.

Cellular antioxidant potential and inhibition of foodborne pathogens by a sesquiterpene ilimaquinone in cold storaged ground chicken and under temperature-abuse condition

A sesquiterpene quinone, ilimaquinone, was accessed for its cellular antioxidant efficacy and possible antimicrobial mechanism of action against foodborne pathogens (Staphylococcus aureus and Escherichia coli) in vitro and in vivo. Ilimaquinone was found to be protective against H2O2-induced oxidative stress as validated by the reduction in the ROS levels, including increasing expression of SOD1 and SOD2 enzymes. Furthermore, ilimaquinone evoked MIC against S. aureus and E. coli within the range of 125–250 µg/mL. Ilimaquinone established its antimicrobial mode of action against both tested pathogens as evident by bacterial membrane depolarization, loss of nuclear genetic material, potassium ion, and release of extracellular ATP, as well as compromised membrane permeabilization and cellular component damage. Also, ilimaquinone showed no teratogenic effect against zebrafish, suggesting its nontoxic nature. Moreover, ilimaquinone significantly reduced the S. aureus count without affecting the sensory properties and color values of cold-storaged ground chicken meat even under temperature abuse condition.

Exerting DNA Damaging Effects of the Ilimaquinones through the Active Hydroquinone Species

Possessing the quinone moiety, ilimaquinone (1), a sponge–derived sesquiterpene quinone, has been hypothesised to express its cytotoxicity through a redox cycling process, yielding active product(s) that can cause DNA damage. To determine the DNA damaging effects of 1 and examine whether a redox transformation may participate in its functions, the DNA damaging properties of 1, the corresponding hydroquinone (2) and hydroquinone triacetates (3) and their 5-epimeric counterparts (4–6) were tested and compared. When incubated directly with plasmid DNA, the hydroquinones were the only active species capable of cleaving the DNA. In cell-based assays, however, the quinones and hydroquinone triacetates were active in the same range as that of the corresponding hydroquinones, and all damaged the cellular DNA in a similar manner. The in situ reduction of 1 and 4 were supported by the decreases in the cytotoxicity when cells were pre-exposed to dicoumarol, an NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitor. The results confirmed the DNA damaging activities of the ilimaquinones 1 and 4, and indicated the necessity to undergo an in-situ transformation into the active hydroquinones, thereby exerting the DNA damaging properties as parts of the cytotoxic mechanisms.

A Timeline of Perezone, the First Isolated Secondary Metabolite in the New World, Covering the Period from 1852 to 2020.

This chapter covers a sesquiterpene quinone, commonly named perezone. This molecule is documented as the first secondary metabolite isolated in crystalline form in the New World in 1852. An introduction, with its structure, the IUPAC nomenclature, and the most recent physical and spectroscopic characterizations are firstly described initially. Alongside this, a timeline and scheme with summarized information of the history of this molecule is given including the "Códice Badiano de la Cruz, 1552, highlighting the year of its isolation culminating with information up to 2005. Subsequently, in a chronological order the most recent advances of the target molecule are included and organized in subsections covering the last 15-year period 2006-2020. Finally, recently submitted contributions from the laboratory of the authors are described. It is important to note that the details provided highlight the importance and relevance of perezone.

Fluorescent image-based high-content screening of extracts of natural resources for cell cycle inhibitors and identification of a new sesquiterpene quinone from the sponge, Dactylospongia metachromia

Natural products are important sources for drug development. Discovery of natural products that inhibit cell cycle progression significantly contributes to the progress of cancer biology and the development of new antitumor agents. In this study, cell cycle inhibitory activity was evaluated with our extract library of natural resources, including marine invertebrates, fungi, and bacteria, using HeLa/Fucci2 cells which allow classification of the cell cycle phases of living cells. Screening of the extract library revealed that the extract of the marine sponge Dactylospongia metachromia inhibited cell cycle progression at S/G2/M phases. Bioassay-guided fractionation afforded a new sesquiterpene quinone, neoisosmenospongine (1), and four known compounds, nakijiquinone I, N, and Q (2–4) and (–)-dictyoceratin-C (5). The chemical structure of 1 was elucidated by interpretating the NMR and mass spectroscopic data, and the absolute configuration was determined by comparison of the experimental and calculated ECD spectra. Fluorescent imaging of HeLa/Fucci2 cells revealed that 1–4 inhibited the cell cycle progression at S/G2/M phases. This study demonstrated that fluorescent image-based high-content screening using HeLa/Fucci2 cells is an effective approach for isolating cell cycle inhibitors from natural resources.

Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity

In cancer cells, aerobic glycolysis rather than oxidative phosphorylation (OxPhos) is generally preferred for the production of ATP. In many cancers, highly expressed pyruvate dehydrogenase kinase 1 (PDK1) reduces the activity of pyruvate dehydrogenase (PDH) by inducing the phosphorylation of its E1α subunit (PDHA1) and subsequently, shifts the energy metabolism from OxPhos to aerobic glycolysis. Thus, PDK1 has been regarded as a target for anticancer treatment. Here, we report that ilimaquinone (IQ), a sesquiterpene quinone isolated from the marine sponge Smenospongia cerebriformis, might be a novel PDK1 inhibitor. IQ decreased the cell viability of human and murine cancer cells, such as A549, DLD-1, RKO, and LLC cells. The phosphorylation of PDHA1, the substrate of PDK1, was reduced by IQ in the A549 cells. IQ decreased the levels of secretory lactate and increased oxygen consumption. The anticancer effect of IQ was markedly reduced in PDHA1-knockout cells. Computational simulation and biochemical assay revealed that IQ interfered with the ATP binding pocket of PDK1 without affecting the interaction of PDK1 and the E2 subunit of the PDH complex. In addition, similar to other pyruvate dehydrogenase kinase inhibitors, IQ induced the generation of mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in the A549 cells. The apoptotic cell death induced by IQ treatment was rescued in the presence of MitoTEMPO, a mitochondrial ROS inhibitor. In conclusion, we suggest that IQ might be a novel candidate for anticancer therapeutics that act via the inhibition of PDK1 activity.

Ilimaquinone Induces Apoptosis and Autophagy in Human Oral Squamous Cell Carcinoma Cells.

In this study, the anti-tumor activity of ilimaquinone (IQ), a sesquiterpene quinone isolated from marine sponge Halichondria sp., in oral squamous cell carcinoma (OSCC) cells, was investigated. IQ suppressed the viability of the OSCC cell lines SCC4 and SCC2095 with IC50 values of 7.5 and 8.5 μM, respectively. Flow cytometric analysis demonstrated that IQ induced caspase-dependent apoptosis in SCC4 cells and modulated the expression of several cell growth-related gene products, including Akt, p38, Mcl-1, and p53. Notably, p53 knockdown caused higher resistance to IQ’s anti-tumor activity. In addition, IQ increased reactive oxygen species generation, which was partially reversed by the addition of antioxidants. Furthermore, it triggered autophagy, as evidenced by acidic organelle formation and LC3B-II and Atg5 expression in SCC4 cells. Pretreatment with the autophagy inhibitor 3-methyladenine or chloroquine partially decreased IQ-induced apoptosis, suggesting that IQ induced protective autophagy. In summary, IQ has potential to be used in OSCC therapy.

Shikimate Kinase Expression; Towards Screening of Potential Antibacterials from Marine Sponges

Tuberculosis is one of the world’s leading cause of mortality from a single bacterial pathogen, with over 10 million reported cases each year. There is an alarming increase in the prevalence of drug‐resistant strains, thus the need for the discovery of novel anti‐tubercular agents. The shikimate pathway is a seven‐step metabolic route that produces aromatic amino acids and other cellular metabolites. It has no mammalian counterpart, making any of the enzymes in this pathway suitable targets for screening of potential anti‐tubercular agents. Mycobacterium tuberculosis shikimate kinase (MtSK) catalyzes the 5th step of this pathway, converting shikimate to shikimate‐3‐phosphate using ATP as a co‐substrate. The overall goal of this project is to express and characterize MtSK and screen for potential anti‐tubercular agents. Transformation of XL‐1 blue competent cells was performed using a pET 21b plasmid with aroK gene inserted at the multiple cloning site. Plasmids were cloned and purified and used to transform BL 21 DE3 competent cells for subsequent protein expression. Small scale expression showed the presence of a band of increasing prominence around 20 kDa. This suggests MtSK was successfully expressed. Expression analysis for larger scale supported data from small scale. Purification, characterization, and MtSK kinetic parameters would be determined prior to enzyme inhibition studies using inhibitors like avarone (below), a marine sponge sesquiterpene quinone and derivatives thereof.Support or Funding InformationEast Stroudsburg University of PennsylvaniaAvaroneFigure 1

Investigating the Antiparasitic Potential of the Marine Sesquiterpene Avarone, Its Reduced form Avarol, and the Novel Semisynthetic Thiazinoquinone Analogue Thiazoavarone.

The chemical analysis of the sponge Dysidea avara afforded the known sesquiterpene quinone avarone, along with its reduced form avarol. To further explore the role of the thiazinoquinone scaffold as an antiplasmodial, antileishmanial and antischistosomal agent, we converted the quinone avarone into the thiazinoquinone derivative thiazoavarone. The semisynthetic compound, as well as the natural metabolites avarone and avarol, were pharmacologically investigated in order to assess their antiparasitic properties against sexual and asexual stages of Plasmodium falciparum, larval and adult developmental stages of Schistosoma mansoni (eggs included), and also against promastigotes and amastigotes of Leishmania infantum and Leishmania tropica. Furthermore, in depth computational studies including density functional theory (DFT) calculations were performed. A toxic semiquinone radical species which can be produced starting both from quinone- and hydroquinone-based compounds could mediate the anti-parasitic effects of the tested compounds.

Puupehenone, a Marine-Sponge-Derived Sesquiterpene Quinone, Potentiates the Antifungal Drug Caspofungin by Disrupting Hsp90 Activity and the Cell Wall Integrity Pathway.

The cell wall-targeting echinocandin antifungals, although potent and well tolerated, are inadequate in treating fungal infections due to their narrow spectrum of activity and their propensity to induce pathogen resistance. A promising strategy to overcome these drawbacks is to combine echinocandins with a molecule that improves their activity and also disrupts drug adaptation pathways. In this study, we show that puupehenone (PUUP), a marine-sponge-derived sesquiterpene quinone, potentiates the echinocandin drug caspofungin (CAS) in CAS-resistant fungal pathogens. We have conducted RNA sequencing (RNA-seq) analysis, followed by genetic and molecular studies, to elucidate PUUP's CAS-potentiating mechanism. We found that the combination of CAS and PUUP blocked the induction of CAS-responding genes required for the adaptation to cell wall stress through the cell wall integrity (CWI) pathway. Further analysis showed that PUUP inhibited the activation of Slt2 (Mpk1), the terminal mitogen-activated protein (MAP) kinase in this pathway. We also found that PUUP induced heat shock response genes and inhibited the activity of heat shock protein 90 (Hsp90). Molecular docking studies predicted that PUUP occupies a binding site on Hsp90 required for the interaction between Hsp90 and its cochaperone Cdc37. Thus, we show that PUUP potentiates CAS activity by a previously undescribed mechanism which involves a disruption of Hsp90 activity and the CWI pathway. Given the requirement of the Hsp90-Cdc37 complex in Slt2 activation, we suggest that inhibitors of this complex would disrupt the CWI pathway and synergize with echinocandins. Therefore, the identification of PUUP's CAS-potentiating mechanism has important implications in the development of new antifungal combination therapies.IMPORTANCE Fungal infections cause more fatalities worldwide each year than malaria or tuberculosis. Currently available antifungal drugs have various limitations, including host toxicity, narrow spectrum of activity, and pathogen resistance. Combining these drugs with small molecules that can overcome these limitations is a useful strategy for extending their clinical use. We have investigated the molecular mechanism by which a marine-derived compound potentiates the activity of the antifungal echinocandin caspofungin. Our findings revealed a mechanism, different from previously reported caspofungin potentiators, in which potentiation is achieved by the disruption of Hsp90 activity and signaling through the cell wall integrity pathway, processes that play important roles in the adaptation to caspofungin in fungal pathogens. Given the importance of stress adaptation in the development of echinocandin resistance, this work will serve as a starting point in the development of new combination therapies that will likely be more effective and less prone to pathogen resistance.

Metachromins X and Y from a marine sponge Spongia sp. and their effects on cell cycle progression

New sesquiterpene quinones, metachromins X (1) and Y (2), together with the known metachromins C (3), J (4), and T (5), were isolated as inhibitors of cell cycle progression in the HeLa/Fucci2 cells. The structure of 1 was assigned by spectroscopic data and confirmed by a total synthesis. The planar structure of 2 was determined by interpretation of spectroscopic data, whereas its absolute configuration was analyzed by a combination of chiral HPLC and CD spectroscopy. Metachromins X (1) and C (3) arrested the cell cycle progression of HeLa/Fucci2 cells at S/G2/M phase.