Sesquiterpene Aminoquinone Research Articles

A Review on Diversity of Anticancer Compounds Derived from Indonesian Marine Sponges

As a tropical archipelago country, Indonesia has a mega diversity of marine organisms, such as sponges. About 850 species of sponges were identified from the east part of Indonesia. The uniqueness of Indonesian marine sponges attracted many researchers to explore the sponge’s potential in producing active substances. During 1995-2016, about 40 genera of Indonesian sponges were investigated for their potential in producing pharmacological activity such as antimicrobial, anticancer, antivirus, multidrug-resistant (MDR), etc. The data showed that 56.7% of 430 reported compounds were confirmed as new compounds. The research trend on Indonesian sponges was high during 2004-2013, but decreasing after 2014. However, researches in the term of active substances from marine sponges should find provide the basic skeleton of anti-cancer drug lead compounds. Chemical structure diversity plays an important role in the exploration of anticancer lead compounds. The purpose of this paper is to review the potential of anticancer diversity compounds derived from Indonesian sponges, to get comprehensive data for further investigation. As the conclusion of our review, the most anticancer compounds derived from Indonesian marine invertebrates are alkaloid groups (such as aaptamine, manzamine, and bromopyrrole derivatives), then terpenoid groups (such as diterpene, coelodiol, and coeloic acid, sesquiterpene aminoquinone, and also (+)-curcuphenol and (+)-curcudiol), and also from the other groups such as sterole, peptide, polyketide, amino acid derivatives, natural organic acid, and quinone. The most effective anticancer compounds were 5-benzoyldemethylaaptamine, isoaaptamine, 3-bromofascaplysin, hyrtioreticulins A, stylissamide X, sigmosceptrellin B, and diacarperoxide S.

Marine sponge-derived smenospongine preferentially eliminates breast cancer stem-like cells via p38/AMPKα pathways.

Breast cancer stem cells (CSCs) have been postulated as responsible for therapeutic failure of breast cancer. Novel agents effectively targeting breast CSCs are urging to be discovered to overcome cancer relapse and metastasis. We recently established a CSC‐like model through ectopic expression Nanog, a core pluripotency factor, in breast cancer cells and validated induced CSC‐like (MCF7‐Nanog) model acquired stem‐like properties. Using this model, we found that smenospongine (Sme), a natural sesquiterpene aminoquinone isolated from marine sponge Spongia pertusa Esper, preferentially inhibited the induced CSC‐like cells proliferation by inducing G0/G1 arrest and intrinsic apoptosis via increasing the phosphorylation level of p38 and AMPKα. Importantly, Sme exhibited the ability to abrogate CSC‐like cells associated with a downregulation of stem cell markers including Nanog, Sox2, and Bmi1. Functionally, Sme inhibited the ability of MCF7‐Nanog cells to form tumor sphere in vitro and develop tumor in vivo. Significant antitumor effects are observed in Sme‐treated mouse xenograft tumor models, with no apparent toxicity to mice. Taken together, our findings provide a CSC‐like model to identify novel CSC‐targeting drugs and identify Sme as a candidate natural agent for treatment of breast cancer.

Two sesquiterpene aminoquinones protect against oxidative injury in HaCaT keratinocytes via activation of AMPKα/ERK-Nrf2/ARE/HO-1 signaling

AimsTo investigate the cytoprotective effects of two sesquiterpene aminoquinones isolated from the marine sponge Dysidea fragilis, Dysidaminone H (DA8) and 3′-methylamino-avarone (DA14), we examined their effects against hydrogen peroxide (H2O2)-induced oxidative injury in human keratinocyte cell line and elucidated the underlying mechanisms. Main methodsCell viability was detected using a CCK-8 assay kit. Intracellular reactive oxygen species (ROS) production was measured by fluorescence of 2, 7-Dichlorodi-hydrofluorescein diacetate (DCFH-DA). Messenger RNA and protein expression were measured by real-time quantitative PCR and western blotting analysis. Immunocytochemistry was performed to determine the intracellular location of nuclear factorerythroid 2 p45 related factor 2 (Nrf2). The antioxidant response element (ARE)-luciferase reporter gene assay and RNA interference were used to establish the role of ARE and Nrf2. Key findingsDA8 and DA14 (DAs) resisted H2O2induced decline of cell viability by inhibiting the accumulation of ROS. Meanwhile, DAs increased HO-1 expression and ARE activity and induced Nrf2 expression, as well as the accumulation of Nrf2 in the cell nucleus. However, silencing of Nrf2 abolished DAs-induced HO-1 expression and ARE luciferase activation. In addition, DAs induced the phosphorylation of both cyclic AMP-activated protein kinase-α (AMPKα) and extracellular signal-regulated kinase (ERK), while specific inhibitors of AMPKα and ERK abrogated HO1 upregulation and Nrf2 activation. SignificanceDAs provided cytoprotective effects against H2O2-induced cytotoxicity by activation of the Nrf2/ARE/HO-1 pathway via phosphorylation of AMPKα and ERK. The findings suggested that DA8 and DA14 might be the candidate therapeutic agents for skin diseases caused by oxidative injury.

Dysifragilone A inhibits LPS‑induced RAW264.7 macrophage activation by blocking the p38 MAPK signaling pathway.

Dysifragilone A, a sesquiterpene aminoquinone based on a rearranged avarone skeleton, has been previously isolated and identified from the South China Sea sponge Dysideafragilis. In the present study, anti‑inflammatory activity and the underlying molecular mechanism of dysifragilone A were studied using the classical inflammation model of lipopolysaccharide (LPS)‑activated RAW264.7 macrophage cells and an MTT assay, Griess method, ELISA and western blotting were used. The results revealed that dysifragilone A significantly reduced the release of inflammatory mediators and inflammatory cytokines in activated RAW264.7 cells, including nitric oxide (NO), prostaglandin E2,(PGE2) and interleukin‑6 (IL‑6). The protein expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase‑2 (COX‑2), and the enzymatic activity of iNOS and COX‑2 were also inhibited by dysifragilone A in a dose dependent manner. Further mechanistic investigations suggested that the anti‑inflammatory activity of dysifragilone A results from the suppression of p38 mitogen‑activated protein kinase (MAPK) activation in LPS‑activated macrophages; however, this was not associated with inhibition of the extracellular signal‑regulated kinase(ERK) or c‑Jun N‑terminal kinase(JNK) signaling pathways. Therefore, dysifragilone A and similar compounds may be anti‑inflammatories that have potential to be used in the clinic.

Three new sesquiterpene aminoquinones from a Vietnamese Spongia sp. and their biological activities.

Sesquiterpenoid quinones with remarkable properties, such as anti-inflammatory, antibacterial, antiviral, antitumor, antiangiogenic, and differentiation-inducing activities, have reportedly been isolated from the marine sponge genera Dysidea, Spongia, and Dactylospongia. In our continuing search for bioactive compounds from marine sponges, three new sesquiterpenoid quinones, langcoquinones D-F (1-3), were isolated from the ethyl acetate extract of Spongia sp. collected from Vietnam. Their chemical structures were elucidated on the basis of extensive spectroscopic analyses. The newly isolated compounds 1-3 were assessed for their antibacterial activities against Gram-positive bacteria, Bacillus subtilis and Staphylococcus aureus, and Gram-negative bacteria, Klebsiella pneumoniae and Escherichia coli, as well as their cytotoxic activities against three human cancer cell lines (A549, lung cancer; MCF7, breast cancer; HeLa, cervical cancer) and a human normal cell line (WI-38 fibroblast). All compounds were inactive against the Gram-negative bacteria. Furthermore, langcoquinones E (2) and F (3) lacked antibacterial activities against the Gram-positive bacteria and cytotoxic activities against the tested cell lines. However, langcoquinone D (1) exhibited good antibacterial activities against Bacillus subtilis and Staphylococcus aureus, with MIC values of 12.5 and 25.0µM, respectively. Furthermore, 1 exhibited significant cytotoxic activities against three human cancer cell lines (A549, lung cancer; MCF7, breast cancer; HeLa, cervical cancer) and a human normal cell line (WI-38 fibroblast).

New antibacterial sesquiterpene aminoquinones from a Vietnamese marine sponge of Spongia sp.

Two new sesquiterpene aminoquinones, langcoquinones A (1) and B (2), together with seven known meroterpenoids (3⿿9), were isolated from the marine sponge Spongia sp. collected in Vietnam. Their structures were determined on the basis of spectroscopic analyses and comparisons with published data. The antibacterial activities of the isolated compounds (1⿿9) were investigated against four bacterial strains. Among these, the new sesquiterpene aminoquinones (1 and 2) and the known related compounds (3, 5, 6, 8, and 9) exhibited significant antibacterial activities against Staphylococcus aureus and Bacillus subtilis, with MICs ranging from 6.25 to 12.5μM.

Antibacterial Meroterpenoids from the South China Sea Sponge Dysidea sp.

Chemical investigation of the sponge Dysidea sp. afforded three new sesquiterpene phenols (1-3) and one new sesquiterpene aminoquinone (4), together with four known sesquiterpene derivatives (5-8). The structures of all compounds were unambiguously elucidated by extensive spectroscopic analysis, as well as by comparison with the literature. The absolute configurations of compounds 1-4 were determined by electron capture detector (ECD) calculations and circular dichroism (CD) spectrum analysis. Their antibacterial activity against Escherichia coli (25922), Bacillus subtilis (6633), and Staphylococcus aureus (25923) were evaluated. Compounds 1 and 3 showed weak antibacterial activity against the above three strains, whereas compounds 4-8 showed potent antibacterial activities with minimum inhibitory concentration (MIC) values in the range of 3.125 to 12.5 µg/mL.

ChemInform Abstract: Dysifragilones A—C, Unusual Sesquiterpene Aminoquinones and Inhibitors of NO Production from the South China Sea Sponge Dysidea fragilis.

AbstractThree unusual sesquiterpene aminoquinones based on a rearranged avarone skeleton, dysifragilones A (Ia), B (Ib), and C (II), are isolated from the marine sponge Dysidea fragilis.

Dysifragilones A–C, Unusual Sesquiterpene Aminoquinones and Inhibitors of NO Production from the South China Sea Sponge Dysidea fragilis

AbstractDysifragilones A–C (1–3), three unusual sesquiterpene aminoquinones based on a rearranged avarone skeleton, were isolated from the South China Sea sponge Dysidea fragilis. Their structures were elucidated by detailed spectroscopic and spectrometric analysis, and their absolute configurations were assigned from calculated electronic circular dichroism (ECD) spectra. The inhibitory activity of each compound on the production of nitric oxide (NO) stimulated by lipopolysaccharide (LPS) in mouse RAW 264.7 macrophages was evaluated. Of the three metabolites, dysifragilone A (1) showed the most potent inhibitory activity, with an IC50 value of 6.61 ± 0.54 μM.

Sesquiterpene Derivatives and Steroids from the Sponge Dactylospongia elegans Collected from the South China Sea

Sponges of the genus Dactylospongia have been widely investigated for their biologically active compounds. The majority of the reported metabolites are sesquiterpene quinones [1, 2], as well as a few macrolides [3]. For example, smenospongine, a sesquiterpene aminoquinone isolated from the Indonesian sponge D. elegans, showed multifaceted antitumor activity on leukemia cells [4]. Sponge Material. The sponge of Dactylospongia elegans was collected in April 2006 from Meishan coral reef, Sanya, China, and was authenticated (RMNH POR. 5235) by Dr. Nicole J. de Voogd, Netherlands Centre for Biodiversity Naturalis, The Netherlands. A voucher specimen (HN-SY-2006WMS-18) was deposited in the Key Laboratory of Marine Drugs, Ministry of Education, Ocean University of China, Qingdao, China. Extraction and Isolation. The sponge Dactylospongia elegans (0.7 kg, dry weight) was extracted exhaustively with 95% ethanol (2000 mL 5) at room temperature. The solvent-free EtOAc extract (1.0 g) was subjected to column chromatography on silica gel and eluted with EtOAc in petroleum (0–100%, gradient) to yield six fractions. The subfractions were then isolated by successive column chromatography on silica gel and Sephadex LH-20 and purified by semi-preparative HPLC, leading to the isolation of compounds (1/2) (50.6 mg), (3) (2.4 mg), (4) (4.2 mg), (5) (1.8 mg), and (6) (8.5 mg). On the basis of extensive spectroscopic analyses and by comparison with those reported in the literature, the structures of compounds 1–6 were established as dactyltronic acids (1/2) [5, 6], dictyoceratin C (3) [7], polyfibrospongol A (4) [8], 3 -hydroxycholesta-5,8-dien-7-one (5) [9], and pregna-1,20-dien-3-one (6) [10]. Compounds 3, 5, and 6 were obtained from the genus Dactylospongia for the first time. The antibacterial activity in vitro of the isolated compounds was evaluated against a panel of pathogenic bacterial strains, Staphylococcus aureus, S. albus, Bacillus subtilis, B. cereus, Micrococcus tetragenus, Kocuria rhizophila, Vibrio parahemolyticus, V. anguillarum, and Pseudomonas putida, by using a standard screening protocol [11]. The results indicated that dactyltronic acids 1/2 showed pronounced antibacterial activity against V. parahemolyticus with a MIC value of 3.45 M (the positive control ciprofloxacin MIC = 1.25 M). Pregna-1,20-dien-3-one (6) also exhibited activity toward B. cereus with a MIC value of 4.19 M (ciprofloxacin MIC = 1.25 M). However, compounds 3, 4, and 5 only showed weak antibacterial activity.

ChemInform Abstract: Dysidaminones A—M, Cytotoxic and NF‐ϰB Inhibitory Sesquiterpene Aminoquinones from the South China Sea Sponge Dysidea fragilis.

AbstractThirteen new sesquiterpene aminoquinones are isolated and their structure is spectroscopically determined.

Cytotoxic and Protein Kinase Inhibiting Nakijiquinones and Nakijiquinols from the Sponge Dactylospongia metachromia

Chemical investigation of the sponge Dactylospongia metachromia afforded five new sesquiterpene aminoquinones (1-5), two new sesquiterpene benzoxazoles (6 and 7), the known analogue 18-hydroxy-5-epi-hyrtiophenol (8), and a known glycerolipid. The structures of all compounds were unambiguously elucidated by one- and two-dimensional NMR and by MS analyses, as well as by comparison with the literature. Compounds 1-5 showed potent cytotoxicity against the mouse lymphoma cell line L5178Y with IC50 values ranging from 1.1 to 3.7 μM. When tested in vitro for their inhibitory potential against 16 different protein kinases, compounds 5, 6, and 8 exhibited the strongest inhibitory activity against ALK, FAK, IGF1-R, SRC, VEGF-R2, Aurora-B, MET wt, and NEK6 kinases (IC50 0.97-8.62 μM).

Dysidaminones A–M, cytotoxic and NF-κB inhibitory sesquiterpene aminoquinones from the South China Sea sponge Dysidea fragilis

Structural determination, absolute configuration assignments, and biological activities of new sesquiterpene aminoquinones from Dysidea fragilis.

Three bioactive sesquiterpene quinones from the Fijian marine sponge of the genus Hippospongia

A sesquiterpenoid quinone, epi-ilimaquinone (1), and two sesquiterpene amino quinones, smenospongine (2) and glycinylilimaquinone (3), were isolated from the Fijian marine sponge Hippospongia sp. The structures of these compounds were determined by spectroscopic analysis. Compounds 1 and 3 were reported for the first time in this study from the sponge of the genus Hippospongia. Compound 1 displayed potent cytotoxic activity and showed antibacterial activity against methicillin-resistant Staphylococcus aureus, wild type S. aureus and vancomycin-resistant Enterococcus faecium and displayed antifungal activity against amphotericin-resistant Candida albicans while compounds 2 and 3 showed moderate cytotoxic activity. However, compound 1 did not show appreciable antifungal activity against wild type C. albicans, Cryptococcus neoformans, Aspergillus niger, Penicillium sp., Rhizopus sporangia or Sordaria sp.

Antiproliferative and Antiangiogenic Activities of Smenospongine, a Marine Sponge Sesquiterpene Aminoquinone

We previously reported that smenospongine, a sesquiterpene aminoquinone isolated from the marine sponge Dactylospongia elegans, showed antiproliferative or cytotoxic activities on leukemia cells. In this study, we investigated the effect of smenospongine on solid tumors. Since angiogenesis is well known to be closely involved in growth and metastasis of solid tumors, the antiangiogenic effect of smenospongine was determined. We found that smenospongine inhibited proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVEC). Moreover, the inhibitory activity of smenospongine on growth of solid tumor cells was investigated. Smenospongine inhibited the growth of 39 human solid cancer cells in vitro, with a mean Log GI50 value of −5.55. In conclusion, smenospongine exhibits antitumor activity on solid tumors via two mechanisms, an antiangiogenic effect on endothelial cells and direct inhibition of growth of tumor cells.

Dysideamine, a new sesquiterpene aminoquinone, protects hippocampal neuronal cells against iodoacetic acid-induced cell death

In the course of our search for neuroprotective agents, dysideamine ( 1), a new sesquiterpene aminoquinone, was isolated along with bolinaquinone ( 2) from Indonesian marine sponge of Dysidea sp. Compounds 1 and 2 showed neuroprotective effect against iodoacetic acid (IAA)-induced cell death at 10 μM concentration in mouse HT22 hippocampal neuronal cells. Dysideamine ( 1) inhibited production of reactive oxygen species (ROS) by IAA treatment, whereas it exhibited no effect on depletion of intracellular ATP of the IAA-treated HT22 cells. Moreover, 1 induced neurite outgrowth against mouse neuroblastma Neuro 2A cells with increase of acetylcholinesterase (AChE) activity, which is a marker of neuronal differentiation.

Smenospongine, a Sesquiterpene Aminoquinone from a Marine Sponge, Induces G1 Arrest or Apoptosis in Different Leukemia Cells

Smenospongine, a sesquiterpene aminoquinone isolated from the marine sponge Dactylospongia elegans, was previously reported by us to induce erythroid differentiation and G1 phase arrest of K562 chronic myelogenous leukemia cells. In this study, we investigated the effect of smenospongine on the cell cycles of other leukemia cells, including HL60 human acute promyelocytic leukemia cells and U937 human histiocytic lymphoma cells by flow cytometric analysis. Smenospongine induced apoptosis dosedependently in HL60 and U937 cells. The smenospongine treatment increased expression of p21 and inhibited phosphorylation of Rb in K562 cells, suggesting the p21-Rb pathway play an important role in G1 arrest in K562 cells. However, the p21 promoter was not activated by the smenospongine treatment based on a luciferase assay using the transfected K562 cells. Smenospongine might induce p21 expression via another mechanism than transactivation of p21 promoter.

Smenospongine, a Sesquiterpene Aminoquinone from Marine Sponge, Induces G1 Arrest or Apoptosis in Different Leukemia Cells

Smenospongine, a sesquiterpene aminoquinone isolated from the marine sponge Dactylospongia elegans, was previously reported by us to induce erythroid differentiation and G1 phase arrest of K562 chronic myelogenous leukemia cells. In this study, we investigated the effect of smenospongine on the cell cycles of other leukemia cells, including HL60 human acute promyelocytic leukemia cells and U937 human histiocytic lymphoma cells by flow cytometric analysis. Smenospongine induced apoptosis dose-dependently in HL60 and U937 cells. The smenospongine treatment increased expression of p21 and inhibited phosphorylation of Rb in K562 cells, suggesting the p21-Rb pathway play an important role in G1 arrest in K562 cells. However, the p21 promoter was not activated by the smenospongine treatment based on a luciferase assay using the transfected K562 cells. Smenospongine might induce p21 expression via another mechanism than transactivation of p21 promoter.

Sesquiterpene Aminoquinones, from a Marine Sponge, Induce Erythroid Differentiation in Human Chronic Myelogenous Leukemia, K562 Cells.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Smenospongine, a spongean sesquiterpene aminoquinone, induces erythroid differentiation in K562 cells.

The differentiation of K562 chronic myelogenous leukemia (CML) cells by smenospongine, which is a sesquiterpene aminoquinone isolated from a marine sponge, was examined. Smenospongine increased hemoglobin production in K562 cells at concentrations of 3-15 microM. In addition, flow cytometric analysis of smenospongine-treated K562 cells with FITC-labeled glycophorin A antibody showed an increase of glycophorin A expression, a marker for erythroid differentiation. Cell-cycle analysis showed G1 arrest in K562 cells after treatment with smenospongine for 24 h. The effect on expression of CIP/KIP family cyclin-dependent kinase inhibitors was investigated by Western blotting analysis and the result showed increased expression of p21, which is known to play an important role in differentiation. Furthermore, smenospongine was also found to inhibit the phosphorylation of Crkl, a substrate of Bcr-Abl tyrosine kinase, which is known as a causative protein of CML. In conclusion, our investigation indicated that smenospongine induced the differentiation of K562 cells into erythroblasts along with cell-cycle arrest at G1 phase and the mechanism might be attributed to the increased expression of p21.