RESUMEN
BACKGROUND: Sesterterpenoids are rare species among the terpenoids family. Ophiobolins are sesterterpenes with a 5-8-5 tricyclic skeleton. The oxidized ophiobolins exhibit significant cytotoxic activity and potential medicinal value. There is an urgent need for large amounts of ophiobolins supplication for drug development. The synthetic biology approach has been successfully employed in lots of terpene compound production and inspired us to develop a cell factory for ophiobolin biosynthesis. RESULTS: We developed a systematic metabolic engineering strategy to construct an ophiobolin biosynthesis chassis based on Saccharomyces cerevisiae. The whole-cell biotransformation methods were further combined with metabolic engineering to enhance the expression of key ophiobolin biosynthetic genes and improve the supply of precursors and cofactors. A high yield of 5.1 g/L of ophiobolin F was reached using ethanol and fatty acids as substrates. To accumulate oxidized ophiobolins, we optimized the sources and expression conditions for P450-CPR and alleviated the toxicity of bioactive compounds to cells through PDR engineering. We unexpectedly obtained a novel ophiobolin intermediate with potent cytotoxicity, 5-hydroxy-21-formyl-ophiobolin F, and the known bioactive compound ophiobolin U. Finally, we achieved the ophiobolin U titer of 128.9 mg/L. CONCLUSIONS: We established efficient cell factories based on S. cerevisiae, enabling de novo biosynthesis of the ophiobolin skeleton ophiobolin F and oxidized ophiobolins derivatives. This work has filled the gap in the heterologous biosynthesis of sesterterpenoids in S. cerevisiae and provided valuable solutions for new drug development based on sesterterpenoids.
Asunto(s)
Ingeniería Metabólica , Saccharomyces cerevisiae , Sesterterpenos , Sesterterpenos/metabolismo , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genéticaRESUMEN
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.
Asunto(s)
Dysidea , Sesterterpenos/farmacología , Animales , Organismos Acuáticos , Línea Celular Tumoral/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Filipinas , Sesterterpenos/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Agaricales/química , Antibacterianos , Bacterias/crecimiento & desarrollo , Proliferación Celular/efectos de los fármacos , Citotoxinas , Micelio/química , Sesterterpenos , Células A549 , Animales , Antibacterianos/química , Antibacterianos/farmacología , Chlorocebus aethiops , Citotoxinas/química , Citotoxinas/farmacología , Células HCT116 , Células HT29 , Células HeLa , Humanos , Sesterterpenos/química , Sesterterpenos/farmacología , Células VeroRESUMEN
In the current study, an NMR spectroscopic pattern-based procedure for probing scalarane derivatives was performed and four new 24-homoscalaranes, lendenfeldaranes A-D (1- 4), along with three known compounds, 12α-acetoxy-22-hydroxy-24-methyl-24-oxoscalar-16-en- 25-al (5), felixin F (6), and 24-methyl-12,24,25-trioxoscalar-16-en-22-oic acid (7) were isolated from the sponge Lendenfeldia sp. The structures of scalaranes 1-7 were elucidated on the basis of spectroscopic analysis. Scalaranes 1-7 were further evaluated for their cytotoxicity toward a series of human cancer cell lines and the results suggested that 5 and 7 dominated in the anti- proliferative activity of the extract. The 18-aldehyde functionality was found to play a key role in their activity.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Poríferos/química , Sesterterpenos/farmacología , Animales , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Sesterterpenos/química , Sesterterpenos/aislamiento & purificaciónRESUMEN
Scalarane-type sesterterpenoids are known for their therapeutic potential in cancer treatments. However, the anti-inflammatory properties of this class of metabolites remain elusive. Our current work aimed to investigate the anti-inflammatory scalaranes from marine sponge Lendenfeldia sp., resulting in the isolation of six new 24-homoscalaranes, lendenfeldaranes E-J (1-6). The structures of the new metabolites were determined by extensive spectroscopic analyses, and the absolute configuration of 1 was established by electronic circular dichroism (ECD) calculations. Compounds 2 and 3 were discovered to individually reduce the generation of superoxide anions, and compound 1 displayed an inhibitor effect on the release of elastase. These three compounds were proven to be the first anti-neutrophilic scalaranes.
Asunto(s)
Antiinflamatorios/farmacología , Neutrófilos/efectos de los fármacos , Poríferos/química , Sesterterpenos/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Humanos , Elastasa de Leucocito/metabolismo , Estructura Molecular , Neutrófilos/metabolismo , Vías Secretoras , Sesterterpenos/química , Sesterterpenos/aislamiento & purificación , Relación Estructura-Actividad , Superóxidos/metabolismoRESUMEN
Three furan-containing scalarane sesterterpenoids (1â»3) and a novel pyrrole-containing analog (4) were isolated from the sponge Scalarispongia species. Compound 3, reported in the literature as a synthetic derivative of furoscalarol 2, was for the first time isolated from a natural source. During the separation performed using a silica column in the presence of methanol, 16-methoxy derivatives (5, 6) were obtained from the unintended reaction of 2. The isolated natural products 3 and 4 and the artifact 5 showed moderate to high cytotoxicity against six human cancer cell lines, whereas compound 6, the C-16 epimer of 5, showed no cytotoxicity at a concentration of 60 µΜ.
Asunto(s)
Antineoplásicos/farmacología , Furanos/química , Neoplasias/patología , Poríferos/química , Sesterterpenos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Supervivencia Celular , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Neoplasias/tratamiento farmacológico , Sesterterpenos/química , Sesterterpenos/aislamiento & purificación , Células Tumorales CultivadasRESUMEN
The Wnt/ß-catenin signaling pathway is known to play critical roles in a wide range of cellular processes: cell proliferation, differentiation, migration and embryonic development. Importantly, dysregulation of this pathway is tightly associated with pathogenesis in most human cancers. Therefore, the Wnt/ß-catenin pathway has emerged as a promising target in anticancer drug screening programs. In the present study, we have isolated three previously unreported metabolites from an undescribed sponge, a species of Monanchora (Order Poecilosclerida, Family Crambidae), closely related to the northeastern Pacific species Monanchora pulchra, collected from deep waters off the Aleutian Islands of Alaska. Through an assortment of NMR, MS, ECD, computational chemical shifts calculation, and DP4, chemical structures of these metabolites have been characterized as spirocyclic ring-containing sesterterpenoid (1) and cholestane-type steroidal analogues (2 and 3). These compounds exhibited the inhibition of ß-catenin response transcription (CRT) through the promotion of ß-catenin degradation, which was in part implicated in the antiproliferative activity against two CRT-positive colon cancer cell lines.
Asunto(s)
Antineoplásicos/farmacología , Organismos Acuáticos/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Poríferos/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , Alaska , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Antineoplásicos/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Proteolisis/efectos de los fármacos , Esteroides/química , Esteroides/metabolismo , Esteroides/farmacología , Terpenos/química , Terpenos/aislamiento & purificación , Terpenos/metabolismo , Terpenos/farmacología , beta Catenina/metabolismoRESUMEN
Two new sesterterpenoids, 1 and 2, were isolated from the sponge Luffariella variabilis. Their planar structures were characterized with spectroscopic analyses. The sole chiral center of compound 1 was elucidated as 12R by comparing observed and calculated optical rotation values. The configurations of compound 2 were determined by NMR and electronic circular dichroism (ECD) studies. Furthermore, compound 2 showed cytotoxicity at IC50 1.0 µM against NBT-T2 cells.
Asunto(s)
Furanos/aislamiento & purificación , Poríferos/química , Sesterterpenos/aislamiento & purificación , Animales , Línea Celular , Furanos/química , Humanos , Biología Marina , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Sesterterpenos/químicaRESUMEN
The phytochemical investigation on 1 g of materials from Gypsoplacamacrophylla (Zahlbr.) Timdal resulted in the discovery of gypmacrophin A, a rare pentacyclic sesterterpenoid; brialmontin III, a new polysubstituted depside and two known ones, brialmontins I and II. The structure and absolute configurations of gypmacrophin A were elucidated by spectroscopic analyses and computational methods. Gypmacrophin A showed weak inhibition of AchE with an IC50 value of 32.03 µM. The four compounds provided new chemical evidence for G. macrophylla identification.
Asunto(s)
Ascomicetos/aislamiento & purificación , Depsidos/química , Sesterterpenos/química , Acetilcolinesterasa , Modelos Moleculares , Estructura Molecular , Fragmentos de Péptidos/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Five new scalarane sesterterpenoids, felixins A-E (1-5), were isolated from the Formosan sponge Ircinia felix. The structures of scalaranes 1-5 were elucidated on the basis of spectroscopic analysis. Cytotoxicity of scalaranes 1-5 against the proliferation of a limited panel of tumor cell lines was evaluated.
Asunto(s)
Poríferos/química , Sesterterpenos/aislamiento & purificación , Terpenos/aislamiento & purificación , Animales , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Sesterterpenos/farmacología , TaiwánRESUMEN
Two new 24-homoscalarane sesterterpenoids, felixins F (1) and G (2), were isolated from the sponge Ircinia felix. The structures of new homoscalaranes 1 and 2 were elucidated by extensive spectroscopic methods, particularly with one-dimensional (1D) and two-dimensional (2D) NMR, and, by comparison, the spectral data with those of known analogues. The cytotoxicity of 1 and 2 against the proliferation of a limited panel of tumor cell lines was evaluated and 1 was found to show cytotoxicity toward the leukemia K562, MOLT-4, and SUP-T1 cells (IC50 ≤ 5.0 µM).
Asunto(s)
Poríferos/química , Sesterterpenos/química , Sesterterpenos/toxicidad , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Humanos , Estructura MolecularRESUMEN
The marine environment has been recognized as a prolific source of potent bioactive compounds with significant anticancer properties. Among these, heteronemin, a sesterterpenoid-type natural product, has shown promise. This study delves into the potential of heteronemin as a ferroptotic agent against pancreatic cancer, using the Panc-1 cell line as a model. The cytotoxic potential of heteronemin was assessed using cell viability assays. Furthermore, its effect on lipid peroxidation was determined spectrophotometrically, while the changes it induced in autophagy- and ferritin-related protein expressions were evaluated using immunoblotting techniques. Various cell-based tests were employed to scrutinize its anticancer efficacy. Heteronemin displayed a notable cytotoxic effect, reducing cell viability by 50% at a concentration of 55 nM. This cytotoxicity was discernibly linked to ferroptosis, as evidenced by the reversal of cell death upon treatment with the ferroptosis inhibitor, ferrostatin-1. Heteronemin treatment led to a marked increase in ferroptosis markers and malondialdehyde (MDA) levels. Conversely, the expression of glutathione peroxidase-4 (GPX4), a key anti-ferroptotic protein, was suppressed. Furthermore, significant modulations in the expression of ferritinophagy- and iron-related proteins such as Atg5, Atg7, FTL, STEAP3, and DMT-1 were evident post-treatment (p < 0.05). This study underscores the potential of heteronemin as a ferroptosis inducer in pancreatic cancer cells. Given its robust cytotoxicity, heteronemin emerges as a promising lead compound for further exploration in cancer therapeutics.
Asunto(s)
Antineoplásicos , Neoplasias Pancreáticas , Humanos , Hierro/metabolismo , Muerte Celular , Terpenos/farmacología , Antineoplásicos/farmacología , Neoplasias Pancreáticas/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Antiinfecciosos , Sesterterpenos , Sesterterpenos/farmacología , Sesterterpenos/química , Bipolaris , Estructura MolecularRESUMEN
Further investigation of secondary metabolites of a marine-alga-derived fungus Aspergillus sp. RR-YLW-12 led to isolate one new ophiobolin-type sesterterpenoid (1), four new drimane-type sesquiterpenoids (2-5) and one natural occurring compound (6), together with seven known compounds (7-13). Their structures and stereochemistry were elucidated by extensive spectroscopic analysis of NMR and HRMS experiments, and by comparison with the literature data. All isolates were evaluated for growth inhibition of five marine harmful microalgae. The new compounds exhibited significant to moderate inhibitory effects towards all tested microalgae species with IC50 values ranging from 5.8 to 54.5 µg/mL.
Asunto(s)
Sesquiterpenos , Estructura Molecular , Aspergillus/química , Hongos , Espectroscopía de Resonancia MagnéticaRESUMEN
One new pentacyclic sesterterpene, hippospongide A (1), and one new scalarane sesterterpenoid, hippospongide B (2), along with six previously reported known scalarane-type sesterterpenes (3-8), were isolated from a sponge Hippospongia sp. The structures of these compounds were elucidated on the basis of their spectroscopic data and comparison of the NMR data with those of known analogues. These metabolites are the first pentacyclic sesterterpene and scalarane-type sesterterpenes to be reported from this genus. Compounds 3-5 exhibited significant cytotoxicity against DLD-1, HCT-116, T-47D and K562 cancer cell lines.
Asunto(s)
Poríferos/química , Sesterterpenos/química , Sesterterpenos/farmacología , Animales , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales/métodos , Humanos , Células K562 , Espectroscopía de Resonancia Magnética/métodos , Sesterterpenos/aislamiento & purificaciónRESUMEN
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⯵M, respectively. Compounds 5 and 7 displayed significant cytotoxicity against the A549 lung cancer cell line (IC50 values of 4.83⯱â¯0.22⯵M and 4.58⯱â¯0.85⯵M, 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⯵M.
Asunto(s)
Penicillium , Hongos , Humanos , Macrófagos , Óxido Nítrico , Sesterterpenos/farmacologíaRESUMEN
Phytochemical investigation on the acetone extract of Salvia mirzayanii Rech. f. and Esfand. aï¬orded seven new isoprenoids including six new sesterterpenoids salvimirzacolide A-F (1-6), and one new nor-diterpenoid (7). Their structures were established by comprehensive spectroscopic and spectrometric data analysis (1D and 2D NMR, HRMS) and DP4+ NMR chemical shift probability calculation technique. Moreover, the absolute conï¬guration of compounds was determined by using electronic circular dichroism spectroscopy. Evaluation of antiproliferative properties of compounds isolated against four human melanoma cancer cells displayed no cytotoxic activity at the concentration range used.
RESUMEN
Zingiber griffithii Baker is one of the native Zingiberaceous species in a tropical forest of North Sumatra, Indonesia. Zingiberaceous species have been intensively studied and reported as herbal ingredients in ethnomedicine and currently their endophytic fungal associates were studied for pharmacological importance. Fifteen endophytic fungi were isolated from Zingiber griffithii following morphological and molecular characterization. All isolates exhibited antibacterial properties to at least one of the tested pathogenic bacteria Staphylococcus aureus, Escherichia coli, Methicilin-resistant S. aureus (MRSA), and Enteropathogenic E. coli (EPEC). The isolate, identified as Hypomontagnella monticulosa strain Zg15SU (syn. Hypoxylon monticulosum Mont.) based on its rDNA/ITS sequence, displayed antibacterial activities to all tested pathogens. The EtOAc extract of the H. monticulosum Zg15SU showed the highest activity for gram-negative bacteria, the E. coli and EPEC, while the extract of Z. griffithii rhizome displayed activity only for E. coli. The gas chromatography-mass spectrometry analysis (GC-MS) indicated a major portion of similar compounds found in both the endophytic fungus and plant extract, revealing the compounds of oleic acid, cyclononasiloxane, octadecamethyl, and eicosanoic acid Furthermore, purification and structural elucidation on the EtOAc extract of both Z. griffithii rhizome and H. monticulos a Zg15SU yielded two bioactive compounds: a novel compound, griffithiiene, a terpenoid-alkaloid bearing the skeleton of a scalarane (1) and scalaradial (2) which were confirmed by 1H- (500 MHz) and 13C-NMR (125 MHz) spectroscopy. Importantly, the elucidated compounds showed a cytotoxicity activity against cancer cell lines, the Panc-1, NBT-T2, and HCT116 based on in vitro MTT proliferation assay. This is the first report of Z. griffithii harboring an endophytic fungus, H. monticulosa, which produced potential antibacterial and anticancer metabolites along with its host to be utilized for future prospects.
RESUMEN
Obesity that is highly associated with numerous metabolic diseases has become a global health issue nowdays. Plant sesterterpenoids are an important group of natural products with great potential; thus, their bioactivities deserve extensive exploration. RNA-seq analysis indicated that leucosceptroid B, a sesterterpenoid previously discovered from the glandular trichomes of Leucosceptrum canum, significantly regulated the expression of 10 genes involved in lipid metabolism in Caenorhabditis elegans. Furthermore, leucosceptroid B was found to reduce fat storage, and downregulate the expression of two stearoyl-CoA desaturase (SCD) genes fat-6 and fat-7, and a fatty acid elongase gene elo-2 in wild-type C. elegans. In addition, leucosceptroid B significantly decreased fat accumulation in both fat-6 and fat-7 mutant worms but did not affect the fat storage of fat-6; fat-7 double mutant. These findings indicated that leucosceptroid B reduced fat storage depending on the downregulated expression of fat-6, fat-7 and elo-2 and thereby inhibiting the biosynthesis of the corresponding unsaturated fatty acid. These findings provide new insights into the development and utilization of plant sesterterpenoids as potential antilipemic agents.
Asunto(s)
Caenorhabditis elegans/efectos de los fármacos , Ácidos Grasos Insaturados/biosíntesis , Ácidos Grasos Insaturados/genética , Lamiaceae/química , Sesterterpenos/farmacología , Tricomas/química , Animales , Caenorhabditis elegans/genéticaRESUMEN
Three new sesterterpene lactones, lachnocalyxolide A-C [1, 2, and 3 (as epimeric pair)] together with nine known compounds, including two sesterterpenoids, three flavonoids, two steroidal compounds, one nor diterpenoid and one triterpenoid, were isolated from the acetone extract of the aerial parts of Salvia lachnocalyx Hedge. Their structures were elucidated on the basis of extensive spectroscopic data, including 1D and 2D NMR spectra, as well as HR-ESI-MS. Compounds 1, 2, 4 and 5 were also tested for their inhibitory activity toward MCF-7 and HeLa cell lines.