RESUMEN
Seven novel isocoumarins, prunolactones A-G (1-7), featuring an unusual 6/6/6/6/6 spiropentacyclic skeleton, together with two biosynthetic precursors phomopsilactone (8) and methyl 3-epi-shikimate (9), were isolated from the endophytic fungus Phomopsis prunorum guided by UPLC-QTOF-MS and 1H NMR spectroscopic analytical techniques. Their structures including absolute configurations of 1-7 were elucidated based on extensive spectroscopic data, X-ray diffraction analysis, and ECD calculations. Biogenetically, compounds 1-7 are proposed to be derived from polyketide and shikimate pathways via key intermolecular Diels - Alder reactions. Compounds 2, 3, and 7 showed significant in vivo proangiogenic activity in transgenic zebrafish.
Asunto(s)
Isocumarinas , Pez Cebra , Animales , Hongos/metabolismo , Isocumarinas/farmacología , Isocumarinas/química , Estructura Molecular , Esqueleto/metabolismo , Pez Cebra/metabolismoRESUMEN
When I started to work on marine natural products some thirty years ago I was attracted to this fascinating field of science by the exotic environment, the colourful shapes of (mostly) marine invertebrates and their complex ecological interactions [...].
Asunto(s)
Productos Biológicos/química , Organismos Acuáticos/química , Biología MarinaRESUMEN
The natural environment represents an important source of drugs that originates from the terrestrial and, in minority, marine organisms. Indeed, the marine environment represents a largely untapped source in the process of drug discovery. Among all marine organisms, sponges with algae represent the richest source of compounds showing anticancer activity. In this study, the two secondary metabolites pelorol (PEL) and 5-epi-ilimaquinone (EPI), purified from Dactylospongia elegans were investigated for their anti-melanoma activity. PEL and EPI induced cell growth repression of 501Mel melanoma cells in a concentration- and time-dependent manner. A cell cycle block in the G1 phase by PEL and EPI was also observed. Furthermore, PEL and EPI induced significant accumulation of DNA histone fragments in the cytoplasmic fraction, indicating a pro-apoptotic effect of both compounds. At the molecular level, PEL and EPI induced apoptosis through the increase in pro-apoptotic BAX expression, confirmed by the decrease in its silencing miR-214-3p and the decrease in the anti-apoptotic BCL-2, MCL1, and BIRC-5 mRNA expression, attested by the increase in their silencing miRNAs, i.e., miR-193a-3p and miR-16-5p. In conclusion, our data indicate that PEL and EPI exert cytotoxicity activity against 501Mel melanoma cells promoting apoptotic signaling and inducing changes in miRNA expression and their downstream effectors. For these reasons could represent promising lead compounds in the anti-melanoma drug research.
Asunto(s)
Melanoma , MicroARNs , Poríferos , Animales , Apoptosis , Organismos Acuáticos/metabolismo , Línea Celular Tumoral , Humanos , Melanoma/tratamiento farmacológico , MicroARNs/genética , MicroARNs/metabolismo , Poríferos/metabolismo , Quinonas , SesquiterpenosRESUMEN
Triple-negative breast cancer (TNBC), representing the most aggressive form of breast cancer with currently no targeted therapy available, is characterized by an inflammatory and hypoxic tumor microenvironment. To date, a broad spectrum of anti-tumor activities has been reported for phenanthroindolizidine alkaloids (PAs), however, their mode of action in TNBC remains elusive. Thus, we investigated six naturally occurring PAs extracted from the plant Tylophora ovata: O-methyltylophorinidine (1) and its five derivatives tylophorinidine (2), tylophoridicine E (3), 2-demethoxytylophorine (4), tylophoridicine D (5), and anhydrodehydrotylophorinidine (6). In comparison to natural (1) and for more-in depth studies, we also utilized a sample of synthetic O-methyltylophorinidine (1s). Our results indicate a remarkably effective blockade of nuclear factor kappa B (NFκB) within 2 h for compounds (1) and (1s) (IC50 = 17.1 ± 2.0 nM and 3.3 ± 0.2 nM) that is different from its effect on cell viability within 24 h (IC50 = 13.6 ± 0.4 nM and 4.2 ± 1 nM). Furthermore, NFκB inhibition data for the additional five analogues indicate a structure-activity relationship (SAR). Mechanistically, NFκB is significantly blocked through the stabilization of its inhibitor protein kappa B alpha (IκBα) under normoxic as well as hypoxic conditions. To better mimic the TNBC microenvironment in vitro, we established a 3D co-culture by combining the human TNBC cell line MDA-MB-231 with primary murine cancer-associated fibroblasts (CAF) and type I collagen. Compound (1) demonstrates superiority against the therapeutic gold standard paclitaxel by diminishing spheroid growth by 40% at 100 nM. The anti-proliferative effect of (1s) is distinct from paclitaxel in that it arrests the cell cycle at the G0/G1 state, thereby mediating a time-dependent delay in cell cycle progression. Furthermore, (1s) inhibited invasion of TNBC monoculture spheroids into a matrigel®-based environment at 10 nM. In conclusion, PAs serve as promising agents with presumably multiple target sites to combat inflammatory and hypoxia-driven cancer, such as TNBC, with a different mode of action than the currently applied chemotherapeutic drugs.
Asunto(s)
Alcaloides , Neoplasias de la Mama Triple Negativas , Alcaloides/farmacología , Alcaloides/uso terapéutico , Animales , Línea Celular Tumoral , Proliferación Celular , Colágeno Tipo I , Humanos , Alcaloides Indólicos , Indolizinas , Inflamación , Ratones , Inhibidor NF-kappaB alfa , FN-kappa B/farmacología , Paclitaxel/farmacología , Fenantrenos , Fenantrolinas , Neoplasias de la Mama Triple Negativas/patología , Microambiente Tumoral , TylophoraRESUMEN
Recently, we identified secalonic acid F (SA), 5-epi-nakijiquinone Q (NQ) and 5-epi-ilimaquinone (IQ) as natural compounds (NC) affecting mechanisms of the DNA damage response (DDR). Here, we further characterized their effects on DDR, DNA repair and cytotoxicity if used in mono- and co-treatment with conventional anticancer therapeutics (cAT) (cisplatin (Cis), doxorubicin (Doxo)) in vitro. All three NC influence the phosphorylation level of selected DDR-related factors (i.e., pCHK1, pKAP1, pP53, pRPA32) in mono- and/or co-treatment. Both SA and NQ attenuate the Cis- and Doxo-induced G2/M-phase arrest and effectively stimulate caspase-mediated apoptosis. Notably, SA impacts DNA repair as reflected by enhanced steady-state levels of Cis-(1,2-GpG)-DNA adducts and Doxo-induced DNA double-strand breaks (DSB). Moreover, SA decreased the mRNA and protein expression of the homologous recombination (HR)-related DSB repair factors RAD51 and BRCA1. Both SA and NQ promote Cis- and Doxo-induced cytotoxicity in an additive to synergistic manner (CI ≤ 1.0). Summarizing, we conclude that SA promotes cAT-driven caspase-dependent cell death by interfering with DSB repair and DDR-related checkpoint control mechanisms. Hence, SA is considered as the most promising lead compound to evaluate its therapeutic window in forthcoming pre-clinical in vivo studies.
Asunto(s)
Reparación del ADN , Neoplasias , Apoptosis , Caspasas , Cisplatino/farmacología , Roturas del ADN de Doble Cadena , Daño del ADN , Doxorrubicina/farmacología , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
Manzamines are chemically related compounds extracted from the methanolic extract of Acanthostrongylophora ingens species. Seven compounds were identified by our research group and are being characterized. As their biological target is unknown, this work is based on previous screening work performed by Mayer et al., who revealed that manzamine A could be an inhibitor of RSK1 kinase. Within this work, the RSK1 N-terminal kinase domain is exploited as a target for our work and the seven compounds are docked using Autodock Vina software. The results show that one of the most active compounds, Manzamine A N-oxide (5), with an IC50 = 3.1 µM, displayed the highest docking score. In addition, the compounds with docking scores lower than the co-crystalized ligand AMP-PCP (-7.5 and -8.0 kcal/mol) for ircinial E (1) and nakadomarin A (7) were found to be inferior in activity in the biological assay. The docking results successfully managed to predict the activities of four compounds, and their in silico results were in concordance with their biological data. The ß-carboline ring showed noticeable receptor binding, which could explain its reported biological activities, while the lipophilic side of the compound was found to fit well inside the hydrophobic active site.
RESUMEN
Fermentation of the marine-derived fungus Aspergillus falconensis, isolated from sediment collected from the Red Sea, Egypt on solid rice medium containing 3.5% NaCl yielded a new dibenzoxepin derivative (1) and a new natural isocoumarin (2) along with six known compounds (3-8). Changes in the metabolic profile of the fungus were induced by replacing NaCl with 3.5% (NH4)2SO4 that resulted in the accumulation of three further known compounds (9-11), which were not detected when the fungus was cultivated in the presence of NaCl. The structures of the new compounds were elucidated by HRESIMS and 1D/2D NMR as well as by comparison with the literature. Molecular docking was conducted for all isolated compounds on crucial enzymes involved in the formation, progression and metastasis of cancer which included human cyclin-dependent kinase 2 (CDK-2), human DNA topoisomerase II (TOP-2) and matrix metalloproteinase 13 (MMP-13). Diorcinol (7), sulochrin (9) and monochlorosulochrin (10) displayed notable stability within the active pocket of CDK-2 with free binding energy (ΔG) equals to -25.72, -25.03 and -25.37 Kcal/mol, respectively whereas sulochrin (9) exerted the highest fitting score within MMP-13 active center (ΔG = -33.83 Kcal/mol). In vitro cytotoxic assessment using MTT assay showed that sulochrin (9) exhibited cytotoxic activity versus L5178Y mouse lymphoma cells with an IC50 value of 5.1 µM and inhibition of migration of MDA-MB 231 breast cancer cells at a concentration of 70 µM.
Asunto(s)
Antineoplásicos/farmacología , Aspergillus/química , Policétidos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Imagen Óptica , Policétidos/química , Policétidos/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
Natural compounds (NC) are an important source of anticancer drugs. The genomic DNA of tumor cells is a major target of conventional anticancer therapeutics (cAT). DNA damage elicits a complex stress response programme termed DNA damage response (DDR), with the PI3-like kinase ATM and ATR being the key regulators. Since the DDR coordinates mechanisms of DNA repair and apoptosis, hence regulating the balance between death and survival, it is an attractive target of novel anticancer strategies. The aim of the study was to identify natural compounds derived from endophytic fungi, lichens, marine sponges or plants that interfere with mechanisms of the DDR. To this end, the cytotoxic and DDR modulating potency of 296 natural compounds, used alone or in combination with the cAT cisplatin (Cis) and doxorubicin (Doxo) was investigated by fluorescence-based analysis of the ATM/ATR-catalyzed S139 phosphorylation of histone 2AX (γH2AX), a surrogate marker of DNA damage-triggered DDR. After initial screening, a total of ten natural compounds were identified that were toxic in pancreatic carcinoma cells and activated the DDR on their own and/or promoted the DDR if used in combination with cAT. Their mode of action was shown to be independent of drug transport mechanisms. Based on their chemical structures, DDR modulatory activity and published data we suggest the marine NC 5-epi-nakijiquinone Q and 5-epi-ilimaquinone as well as the fungal compound secalonic acid F as most promising NC-based drug candidates for future synthesis of DDR-modulating chemical derivatives and their preclinical in vitro and in vivo testing.
Asunto(s)
Antineoplásicos/farmacología , Productos Biológicos/farmacología , ADN de Neoplasias/efectos de los fármacos , Antineoplásicos/química , Productos Biológicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Daño del ADN , Relación Dosis-Respuesta a Droga , Doxorrubicina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Six new polyketides aplojaveediins A-F (1-6) were isolated from the endophytic fungus Aplosporella javeedii associated with the host plant Orychophragmus violaceus (Brassicaceae). The structures of the new metabolites were elucidated by analysis of their NMR and MS data. Compound 1 exhibited antifungal activity against the hyphae form of Candida albicans strain ATCC 24433 in the agar plate diffusion assay and the microbroth dilution assay. The kinetic of killing of C. albicans cells for compound 1 was considerably faster than that of the positive control hygromycin B. Compounds 1 and 6 also exhibited moderate antibacterial activities against sensitive (ATCC 29213) and drug-resistant (ATCC 700699) strains of Staphylococcus aureus.
Asunto(s)
Antibacterianos/farmacología , Antifúngicos/farmacología , Ascomicetos/química , Candida albicans/efectos de los fármacos , Policétidos/farmacología , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Policétidos/química , Policétidos/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
Due to a high unresponsiveness to chemotherapy, biofilm formation is an important medical problem that frequently occurs during infection with many bacterial pathogens. In this study, the marine sponge-derived natural compounds 4,6-dibromo-2-(2',4'-dibromophenoxy)phenol and 3,4,6-tribromo-2-(2',4'-dibromophenoxy)phenol were found to exhibit broad antibacterial activity against medically relevant gram-positive and gram-negative pathogens. The compounds were not only bactericidal against both replicating and stationary phase-persistent planktonic cells of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa; they also killed biofilm-incorporated cells of both species while not affecting biofilm structural integrity. Moreover, these compounds were active against carbapenemase-producing Enterobacter sp. This simultaneous activity of compounds against different growth forms of both gram-positive and gram-negative bacteria is rare. Genome sequencing of spontaneous resistant mutants and proteome analysis suggest that resistance is mediated by downregulation of the bacterial EIIBC phosphotransferase components scrA and mtlA in MRSA likely leading to a lower uptake of the molecules. Due to their only moderate cytotoxicity against human cell lines, phenoxyphenols provide an interesting new scaffold for development of antimicrobial agents with activity against planktonic cells, persisters and biofilm-incoporated cells of ESKAPE pathogens. KEY POINTS: ⢠Brominated phenoxyphenols kill actively replicating and biofilm-incorporated bacteria. ⢠Phosphotransferase systems mediate uptake of brominated phenoxyphenols. ⢠Downregulation of phosphotransferase systems mediate resistance.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Biopelículas/efectos de los fármacos , Productos Biológicos/farmacología , Fenoles/farmacología , Animales , Antibacterianos/química , Biopelículas/crecimiento & desarrollo , Productos Biológicos/química , Línea Celular , Farmacorresistencia Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/genética , Humanos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Mutación , Fenoles/química , Sistema de Fosfotransferasa de Azúcar del Fosfoenolpiruvato/genética , Poríferos/químicaRESUMEN
The endophytic fungus Coniothyrium sp. was isolated from leaves of Quercus robur. Fermentation of this fungus on solid rice medium yielded two new furoic acid derivatives (1 and 2) and two additional known compounds. The structures of the new compounds were determined by extensive analysis of 1D and 2D nuclear magnetic resonance spectra as well as high-resolution mass spectrometry data. Compound 1, containing three aromatic chromophores attached by rotatable sigma bonds and a chirality center in benzylic position, was found to be a scalemic mixture with an excess of the (S) enantiomer, the absolute configuration of which was elucidated as by the solution time-dependent density functional theory-electronic circular dichroism approach. The ωB97X/TZVP PCM/MeCN and SOGGA11-X/TZVP SMD/MeCN methods were used for geometry reoptimization to reproduce the solution conformational ensemble. All isolated compounds were tested for their cytotoxicity but proved to be inactive.
Asunto(s)
Antineoplásicos/química , Ascomicetos/química , Furanos/química , Animales , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Línea Celular Tumoral , Furanos/aislamiento & purificación , Furanos/farmacología , Ratones , Modelos Moleculares , Conformación Molecular , EstereoisomerismoRESUMEN
Chemical investigation of secondary metabolites from the endophytic fungus Pseudopestalotiopsis theae led to the isolation of eighteen new polyketide derivatives, pestalotheols I-Q (1-9) and cytosporins O-W (15-23), together with eight known analogs (10-14 and 24-26). The structures of the new compounds were elucidated by HRMS and 1D and 2D NMR data, as well as by comparison with literature data. Modified Mosher's method was applied to determine the absolute configuration of some compounds. Compound 23 showed significant cytotoxicity against the mouse lymphoma cell line L5178Y with an IC50 value of 3.0 µM. Furthermore, compounds 22 and 23 showed moderate antibacterial activity against drug-resistant Acinetobacter baumannii (ATCC BAA-1605) in combination with sublethal colistin concentrations.
Asunto(s)
Hongos/metabolismo , Policétidos/química , Policétidos/metabolismo , Rhizophoraceae/microbiología , Endófitos , Fermentación , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura MolecularRESUMEN
The marine-derived fungus Aspergillus falconensis, isolated from sediment collected from the Canyon at Dahab, Red Sea, yielded two new chlorinated azaphilones, falconensins O and P (1 and 2) in addition to four known azaphilone derivatives (3-6) following fermentation of the fungus on solid rice medium containing 3.5% NaCl. Replacing NaCl with 3.5% NaBr induced accumulation of three additional new azaphilones, falconensins Q-S (7-9) including two brominated derivatives (7 and 8) together with three known analogues (10-12). The structures of the new compounds were elucidated by 1D and 2D NMR spectroscopy and HRESIMS data as well as by comparison with the literature. The absolute configuration of the azaphilone derivatives was established based on single-crystal X-ray diffraction analysis of 5, comparison of NMR data and optical rotations as well as on biogenetic considerations. Compounds 1, 3-9, and 11 showed NF-κB inhibitory activity against the triple negative breast cancer cell line MDA-MB-231 with IC50 values ranging from 11.9 to 72.0 µM.
Asunto(s)
Antineoplásicos/química , Organismos Acuáticos/química , Aspergillus/química , Benzopiranos/química , Sedimentos Geológicos/microbiología , Pigmentos Biológicos/química , Animales , Antineoplásicos/farmacología , Organismos Acuáticos/aislamiento & purificación , Aspergillus/aislamiento & purificación , Benzopiranos/farmacología , Línea Celular Tumoral/efectos de los fármacos , Océano Índico , Concentración 50 Inhibidora , Pigmentos Biológicos/farmacologíaRESUMEN
Bioactivity-guided investigation of the methanol extract of Crepis sancta aerial parts, collected off Al-Tafilah, South Jordan, was applied, and in this study, the extract was explored for its phytochemical components and in vivo antiulcer activity. In addition, a docking study involving the purified compounds with the newly crystalized gastric proton pump (PDB # 5YLU) was performed. In-depth phytochemical investigation using the state-of-the-art chromatographic and analytical techniques was implemented resulting in the identification of two eudesmane-type sesquiterpenoids, 3-oxo-γ-costic acid (1) and its methyl ester (2) together with seven different methoxylated flavonols (3-9) as the extract's major components. The in vivo antiulcer study at three different doses (50, 100, and 200 mg/kg) against ethanol-induced gastric ulcer in male albino rats, compared to omeprazole (20 mg/kg) as a standard proton pump inhibitor antiulcer drug, revealed that the tested extract, at the middle and the highest doses, featured comparable or even superior activities relative to omeprazole as deduced from histopathological examination, in particular with regard to reducing inflammatory cell infiltration and ceasing mucosal haemorrhage. The tested extract revealed also a dose-dependent reduction in the volume and titrable acidity of the gastric juice together with a dose-dependent increase in the protective gastric mucin content which may explain the noticeable gastroprotective effect. Molecular modelling study of the isolated compounds showed a binding mode similar to the co-crystallized substrate vonoprazan in 5YLU which strengthens the importance of the tested extract as a potential natural remedy for treating gastric ulcer.
Asunto(s)
Antiulcerosos/farmacología , Crepis/química , Fitoquímicos/farmacología , Extractos Vegetales/farmacología , Polifenoles/farmacología , Úlcera Gástrica/tratamiento farmacológico , Animales , Mucosa Gástrica/efectos de los fármacos , Masculino , Omeprazol/farmacología , Fitoterapia/métodos , Pirroles/farmacología , Ratas , Ratas Wistar , Sulfonamidas/farmacologíaRESUMEN
In the quest for new antibacterial lead structures, activity screening against Mycobacterium tuberculosis identified antitubercular effects of gallic acid derivatives isolated from the Nigerian mistletoe Loranthus micranthus Structure-activity relationship studies indicated that 3-O-methyl-alkylgallates comprising aliphatic ester chains with four to eight carbon atoms showed the strongest growth inhibition in vitro against M. tuberculosis, with a MIC of 6.25 µM. Furthermore, the most active compounds (3-O-methyl-butyl-, 3-O-methyl-hexylgallate, and 3-O-methyl-octylgallate) were devoid of cytotoxicity against various human cell lines. Furthermore, 3-O-methyl-butylgallate showed favorable absorption, distribution, metabolism, and excretion (ADME) criteria, with a Papp of 6.2 × 10-6 cm/s, and it did not inhibit P-glycoprotein (P-gp), CYP1A2, CYP2B6 or CYP3A4. Whole-genome sequencing of spontaneous resistant mutants indicated that the compounds target the stearoyl-coenzyme A (stearoyl-CoA) delta-9 desaturase DesA3 and thereby inhibit oleic acid synthesis. Supplementation assays demonstrated that oleic acid addition to the culture medium antagonizes the inhibitory properties of gallic acid derivatives and that sodium salts of saturated palmitic and stearic acid did not show compensatory effects. The moderate bactericidal effect of 3-O-methyl-butylgallate in monotreatment was synergistically enhanced in combination treatment with isoniazid, leading to sterilization in liquid culture.
Asunto(s)
Antituberculosos/química , Antituberculosos/farmacología , Ácido Gálico/química , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antibacterianos/química , Antibacterianos/farmacología , Antituberculosos/farmacocinética , Línea Celular , Inhibidores Enzimáticos del Citocromo P-450/química , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/genética , Ácidos Grasos/metabolismo , Ácido Gálico/farmacología , Humanos , Loranthaceae/química , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/genética , Ácido Oléico/biosíntesis , Ácido Oléico/farmacología , Estearoil-CoA Desaturasa/metabolismo , Relación Estructura-ActividadRESUMEN
The therapy of cancer continues to be a challenge aggravated by the evolution of resistance against current medications. As an alternative for the traditional tripartite treatment options of surgery, radiation and chemotherapy, immunotherapy is gaining increasing attention due to the opportunity of more targeted approaches. Promising targets are antigen-presenting cells which drive innate and adaptive immune responses. The discovery and emergence of new drugs and lead structures can be inspired by natural products which comprise many highly bioactive molecules. The development of new drugs based on natural products is hampered by the current lack of guidelines for screening these structures for immune activating compounds. In this work, we describe a phenotypic preclinical screening pipeline for first-line identification of promising natural products using the mouse as a model system. Favorable compounds are defined to be non-toxic to immune target cells, to show direct anti-tumor effects and to be immunostimulatory at the same time. The presented screening pipeline constitutes a useful tool and aims to integrate immune activation in experimental approaches early on in drug discovery. It supports the selection of natural products for later chemical optimization, direct application in in vivo mouse models and clinical trials and promotes the emergence of new innovative drugs for cancer treatment.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Antineoplásicos/farmacología , Productos Biológicos/farmacología , Descubrimiento de Drogas/métodos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Neoplasias/tratamiento farmacológico , Adyuvantes Inmunológicos/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , Productos Biológicos/uso terapéutico , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Inmunoterapia , Ratones , Neoplasias/terapiaRESUMEN
In order to overcome therapy resistance in cancer, scientists search in nature for novel lead structures for the development of improved chemotherapeutics. Anthraquinones belong to a class of tricyclic organic natural compounds with promising anti-cancer effects. Anthraquinone derivatives are rich in structural diversity, and exhibit pleiotropic properties, among which the modulation of autophagy seems promising in the context of overcoming cancer-therapy resistance. Among the most promising derivatives in this regard are emodin, aloe emodin, rhein, physcion, chrysophanol and altersolanol A. On the molecular level, these compounds target autophagy via different upstream pathways including the AKT/mTOR-axis and transcription of autophagy-related proteins. The role of autophagy is pro-survival as well as cell death-promoting, depending on derivatives and their cell type specificity. This review summarizes observed effects of anthraquinone derivatives on autophagy and discusses targeted pathways and crosstalks. A cumulative knowledge about this topic paves the way for further research on modes of action, and aids to find a therapeutic window of anthraquinones in cancer-therapy.
Asunto(s)
Antraquinonas/farmacología , Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antraquinonas/química , Antineoplásicos/química , Muerte Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Neoplasias/metabolismo , Neoplasias/patología , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Five new metabolites, including the xanthone derivative wentixanthone A (1), the benzophenone wentiphenone A (2), the diastereomeric mixtures of the bianthrones wentibianthrone A (3a, b) and wentibianthrone B (4a, b), as well as (10R,10'S)-wentibianthrone C (5a) and (10R,10'R)-wentibianthrone C (5b) were obtained from the fungus Aspergillus wentii, isolated from soil of the hypersaline lake El Hamra in Wadi El-Natrun, Egypt. The structures of the isolated compounds were established by one and two-dimensional NMR and MS spectroscopic analysis. The relative configuration of bianthrones (3-5) was elucidated by comparison of experimental and computed 1H NMR chemical shifts. Results of biological assays are reported.
Asunto(s)
Antracenos/aislamiento & purificación , Aspergillus/química , Benzofenonas/aislamiento & purificación , Xantonas/aislamiento & purificación , Animales , Antracenos/química , Benzofenonas/química , Línea Celular Tumoral , Teoría Funcional de la Densidad , Relación Dosis-Respuesta a Droga , Lagos/microbiología , Ratones , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Xantonas/químicaRESUMEN
Xanthoangelol is a geranylated chalcone isolated from fruits of Amorpha fructicosa that exhibits antibacterial effects at low micromolar concentration against Gram-positive bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecium and Enterococcus faecalis. We demonstrate that Xanthoangelol treatment of Gram-positive bacteria affects bacterial membrane integrity and leads to a leakage of intracellular metabolites. This correlates with a rapid collapse of the membrane potential and results in a fast and strong bactericidal effect. Proteomic profiling of Xanthoangelol-treated cells revealed signatures of cell wall and/or membrane damage and oxidative stress. Xanthoangelol specifically disturbs the membrane of Gram-positive bacteria potentially by forming pores resulting in cell lysis. In contrast, Xanthoangelol treatment of human cells showed only mildly hemolytic and cytotoxic effects at higher concentrations. Therefore, geranylated chalcones such as Xanthoangelol are promising lead structures for new antimicrobials against drug-resistant gram-positive pathogens.
Asunto(s)
Antibacterianos/farmacología , Chalcona/análogos & derivados , Bacterias Grampositivas/efectos de los fármacos , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Antibacterianos/química , Línea Celular , Chalcona/química , Chalcona/farmacología , Fabaceae/química , Bacterias Grampositivas/metabolismo , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/metabolismo , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/metabolismoRESUMEN
Two new sesquiterpene-based analogues, namely harzianoic acids A (1) and B (2), were isolated from a sponge-associated fungus Trichoderma harzianum. Their structures were determined on the basis of the extensive spectroscopic analyses in association with the ECD data for the configurational assignment. Harzianoic acids A and B were structurally characterized as a sesquiterpene and a norsesquiterpene with a cyclobutane nucleus, which is uncommonly found from nature. Both compounds exhibited the inhibitory activity to reduce the HCV RNA levels with low cytotoxicity. The preliminary investigation of the mode of action revealed that the compounds blocked the entry step in the HCV life cycle, while the viral E1/E2 and the host cell CD81 were the potential target proteins.