RESUMO
The pterocarpan fraction from aerial parts of Bituminaria bituminosa was investigated for both chemical characterization and biological evaluation. Chemical studies were in accordance with the literature data on Bituminaria genus resulting in the identification of typical 4,8-prenyl pterocarpans. Three new members, bituminarins A-C (1-3), were isolated along with main bitucarpin A (4), erybraedin C (5) and erybraedin D (6) already reported from this plant. Further, biological studies evidenced antiproliferative properties of the most abundant pterocarpans 4 and 5 on neuroblastoma SH-SY5Y cell line, in agreement with previously described antiproliferative activity of these compounds against cancer cell lines other than neuroblastoma. The structure and the stereochemistry of the new molecules was determined by extensive spectroscopic analysis and chemical derivatization methods. The biological investigation was carried out by using an assay platform based on a live-cell imaging system revealing an apoptotic cell death induction.
Assuntos
Antineoplásicos Fitogênicos , Neuroblastoma , Pterocarpanos , Humanos , Neuroblastoma/patologia , Neuroblastoma/tratamento farmacológico , Linhagem Celular Tumoral , Pterocarpanos/química , Pterocarpanos/farmacologia , Pterocarpanos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Apoptose/efeitos dos fármacosRESUMO
Cavoxin (1) was isolated as the main phytotoxin produced by Phoma cava Schulzer, a toxigenic fungus isolated from Castanea spp. Its structure was determined by 1D NMR and MS in 1985 along with that of the corresponding chroman-4-one cavoxone (2), an artifact formed by acid treatment of 1. Since that time cavoxin was shown to be phytotoxic, antifungal, antifeedant, herbicidal, and antirust with potential application in agriculture and medicine. During a study aimed at improving cavoxin's production by P. cava, single crystals for X-ray diffractometric analysis were obtained. The X-ray crystallography characterization confirmed only in part the structure proposed for cavoxin (1), revealing a different substitution pattern on the aromatic ring, as depicted in the revised structure 3.
Assuntos
Micotoxinas , Cristalografia por Raios X/métodos , Estrutura Molecular , Micotoxinas/química , Micotoxinas/farmacologia , Ascomicetos/química , Cromanos/química , Cromanos/farmacologiaRESUMO
The occurrence of increased antibiotic resistance has reduced the availability of drugs effective in the control of infectious diseases, especially those caused by various combinations of bacteria and/or fungi that are often associated with poorer patient outcomes. In the hunt for novel antibiotics of interest to treat polymicrobial diseases, molecules bearing guanidine moieties have recently come to the fore in designing and optimizing antimicrobial agents. Due to their remarkable antibacterial and antifungal activities, labdane diterpenes are also attracting increasing interest in antimicrobial drug discovery. In this study, six different guanidines prenylated with labdanic fragments were synthesized and evaluated for their antimicrobial properties. Assays were carried out against both non-resistant and antibiotic-resistant bacteria strains, while their possible antifungal activities have been tested on the yeast Candida albicans. Two of the synthesized compounds, namely labdan-8,13(R)-epoxy-15-oyl guanidine and labdan-8,13(S)-epoxy-15-oyl guanidine, were finally selected as the best candidates for further developments in drug discovery, due to their antimicrobial effects on both Gram-negative and Gram-positive bacterial strains, their fungicide action, and their moderate toxicity in vivo on zebrafish embryos. The study also provides insights into the structure-activity relationships of the guanidine-functionalized labdane-type diterpenoids.
Assuntos
Anti-Infecciosos , Diterpenos , Animais , Humanos , Antifúngicos/farmacologia , Guanidina/farmacologia , Peixe-Zebra , Anti-Infecciosos/farmacologia , Antibacterianos/farmacologia , Bactérias , Diterpenos/farmacologia , Candida albicans , Guanidinas/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
The invasive macroalga Caulerpa cylindracea has spread widely in the Mediterranean Sea, becoming a favorite food item for native fish for reasons yet unknown. By using a combination of behavioral, morphological, and molecular approaches, herein we provide evidence that the bisindole alkaloid caulerpin, a major secondary metabolite of C. cylindracea, significantly increases food intake in the model fish Danio rerio, influencing the regulation of genes involved in the orexigenic pathway. In addition, we found that the compound improves fish reproductive performance by affecting the hypothalamus-pituitary-gonadal axis. The obtained results pave the way for the possible valorization of C. cylindracea as a sustainable source of a functional feed additive of interest to face critical challenges both in aquaculture and in human nutrition.
Assuntos
Alcaloides , Caulerpa , Dourada , Alga Marinha , Animais , Humanos , Mar MediterrâneoRESUMO
Longer life expectancy has led to an increase in efforts directed to the discovery of new healing agents for disorders related to aging, such as bone diseases. Harboring an incredible variety of bioactive metabolites, marine organisms are standing out as fruitful sources also in this therapeutic field. On the other hand, the in vivo zebrafish model has proven to be an excellent low-cost screening platform for the fast identification of molecules able to regulate bone development. By using zebrafish larvae as a mineralization model, we have thus evaluated the effects of the crude acetonic extract from the marine sponge Aplysina aerophoba and its bromotyrosine components on bone development. Obtained results led to the selection of aerophobin-1 (1) as a promising candidate for applications in regenerative medicine, paving the way for the development of a novel therapeutic option in osteoporosis treatment.
Assuntos
Produtos Biológicos/farmacologia , Osteogênese/efeitos dos fármacos , Poríferos/metabolismo , Animais , Produtos Biológicos/isolamento & purificação , Desenvolvimento Ósseo/efeitos dos fármacos , Larva/efeitos dos fármacos , Peixe-ZebraRESUMO
In continuing our investigation on the chemical diversity of Algerian plants, we examined Centaurea omphalotricha, whose chemical composition has been poorly studied. The present work was aimed at characterizing the secondary metabolite pattern of the CHCl3 extract of the aerial parts of this plant that displayed antiproliferative properties in a preliminary screening on HeLa cell line. The chemical analysis led us to characterize the bioactive oxygenated terpenoid fraction which includes, within major known metabolites, two new minor sesquiterpene lactones, centaurolide-A (1) and centaurolide-B (2). The structures of two compounds exhibiting the 12,8-guaianolide skeleton were determined by spectroscopic methods as well as by chemical correlation with inuviscolide (3), a well-known bioactive guaianolide isolated from Dittrichia (=Inula) viscosa. Centaurolides A and B represent the first report of 8,12-guaianolide skeleton in Centaurea genus. The effect of new compounds 1 and 2 and inuviscolide (3) on HeLa cell has also been evaluated.
Assuntos
Centaurea/química , Lactonas/química , Sesquiterpenos de Guaiano/química , Argélia , Sobrevivência Celular/efeitos dos fármacos , Centaurea/metabolismo , Células HeLa , Humanos , Lactonas/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Extratos Vegetais/química , Metabolismo Secundário , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Sesquiterpenos de Guaiano/farmacologiaRESUMO
CXCR4 chemokine receptor represents an attractive pharmacological target due to its key role in cancer metastasis and inflammatory diseases. Starting from our previously-developed pharmacophoric model, we applied a combined computational and experimental approach that led to the identification of the hydantoin alkaloids parazoanthines, isolated from the Mediterranean Sea anemone Parazoanthus axinellae, as novel CXCR4 antagonists. Parazoanthine analogues were then synthesized to evaluate the contribution of functional groups to the overall activity. Within the panel of synthesized natural and non-natural parazoanthines, parazoanthine-B was identified as the most potent CXCR4 antagonist with an IC50 value of 9.3 nM, even though all the investigated compounds were able to antagonize in vitro the down-stream effects of CXC12, albeit with variable potency and efficacy. The results of our study strongly support this class of small molecules as potent CXCR4 antagonists in tumoral pathologies characterized by an overexpression of this receptor. Furthermore, their structure-activity relationships allowed the optimization of our pharmacophoric model, useful for large-scale in silico screening.
Assuntos
Alcaloides/química , Antozoários/química , Receptores CXCR4/antagonistas & inibidores , Alcaloides/farmacologia , Animais , Antozoários/metabolismo , Clonagem Molecular , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Descoberta de Drogas , Humanos , Hidantoínas , Simulação de Acoplamento Molecular , Ratos , Transdução de Sinais , Relação Estrutura-AtividadeRESUMO
Less than one percent of marine natural products characterized since 1963 have been obtained from the phylum Bryozoa which, therefore, still represents a huge reservoir for the discovery of bioactive metabolites with its ~6000 described species. The current review is designed to highlight how bryozoans use sophisticated chemical defenses against their numerous predators and competitors, and which can be harbored for medicinal uses. This review collates all currently available chemoecological data about bryozoans and lists potential applications/benefits for human health. The core of the current review relates to the potential of bryozoan metabolites in human diseases with particular attention to viral, brain, and parasitic diseases. It additionally weighs the pros and cons of total syntheses of some bryozoan metabolites versus the synthesis of non-natural analogues, and explores the hopes put into the development of biotechnological approaches to provide sustainable amounts of bryozoan metabolites without harming the natural environment.
Assuntos
Produtos Biológicos/farmacologia , Briozoários/química , Briozoários/metabolismo , Animais , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Biologia , Encefalopatias/tratamento farmacológico , Briozoários/classificação , Humanos , Estrutura Molecular , Doenças Parasitárias/tratamento farmacológico , Filogenia , Viroses/tratamento farmacológicoRESUMO
Terpene content of two distinct collections of the nudibranch Phyllidia coelestis from the South China Sea has been chemically analyzed. A series of amphilectene diterpenes, most likely of dietary origin, with isocyano and formamido functionalities have been isolated from both collections and spectroscopically characterized by an exhaustive nuclear magnetic resonance (NMR) analysis. Interestingly, the structural architecture of compounds 5-7 and 9 with both 8,13-cis and 12,13-cis ring junctions is unprecedented in the amphilectene skeleton. Metabolite 3, which was the most abundant in the nudibranch's mantle, has been shown to deter feeding by a generalist predator, supporting its involvement in chemical defense.
Assuntos
Diterpenos/química , Gastrópodes/química , Animais , China , Diterpenos/isolamento & purificação , Gastrópodes/metabolismo , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Phenolic profiling of ten plant samples of Mentha rotundifolia (L.) Huds. collected from different bioclimatic areas of Tunisia, was for the first time carried out by using a fast ultra-high-performance liquid chromatography (UHPLC)-high resolution tandem mass spectrometry (HRMS/MS) method on a Q Exactive platform equipped with an electrospray ionization (ESI) source. An intraspecific, interpopulation variability was evidenced and a total of 17 polyphenolic metabolites were identified and quantified by using the UHPLC-HRESIMS/MS method, here validated for specificity, linearity, limit of detection, limit of quantitation, accuracy and precision. The quantitative method resulted sensitive at the nM level and reliable for rapid polyphenol quantification in vegetal matrices. The metabolomic study allowed us to identify a new compound, named salvianolic acid W, which was isolated and characterized mainly by NMR and MS analysis. A statistical correlation of the phenolic composition with antioxidant and anti-acetylcholinesterase activities was provided.
Assuntos
Mentha/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Cromatografia Líquida de Alta Pressão , Flavonoides , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , TunísiaRESUMO
The nuclear receptors (NRs) RARα, RXRα, PPARα, and PPARγ represent promising pharmacological targets for the treatment of neurodegenerative diseases. In the search for molecules able to simultaneously target all the above-mentioned NRs, we screened an in-house developed molecular database using a ligand-based approach, identifying (-)-Muqubilin (Muq), a cyclic peroxide norterpene from a marine sponge, as a potential hit. The ability of this compound to stably and effectively bind these NRs was assessed by molecular docking and molecular dynamics simulations. Muq recapitulated all the main interactions of a canonical full agonist for RXRα and both PPARα and PPARγ, whereas the binding mode toward RARα showed peculiar features potentially impairing its activity as full agonist. Luciferase assays confirmed that Muq acts as a full agonist for RXRα, PPARα, and PPARγ with an activity in the low- to sub-micromolar range. On the other hand, in the case of RAR, a very weak agonist activity was observed in the micromolar range. Quite surprisingly, we found that Muq is a positive allosteric modulator for RARα, as both luciferase assays and in vivo analysis using a zebrafish transgenic retinoic acid (RA) reporter line showed that co-administration of Muq with RA produced a potent synergistic enhancement of RARα activation and RA signaling.
Assuntos
PPAR alfa/agonistas , PPAR gama/agonistas , Peróxidos/farmacologia , Receptor alfa de Ácido Retinoico/agonistas , Terpenos/farmacologia , Regulação Alostérica , Animais , Animais Geneticamente Modificados , Sinergismo Farmacológico , Ensaios de Triagem em Larga Escala , Humanos , Larva , Modelos Moleculares , Simulação de Acoplamento Molecular , Poríferos/química , Tretinoína/farmacologia , Peixe-ZebraRESUMO
Multitargeting or polypharmacological approaches, looking for single chemical entities retaining the ability to bind two or more molecular targets, are a potentially powerful strategy to fight complex, multifactorial pathologies. Unfortunately, the search for multiligand agents is challenging because only a small subset of molecules contained in molecular databases are bioactive and even fewer are active on a preselected set of multiple targets. However, collections of natural compounds feature a significantly higher fraction of bioactive molecules than synthetic ones. In this view, we searched our library of 1175 natural compounds from marine sources for molecules including a 2-aminoimidazole+aromatic group motif, found in known compounds active on single relevant targets for Alzheimer's disease (AD). This identified two molecules, a pseudozoanthoxanthin (1) and a bromo-pyrrole alkaloid (2), which were predicted by a computational approach to possess interesting multitarget profiles on AD target proteins. Biochemical assays experimentally confirmed their biological activities. The two compounds inhibit acetylcholinesterase, butyrylcholinesterase, and ß-secretase enzymes in high- to sub-micromolar range. They are also able to prevent and revert ß-amyloid (Aß) aggregation of both Aß1-40 and Aß1-42 peptides, with 1 being more active than 2. Preliminary in vivo studies suggest that compound 1 is able to restore cholinergic cortico-hippocampal functional connectivity.
Assuntos
Acetilcolinesterase/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Ligantes , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Humanos , Fragmentos de Peptídeos/metabolismo , SilícioRESUMO
Chemical investigation of the rhizomes of the marine phanerogam Cymodocea nodosa resulted in the isolation of two new prenylated flavon-di-O-glycosides, cymodioside A (1: ) and B (2: ), along with known phenolic compounds 3: -7: , some of which never reported from seagrasses to date. The structures of compounds 1: and 2: were established by extensive nuclear magnetic resonance analysis. In addition, the absolute configuration of 4-(2,5-dihydroxyhexyl) benzene-1,2-diol (7: ), which was not previously reported in the literature, has been now determined.
Assuntos
Flavonas/química , Glicosídeos/química , Magnoliopsida/química , Fenóis/química , Rizoma/química , Flavonas/isolamento & purificação , Glicosídeos/isolamento & purificação , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Fenóis/isolamento & purificação , PrenilaçãoRESUMO
The lipophilic extracts of two marine aeolid nudibranch molluscs of the genus Spurilla collected in distinct geographical areas have been chemically analyzed. The Et2 O extracts of the nudibranchs were dominated by the presence of usual fatty acids and sterols and contained terpenoid compounds 1 - 3 as minor metabolites. Spurillin A (1) and spurillin B (3) were new molecules whereas cis-γ-monocyclofarnesol (2) was already reported in the literature as a synthesis product. Interestingly, bursatellin (4), previously isolated from anaspidean molluscs of the genus Bursatella, was found in the butanol extract of both Spurilla species. Compounds 1 - 4 were not detected in the extracts of the sea-anemone preys collected together with the molluscs.
Assuntos
Gastrópodes/química , Animais , Ácidos Graxos/análise , Anêmonas-do-Mar/química , Esteróis/análise , Terpenos/análiseRESUMO
Olfaction is considered a distance sense; hence, aquatic olfaction is thought to be mediated only by molecules dissolved in water. Here, we challenge this view by showing that shrimp and fish can recognize the presence of hydrophobic olfactory cues by a "tactile" form of chemoreception. We found that odiferous furanosesquiterpenes protect both the Mediterranean octocoral Maasella edwardsi and its specialist predator, the nudibranch gastropod Tritonia striata, from potential predators. Food treated with the terpenes elicited avoidance responses in the cooccurring shrimp Palaemon elegans Rejection was also induced in the shrimp by the memory recall of postingestive aversive effects (vomiting), evoked by repeatedly touching the food with chemosensory mouthparts. Consistent with their emetic properties once ingested, the compounds were highly toxic to brine shrimp. Further experiments on the zebrafish showed that this vertebrate aquatic model also avoids food treated with one of the terpenes, after having experienced gastrointestinal malaise. The fish refused the food after repeatedly touching it with their mouths. The compounds studied thus act simultaneously as (i) toxins, (ii) avoidance-learning inducers, and (iii) aposematic odorant cues. Although they produce a characteristic smell when exposed to air, the compounds are detected by direct contact with the emitter in aquatic environments and are perceived at high doses that are not compatible with their transport in water. The mouthparts of both the shrimp and the fish have thus been shown to act as "aquatic noses," supporting a substantial revision of the current definition of the chemical senses based upon spatial criteria.
Assuntos
Organismos Aquáticos/fisiologia , Gastrópodes/fisiologia , Olfato , Compostos Orgânicos Voláteis/metabolismo , Peixe-Zebra/fisiologia , Animais , Comportamento Animal , Odorantes/análise , Metabolismo Secundário , Compostos Orgânicos Voláteis/químicaRESUMO
The chemical investigation of marine mollusks has led to the isolation of a wide variety of bioactive metabolites, which evolved in marine organisms as favorable adaptations to survive in different environments. Most of them are derived from food sources, but they can be also biosynthesized de novo by the mollusks themselves, or produced by symbionts. Consequently, the isolated compounds cannot be strictly considered as "chemotaxonomic markers" for the different molluscan species. However, the chemical investigation of this phylum has provided many compounds of interest as potential anticancer drugs that assume particular importance in the light of the growing literature on cancer biology and chemotherapy. The current review highlights the diversity of chemical structures, mechanisms of action, and, most importantly, the potential of mollusk-derived metabolites as anticancer agents, including those biosynthesized by mollusks and those of dietary origin. After the discussion of dolastatins and kahalalides, compounds previously studied in clinical trials, the review covers potentially promising anticancer agents, which are grouped based on their structural type and include terpenes, steroids, peptides, polyketides and nitrogen-containing compounds. The "promise" of a mollusk-derived natural product as an anticancer agent is evaluated on the basis of its ability to target biological characteristics of cancer cells responsible for poor treatment outcomes. These characteristics include high antiproliferative potency against cancer cells in vitro, preferential inhibition of the proliferation of cancer cells over normal ones, mechanism of action via nonapoptotic signaling pathways, circumvention of multidrug resistance phenotype, and high activity in vivo, among others. The review also includes sections on the targeted delivery of mollusk-derived anticancer agents and solutions to their procurement in quantity.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Moluscos/química , Neoplasias/tratamento farmacológico , Animais , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Esteroides/química , Esteroides/farmacologia , Terpenos/química , Terpenos/farmacologiaRESUMO
The chemical study of Launaea acanthoclada from South-East Algeria led to the isolation of twelve oxygenated terpenoid compounds, including three new pentacyclic triterpenoids 1-3 with either lupane or ursane rearranged skeletons. The structure and the stereochemistry of these compounds were established by spectroscopic methods, including NMR techniques. The chemical pattern of L. acanthoclada is in accordance with the triterpenoid scenario of the genus Launaea embracing to date lupane, oleane, ursane and taraxastane skeletons. However, the carbon frameworks exhibited by new compounds 1-3 have never been reported from Launaea species.
Assuntos
Asteraceae/química , Extratos Vegetais/química , Raízes de Plantas/química , Triterpenos/química , Argélia , Triterpenos/isolamento & purificaçãoRESUMO
Marine sponges of the Irciniidae family contain both bioactive furanosesterterpene tetronic acids (FTAs) and prenylated hydroquinones (PHQs). Both classes of compounds are known for their anti-inflammatory, antioxidant, and antimicrobial properties and known to display growth inhibitory effects against various human tumor cell lines. However, the different experimental conditions of the reported in vitro bioassays, carried out on different cancer cell lines within separate studies, prevent realistic actual discrimination between the two classes of compounds from being carried out in terms of growth inhibitory effects. In the present work, a chemical investigation of irciniid sponges from Tunisian coasts led to the purification of three known FTAs and three known PHQs. The in vitro growth inhibitory properties of the six purified compounds have been evaluated in the same experiment in a panel of five human and one murine cancer cell lines displaying various levels of sensitivity to proapoptotic stimuli. Surprisingly, FTAs and PHQs elicited distinct profiles of growth inhibitory-responses, differing by one to two orders of magnitude in favor of the PHQs in all cell lines. The obtained comparative results are discussed in the light of a better selection of drug candidates from natural sources.
Assuntos
Antineoplásicos , Organismos Aquáticos/química , Bioensaio , Neoplasias/tratamento farmacológico , Poríferos/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Células MCF-7 , Camundongos , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
Phytochemical investigation of the ethyl acetate extract from the aerial parts of Eryngium triquetrum Vahl resulted in the isolation of new polyacetylenes, triquetridiol (6) and trans-epoxy-triquetrol (7a/7b, diastereomeric mixture), and the lignan demethoxy carolignan Z (8a/8b, erythro/threo pair), together with a series of related known metabolites. Additionally, some already reported phenolic and flavonoid compounds were also identified in the extract. Structural elucidation of the new compounds was made by spectroscopic analysis, mainly NMR and mass spectrometry. To the best of our knowledge, this is the first report of polyacetylenes and lignans from E. triquetrum.
Assuntos
Eryngium/química , Lignanas/isolamento & purificação , Poli-Inos/isolamento & purificação , Lignanas/química , Poli-Inos/químicaRESUMO
Eight cyclic peroxide norterpenoids, compounds 1-8, have been isolated and characterized from the Red Sea sponge Diacarnus erythraeanus, including two new norsesterterpene derivatives (3, 4). Among these metabolites, (-)-muqubilin A (5) (nine cell lines analyzed) and the new compounds 3 and 4 (seven cell lines analyzed) displayed mean IC50 growth inhibitory concentrations in vitro of <10 µM, while the remaining compounds (1, 6-8) were inactive in these cancer cell lines. Compound 5 displayed no selectivity between normal and cancer cells in terms of in vitro growth inhibition. Quantitative video microscopy analysis carried out on (-)-muqubilin A-treated cells validated the data obtained by means of the MTT colorimetric assay, while flow cytometry analysis revealed ROS production but no induction of apoptosis in cancer cells.