RESUMEN
Highly functionalized spirobisnaphthalenes, preussomerins N (1) and O (2), and simpler compounds, such as 2,3-α-epoxypalmarumycin CP18 (3), 3α-hydroxy-CJ-12,372 (4), and 16 known structurally related congeners, were isolated from a culture broth of Roussoella sp. KT4147. Structural analysis revealed that 1 was a dimer of preussomerin G (6), connected by a nitrogen atom, and 2 was a derivative of 6 with a macommelin substructure. Preussomerin N (1) was considered to be biosynthetically derived via the Michael-type 1,4-addition of ammonia to 6, followed by another Michael addition to another molecule of 6. Contrarily, 2 was suggested to be derived through an endo-Diels-Alder cycloaddition between a diene derived from the (E)-enol form of macommelinal via an ene-reaction and dienophile 6. Compounds 1 and 2 exhibited potent cytotoxicity against COLO-201 human colorectal cancer cells.
Asunto(s)
Naftalenos , Compuestos de Espiro , Humanos , Estructura Molecular , Compuestos de Espiro/química , Compuestos de Espiro/aislamiento & purificación , Compuestos de Espiro/farmacología , Naftalenos/química , Naftalenos/farmacología , Naftalenos/aislamiento & purificación , Ensayos de Selección de Medicamentos Antitumorales , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Reacción de Cicloadición , Línea Celular TumoralRESUMEN
Two undescribed cladosporol derivatives, cladosporols J-K (1-2), and three previously unreported spirobisnaphthalenes, urnucratins D-F (3-5), as well as eleven known cladosporols (6-16), were characterized from Cladosporium cladosporioides (Cladosporiaceae), a common plant pathogen isolated from the skin of Chinese toad. Cladosporols J-K (1-2) with a single double bond have been rarely reported, while urnucratins D-F (3-5) featured an unusual benzoquinone bisnaphthospiroether skeleton, contributing to an expanding category of undiscovered natural products. Their structures and absolute configurations were determined using extensive spectroscopic methods, including NMR, HRESIMS analyses, X-ray single crystal diffraction, as well as through experimental ECD analyses. Biological assays revealed that compounds 1 and 2 exhibited inhibitory activity against A549 cells, with IC50 values of 30.11 ± 3.29 and 34.32 ± 2.66 µM, respectively.
Asunto(s)
Cladosporium , Naftalenos , Cladosporium/química , Humanos , Naftalenos/química , Naftalenos/aislamiento & purificación , Naftalenos/farmacología , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Células A549 , Compuestos de Espiro/química , Compuestos de Espiro/aislamiento & purificación , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Proliferación Celular/efectos de los fármacosRESUMEN
Bafilomycins are macrocyclic polyketides with intriguing structures and therapeutic value. Genomic analysis of Streptomyces sp. SCSIO 66814 revealed a type I polyketide synthase biosynthetic gene cluster (BGC), namely blm, which encoded bafilomycins and featured rich post-modification genes. The One strain many compounds (OSMAC) strategy led to the discovery of six compounds related to the blm BGC from the strain, including two previously undescribed 6,6-spiroketal polyketides, streptospirodienoic acids D (1) and E (2), and four known bafilomycins, bafilomycins P (3), Q (4), D (5), and G (6). The structures of 1 and 2 were determined by extensive spectroscopic analysis, quantum calculation, and biosynthetic analysis. Additionally, the absolute configurations of the 6/5/5 tricyclic ring moiety containing six consecutive chiral carbons in the putative structures of 3 and 4 were corrected through NOE analysis, DP4+ calculation, and single-crystal X-ray diffraction data. Bioinformatic analysis uncovered a plausible biosynthetic pathway for compounds 1-6, indicating that both streptospirodienoic acids and bafilomycins were derived from the same blm BGC. Additionally, sequence analysis revealed that the KR domains of module 2 from blm BGC was B1-type, further supporting the configurations of 1-4. Notably, compounds 3 and 4 displayed significant cytotoxic activities against A-549 human non-small cell lung cancer cells and HCT-116 human colon cancer cells.
Asunto(s)
Policétidos , Streptomyces , Streptomyces/química , Streptomyces/metabolismo , Streptomyces/genética , Policétidos/química , Policétidos/farmacología , Policétidos/aislamiento & purificación , Humanos , Estereoisomerismo , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Macrólidos/química , Macrólidos/farmacología , Macrólidos/aislamiento & purificación , Macrólidos/metabolismo , Proliferación Celular/efectos de los fármacos , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/aislamiento & purificación , Relación Estructura-Actividad , Sintasas Poliquetidas/metabolismo , Sintasas Poliquetidas/genética , Línea Celular Tumoral , Genoma Bacteriano , Familia de MultigenesRESUMEN
Four compounds (1-4) featuring with an L-rhodinose and spiroketal, possess uncommon continuous hydroxy groups in the macrolide skeleton, and a dichloro-diketopiperazine (5) were isolated from a marine derived Micromonospora sp. FIMYZ51. The determination of the relative and absolute configurations of all isolates was achieved by extensive spectroscopic analyses, single-crystal X-ray diffraction analysis, and ECD calculations. According to structural characteristic and genomic sequences, a plausible biosynthetic pathway for compound 1-4 was proposed and a spirocyclase was inferred to be responsible for the formation of the rare spirocyclic moiety. Compounds 1-4 exhibited potent antifungal activities which is equal to itraconazole against Aspergillus niger. Compounds 1-5 exhibited different degree of inhibitory activities against opportunistic pathogenic bacteria of endocarditis (Micrococcus luteus) with MIC values ranging from 0.0625 µg/mL to 32 µg/mL. Compounds 2 and 3 showed moderate cytotoxicity against drug-resistant tumor cell lines (Namalwa and U266). The result not only provides active lead-compounds, but also reveal the potential of the spirocyclase gene resources from Micromonospora sp., which highlights the promising potential of the strain for biomedical applications.
Asunto(s)
Dicetopiperazinas , Macrólidos , Micromonospora , Compuestos de Espiro , Estructura Molecular , Dicetopiperazinas/farmacología , Dicetopiperazinas/aislamiento & purificación , Dicetopiperazinas/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/aislamiento & purificación , Compuestos de Espiro/química , Línea Celular Tumoral , Humanos , Macrólidos/farmacología , Macrólidos/aislamiento & purificación , Macrólidos/química , Antibacterianos/farmacología , Antibacterianos/aislamiento & purificación , Antibacterianos/química , Antifúngicos/farmacología , Antifúngicos/aislamiento & purificación , Antifúngicos/química , Pruebas de Sensibilidad Microbiana , China , Antineoplásicos/farmacología , Antineoplásicos/aislamiento & purificación , Antineoplásicos/química , FuranosRESUMEN
Two novel polyketides, accraspiroketides A (1) and B (2), which feature unprecedented [6 + 6+6 + 6] + [5 + 5] spiro chemical architectures, were isolated from Streptomyces sp. MA37 ΔaccJ mutant strain. Compounds 1-2 exhibit excellent activity against Gram-positive bacteria (MIC = 1.5-6.3 µg/mL). Notably, 1 and 2 have superior activity against clinically isolated Enterococcus faecium K60-39 (MIC = 4.0 µg/mL and 4.7 µg/mL, respectively) than ampicillin (MIC = 25 µg/mL).
Asunto(s)
Antibacterianos , Enterococcus faecium , Pruebas de Sensibilidad Microbiana , Policétidos , Streptomyces , Policétidos/farmacología , Policétidos/química , Policétidos/aislamiento & purificación , Streptomyces/química , Estructura Molecular , Antibacterianos/farmacología , Antibacterianos/química , Enterococcus faecium/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/aislamiento & purificación , Naftacenos/química , Naftacenos/farmacologíaRESUMEN
Schistosomiasis has been controlled for more than 40 years with a single drug, praziquantel, and only one molluscicide, niclosamide, raising concern of the possibility of the emergence of resistant strains. However, the molecular targets for both agents are thus far unknown. Consequently, the search for lead compounds from natural sources has been encouraged due to their diverse structure and function. Our search for natural compounds with potential use in schistosomiasis control led to the identification of an algal species, Laurencia dendroidea, whose extracts demonstrated significant activity toward both Schistosoma mansoni parasites and their intermediate host snails Biomphalaria glabrata. In the present study, three seaweed-derived halogenated sesquiterpenes, (-)-elatol, rogiolol, and obtusol are proposed as potential lead compounds for the development of anthelminthic drugs for the treatment of and pesticides for the environmental control of schistosomiasis. The three compounds were screened for their antischistosomal and molluscicidal activities. The screening revealed that rogiolol exhibits significant activity toward the survival of adult worms, and that all three compounds showed activity against S. mansoni cercariae and B. glabrata embryos. Biomonitored fractioning of L. dendroidea extracts indicated elatol as the most active compound toward cercariae larvae and snail embryos.
Asunto(s)
Antihelmínticos , Laurencia , Moluscocidas , Sesquiterpenos , Animales , Antihelmínticos/aislamiento & purificación , Antihelmínticos/farmacología , Larva , Laurencia/química , Moluscocidas/aislamiento & purificación , Moluscocidas/farmacología , Schistosoma mansoni/efectos de los fármacos , Esquistosomiasis/tratamiento farmacológico , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacología , Compuestos de Espiro/aislamiento & purificación , Compuestos de Espiro/farmacologíaRESUMEN
The U rhynchophylla, U tomentosa, Isatis indigotica Fortune, Voacanga Africana, herbal constituents, fungal extracts from Aspergillus duricaulis culture media, include spirooxindoles, polyphenols or bridged spirocyclic alkaloids. Their constituents exhibit specific and synergistic multiple neuroprotective properties including inhibiting of Aß fibril induced cytotoxicity, NMDA receptor inhibition in mice models of Alzheimer's disease (AD). The pioneering research from Woodward to Waldmann has advanced the synthesis of spirocyclic alkaloids. Furthermore, the elucidation of the genetic analysis, biochemical pathways that links strictosidine to the alkaloids akuammicine, stemmadenine, tabersonine, catharanthine, will now enable the biotechnological generation, also stimulate synthesis of related bridged spirocyclic alkaloids for medicinal investigations. From the value of spirocyclic structures as multi target dementia leads, we hypothesise that simpler Lipinski-like natural/synthetic alkaloid analogues may likewise be discovered that provide neurocognitive enhancing activities against dementia and AD.
Asunto(s)
Alcaloides/farmacología , Productos Biológicos/farmacología , Medicamentos Herbarios Chinos/farmacología , Fármacos Neuroprotectores/farmacología , Polifenoles/farmacología , Compuestos de Espiro/farmacología , Alcaloides/química , Alcaloides/aislamiento & purificación , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Amiloide/antagonistas & inhibidores , Amiloide/metabolismo , Animales , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Ratones , Estructura Molecular , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Polifenoles/química , Polifenoles/aislamiento & purificación , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Compuestos de Espiro/química , Compuestos de Espiro/aislamiento & purificaciónRESUMEN
Two new polyketide natural products, globosuxanthone F (1), and 2'-hydroxy bisdechlorogeodin (2), were isolated from the fungus Pleosporales sp. NBUF144, which was derived from a 62 m deep Chalinidae family sponge together with four known metabolites, 3,4-dihydroglobosuxanthone A (3), 8-hydroxy-3-methylxanthone-1-carboxylate (4), crosphaeropsone C (5), and 4-megastigmen-3,9-dione (6). The structures of these compounds were elucidated on the basis of extensive spectroscopic analysis, including 1D and 2D NMR and high-resolution electrospray ionization mass spectra (HRESIMS) data. The absolute configuration of 1 was further established by single-crystal X-ray diffraction studies. Compounds 1-5 were evaluated for cytotoxicity towards CCRF-CEM human acute lymphatic leukemia cells, and it was found that 1 had an IC50 value of 0.46 µM.
Asunto(s)
Antineoplásicos/farmacología , Ascomicetos/metabolismo , Leucemia de Células T/tratamiento farmacológico , Policétidos/farmacología , Poríferos/microbiología , Animales , Antineoplásicos/aislamiento & purificación , Benzofuranos/aislamiento & purificación , Benzofuranos/farmacología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Leucemia de Células T/patología , Estructura Molecular , Policétidos/aislamiento & purificación , Compuestos de Espiro/aislamiento & purificación , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
Two new tetrahydrobenzannulated 5,5-spiroketal sesquiterpenes (1 and 2) and three novel benzannulated 5,5-spiroketal sesquiterpenes (3-5) namely angepubesins A-E, together with a new heliannane-type benzannulated sesquiterpene namely angepubesin F (6) and two known monoterpenes (7 and 8), were isolated from the roots of Angelica Pubescens. Their structures were identified by various spectroscopic analyses (NMR, MS, UV, IR), in combination with 13C NMR calculation as well as MAE, CMAE, DP4 + and MAEΔΔδ values analyses. The absolute configurations of 1-6 were determined by modified Mosher's method, ECD calculation and single-crystal X-ray diffraction (Cu Kα). Furthermore, the inhibitory activities of these isolated compounds against nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophage cells were evaluated. The results showed that compounds 2-4, 6 and 7, especially 6, displayed markedly inhibitory effects on NO production in a concentration-dependent manner. Mechanical study revealed that compound 6 could significantly inhibit the expression of nitric oxide synthase (iNOS) protein at a concentration of 10 µM. In addition, compound 6 suppressed the activation of JAK-STAT and NF-κB pathways.
Asunto(s)
Angelica/química , Antiinflamatorios/farmacología , Inhibidores Enzimáticos/farmacología , Extractos Vegetales/farmacología , Sesquiterpenos/farmacología , Compuestos de Espiro/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Raíces de Plantas/química , Células RAW 264.7 , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Compuestos de Espiro/química , Compuestos de Espiro/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
The inflammation pathology is an orchestrated biological process and the dual inhibition of pro-inflammatory enzymes 5-lipoxygenase and cyclooxygenase-2 has been found to be an effective approach against inflammation. This study involves the characterisation of two previously undescribed spiro[5.5]undecanes, 3-(hydroxymethyl)-7-(methoxymethyl)-3,11-dimethyl-9-oxospiro[5.5]undec-4-en-10-methylbutanoate (1) and 4-ethoxy-11,11-dimethyl-7-methylene-8-(propionyloxy)spiro[5.5]undec-2-en-104,106-dihydroxytetrahydro-2H-pyran-10-carboxylate (2) with potential anti-inflammatory properties, from seaweed Gracilaria salicornia by extensive-spectroscopic-experiments. These metabolites recorded prospective bioactivities against 5-lipoxygenase (IC50 < 2.80 mM), whereas their selectivity indices were significantly greater (â¼1) than ibuprofen (0.89) (p < 0.05), which attributed selective anti-inflammatory potencies of the studied spiro[5.5]undecane derivatives against inducible cyclooxygenase-2 than constitutive cyclooxygenase-1. Radical scavenging potential of spiro[5.5]undec-2-en-104,106-dihydroxytetrahydro-2H-pyran-10-carboxylate analogue (2) against oxidants, 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis-3 ethylbenzothiozoline-6-sulfonic acid were found to be greater (IC50 < 1.25 mM) than commercial standard, α-tocopherol (IC50 1.42-1.79 mM). The greater hydrogen-bonding interactions and binding affinity of 2 (-10.13 kcal/mol) with 5-LOX appropriately corroborated its prospective anti-inflammatory activity.
Asunto(s)
Antiinflamatorios/farmacología , Organismos Acuáticos/química , Araquidonato 5-Lipooxigenasa/metabolismo , Ciclooxigenasa 2/metabolismo , Gracilaria/química , Compuestos de Espiro/farmacología , Animales , Antioxidantes/farmacología , Bioensayo , Espectroscopía de Resonancia Magnética con Carbono-13 , Fraccionamiento Químico , Inhibidores de la Lipooxigenasa/farmacología , Modelos Moleculares , Espectroscopía de Protones por Resonancia Magnética , Compuestos de Espiro/química , Compuestos de Espiro/aislamiento & purificaciónRESUMEN
Four undescribed polyketide derivatives, named arthproliferins A-D (1-4), and one undescribed phenylspirodrimane derivative, named arthproliferin E (7), along with 11 known metabolites (5, 6, 8-16) were isolated from the soft coral-associated fungus Stachybotrys chartarum SCSIO41201. Their structures were determined through spectroscopic methods, X-ray crystallography, and ECD analysis. Compounds 1 and 3-15 were evaluated for their cytotoxic, and antibacterial activities. Among them, compounds 1 and 15 displayed moderate inhibitory activity against methicillin-resistant Staphylococcus aureus ATCC 29213 with an MIC value of 78 and 39 µg/mL, respectively. Furthermore, compound 15 displayed strong cytotoxic activities against the tested cell line with IC50 values less than 39 nM.
Asunto(s)
Antibacterianos/aislamiento & purificación , Antineoplásicos/aislamiento & purificación , Policétidos/aislamiento & purificación , Compuestos de Espiro/aislamiento & purificación , Stachybotrys/metabolismo , Antibacterianos/química , Antibacterianos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Policétidos/química , Policétidos/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacologíaRESUMEN
Gymnodimines and spirolides are cyclic imine phycotoxins and known antagonists of nicotinic acetylcholine receptors (nAChRs). We investigated the effect of gymnodimine A (GYM A) and 13-desmethyl spirolide C (SPX 1) from Alexandrium ostenfeldii on rat pheochromocytoma (PC12) cells by monitoring intracellular calcium levels ([Ca]i). Using whole cells, the presence of 0.5 µM of GYM A or SPX 1 induced an increase in [Ca]i mediated by acetylcholine receptors (AChRs) and inhibited further activation of AChRs by acetylcholine (ACh). To differentiate the effects of GYM A or SPX 1, the toxins were applied to cells with pharmacologically isolated nAChRs and muscarinic AChRs (mAChRs) as mediated by the addition of atropine and tubocurarine, respectively. GYM A and SPX 1 activated nAChRs and inhibited the further activation of nAChRs by ACh, indicating that both toxins mimicked the activity of ACh. Regarding mAChRs, a differential response was observed between the two toxins. Only GYM A activated mAChRs, resulting in elevated [Ca]i, but both toxins prevented a subsequent activation by ACh. The absence of the triketal ring system in GYM A may provide the basis for a selective activation of mAChRs. GYM A and SPX 1 induced no changes in [Ca]i when nAChRs and mAChRs were inhibited simultaneously, indicating that both toxins target AChRs.
Asunto(s)
Calcio/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Iminas/farmacología , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/metabolismo , Compuestos de Espiro/farmacología , Animales , Canales de Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Línea Celular , Dinoflagelados/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/aislamiento & purificación , Iminas/aislamiento & purificación , Toxinas Marinas/aislamiento & purificación , Toxinas Marinas/farmacología , Antagonistas Muscarínicos , Agonistas Nicotínicos , Células PC12 , Ratas , Compuestos de Espiro/aislamiento & purificaciónRESUMEN
The spirooxepinisoxazoline alkaloid psammaplysin F (1) was selected as a scaffold for the generation of a unique screening library for both drug discovery and chemical biology research. Large-scale extraction and isolation chemistry was performed on a marine sponge (Hyattella sp.) collected from the Great Barrier Reef in order to acquire >200 mg of the desired bromotyrosine-derived alkaloidal scaffold. Parallel solution-phase semisynthesis was employed to generate a series of psammaplysin-based urea (2-9) and amide analogues (10-11) in low to moderate yields. The chemical structures of all analogues were characterized using NMR and MS data. The absolute configuration of psammaplysin F and all semisynthetic analogues was determined as 6R, 7R by comparison of ECD data with literature values. All compounds (1-11) were evaluated for their effect on cell cycle distribution and changes to cancer metabolism in LNCaP prostate cancer cells using a multiparametric quantitative single-cell imaging approach. These investigations identified that in LNCaP cells psammaplysin F and some urea analogues caused loss of mitochondrial membrane potential, fragmentation of the mitochondrial tubular network, chromosome misalignment, and cell cycle arrest in mitosis.
Asunto(s)
Neoplasias de la Próstata/patología , Análisis de la Célula Individual/métodos , Compuestos de Espiro/síntesis química , Tirosina/análogos & derivados , Animales , Línea Celular Tumoral , Humanos , Masculino , Poríferos/química , Análisis Espectral/métodos , Compuestos de Espiro/aislamiento & purificación , Tirosina/síntesis química , Tirosina/aislamiento & purificaciónRESUMEN
The chemical investigation on endophytic fungus Annulohypoxylon cf. stygium in leaves of Anoectochilus roxburghii (Wall.) Lindl. has been performed. Sixteen compounds were isolated and their structures were identified as (-)-notoamide A, (-)-notoamide B, (+)-versicolamide B, notoamide C, notoamide D, stephacidin A, sterigmatocystin, dihydrosterigmatocystin, secosterigmatocystin, versiconol, averufanin, kipukasin D, kipukasin E, diorcinal, palmarumycin CP2 and (-)-(3R)-mellein methyl ether, respectively, by spectroscopic analysis and comparison with literature data. All the compounds were isolated from Annulohypoxylon genus for the first time. Sterigmatocystin and palmarumycin CP2 showed selective cytotoxic activities against HepG2, HeLa, MCF-7 and HT-29.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Ascomicetos/química , Naftalenos/farmacología , Orchidaceae/microbiología , Hojas de la Planta/microbiología , Compuestos de Espiro/farmacología , Esterigmatocistina/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Ascomicetos/metabolismo , Línea Celular , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Naftalenos/química , Naftalenos/aislamiento & purificación , Compuestos de Espiro/química , Compuestos de Espiro/aislamiento & purificación , Esterigmatocistina/química , Esterigmatocistina/aislamiento & purificaciónRESUMEN
Three new bromotyrosine spiroisoxazoline alkaloids, lacunosins A and B (1 and 2) and desaminopurealin (3), were isolated from a MeOH extract of the marine sponge Aplysina lacunosa that showed modest α-chymotrypsin inhibitory activity. The structures of 1-3 share the spirocyclohexadienyl-isoxazoline ring system found in purealidin-R and several other Verongid sponge secondary metabolites. Compounds 1 and 2 are coupled to a glycine and an isoserine methyl ester, respectively. Alkaloid 3 is linked, contiguously, to an O-1-aminopropyl 3,5-dibromotyrosyl ether and, finally, to histamine through an amide bond. The planar structures of all three compounds were obtained from analysis of MS and 1D and 2D NMR data. The absolute configuration of the SIO unit of 1-3 was assigned by electronic circular dichroism (ECD). The isoserine amino acid residue in 2 was found to be a 1:1 mixture of epimers using a new Marfey's type reagent, derived from Trp-NH2. Allylic O-naphthoylation of the SIO subunit enhances the ECD spectrum of SIOs and improves discrimination of enantiomorphs. A unifying hypothesis is proposed that links the biosynthesis of several of the new compounds with previously reported analogues.
Asunto(s)
Alcaloides/aislamiento & purificación , Quimotripsina/química , Péptidos/química , Poríferos/química , Compuestos de Espiro/aislamiento & purificación , Tirosina/análogos & derivados , Alcaloides/química , Animales , Región del Caribe , Quimotripsina/antagonistas & inhibidores , Dicroismo Circular , Espectroscopía de Resonancia Magnética , Estructura Molecular , Péptidos/metabolismo , Compuestos de Espiro/química , Tirosina/químicaRESUMEN
Chemical screening of culture medium from the soil fungus Stachybotrys sp. resulted in the isolation of the three new phenylspirodrimanes MBJ-0030 (1), MBJ-0031 (2) and MBJ-0032 (3). Their structures were determined by detailed analysis of spectroscopic data. The absolute configurations of 1-3 were determined by modified Mosher's and Marfey's methods. In addition, cytotoxic and antimicrobial evaluations of the compounds were conducted.
Asunto(s)
Sesquiterpenos Policíclicos/química , Compuestos de Espiro/química , Stachybotrys/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Micrococcus luteus/efectos de los fármacos , Micrococcus luteus/crecimiento & desarrollo , Sesquiterpenos Policíclicos/aislamiento & purificación , Microbiología del Suelo , Compuestos de Espiro/aislamiento & purificación , Stachybotrys/aislamiento & purificaciónRESUMEN
The emergence of antibiotic resistance necessitates not only the identification of new compounds with antimicrobial properties, but also new strategies and combination therapies to circumvent this growing problem. Here, we report synergistic activity against methicillin-resistant Staphylococcus aureus (MRSA) of the ß-lactam antibiotic oxacillin combined with 7,8-dideoxygriseorhodin C in vitro. Ongoing efforts to identify antibiotics from marine mollusk-associated bacteria resulted in the isolation of 7,8-dideoxygriseorhodin C from a Streptomyces sp. strain cultivated from a marine gastropod tissue homogenate. Despite the long history of 7,8-dideoxygriseorhodin C in the literature, the absolute configuration has never been previously reported. A comparison of measured and calculated ECD spectra resolved the configuration of the spiroketal carbon C6, and 2D ROESY NMR spectroscopy established the absolute configuration as 6s,6aS. The compound is selective against Gram-positive bacteria including MRSA and Enterococcus faecium with an MIC range of 0.125-0.5 µg ml-1. Moreover, the compound synergizes with oxacillin against MRSA as observed in the antimicrobial microdilution and time-kill assays. Simultaneous treatment of the compound with oxacillin resulted in an approximately tenfold decrease in MIC with a combination index of <0.5, indicating synergistic anti-MRSA activity.
Asunto(s)
Antibacterianos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Oxacilina/farmacología , Antibacterianos/administración & dosificación , Antibacterianos/aislamiento & purificación , Sinergismo Farmacológico , Enterococcus faecium/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Naftoquinonas/administración & dosificación , Naftoquinonas/química , Naftoquinonas/aislamiento & purificación , Naftoquinonas/farmacología , Oxacilina/administración & dosificación , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/química , Compuestos de Espiro/aislamiento & purificación , Compuestos de Espiro/farmacología , Streptomyces/metabolismoRESUMEN
A new prenylated indole alkaloid, named paraherquamide J (1), together with four known compounds (2-5), were isolated from the mangrove rhizosphere soil-derived fungus Penicillium janthinellum HK1-6. The planar structure and relative configuration of 1 were determined by detailed analysis of the spectroscopic data especially the NOESY spectrum. The absolute configuration of 1 was determined by ECD spectra. Compound 2 was first isolated as a natural product and named as paraherquamide K. All isolated metabolites were evaluated for their antibacterial, topoisomerase I (topo I) inhibitory activities and lethality towards brine shrimp Artemia salina.
Asunto(s)
Antibacterianos/aislamiento & purificación , Indolizinas/aislamiento & purificación , Penicillium/química , Compuestos de Espiro/aislamiento & purificación , Animales , Antibacterianos/química , Antibacterianos/farmacología , Artemia/efectos de los fármacos , Alcaloides Indólicos/química , Alcaloides Indólicos/aislamiento & purificación , Alcaloides Indólicos/farmacología , Indolizinas/toxicidad , Estructura Molecular , Prenilación , Rizosfera , Compuestos de Espiro/toxicidad , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/aislamiento & purificación , Inhibidores de Topoisomerasa I/farmacologíaRESUMEN
Two new compounds Talaromycin A (1) and Talaromycin B (2) were isolated from a liquid culture of Talaromyces aurantiacus. The structures of 1 and 2 were elucidated by IR, MS, 1D and 2D NMR spectra and comparison of the experimental and calculated electronic circular dichroism spectra. Additional known compounds (3-6) were also isolated. These compounds were tested for monoamine oxidase, acetylcholinesterase and PI3K inhibitory activity, but showed only weak activity.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Compuestos de Espiro/química , Talaromyces/química , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Dicroismo Circular , Evaluación Preclínica de Medicamentos , Endófitos/química , Inhibidores Enzimáticos/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Estructura Molecular , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Compuestos de Espiro/aislamiento & purificación , Compuestos de Espiro/farmacologíaRESUMEN
The first representative of a new type of spirobisnaphthalene with a previously unknown skeletal system, Spiroaxillarone A (1), was isolated from Cyanotis axillaris. The planar structure was determined through analysis of spectroscopic evidence, while electronic circular dichroism (ECD) calculations were used to determine its absolute configuration. The structure of 1 was further confirmed through X-ray diffraction studies of its tetrabromobenzoate derivative (1a). Spiroaxillarone A exhibited significant antimalarial activity against resistant Plasmodium falciparum (IC50 = 2.32 µM).