RESUMEN
In this short review, including 113 references, issues related to dibenzo[b,f]oxepine derivatives are presented. Dibenzo[b,f]oxepine scaffold is an important framework in medicinal chemistry, and its derivatives occur in several medicinally relevant plants. At the same time, the structure, production, and therapeutic effects of dibenzo[b,f]oxepines have not been extensively discussed thus far and are presented in this review. This manuscript addresses the following issues: extracting dibenzo[b,f]oxepines from plants and its significance in medicine, the biosynthesis of dibenzo[b,f]oxepines, the active synthetic dibenzo[b,f]oxepine derivatives, the potential of dibenzo[b,f]oxepines as microtubule inhibitors, and perspective for applications of dibenzo[b,f]oxepine derivatives. In conclusion, this review describes studies on various structural features and pharmacological actions of dibenzo[b,f]oxepine derivatives.
Asunto(s)
Oxepinas , Oxepinas/química , Oxepinas/farmacologíaRESUMEN
Empetroxepins A and B, which are 10,11-dihydrodibenz[b,f]oxepins produced by the Black Crowberry (Empetrum nigrum), displayed weak anti-tubercular activity upon isolation, but have not been explored for antibiotic activity despite their molecular similarity to other phenolic antibacterial natural products. Herein we detail the first total synthesis of Empetroxepins A and B via a selective demethylation strategy and antibacterial structure activity relationship (SAR) study of the natural products and related analogs. Empetroxepin A was found to be weakly active against susceptible strains of Staphylococcus aureus (SA) and Bacillus subtilis (BS) with a minimum inhibitory concentration (MIC) of 256 µg/mL against both bacteria, whereas Empetroxepin B was found to be weakly active against only BS (MIC = 256 µg/mL). Neither natural product was active against Escherichia coli (EC). Antibiotic activity was improved through derivatization of the 10,11-dihydrodibenz[b,f]oxepin core with the best compound of the SAR series, 9-chloro-10,11-dihydrodibenzo[b,f]oxepine-2,3,4-triol, having MICs of 8 µg/mL, 16 µg/mL, and 256 µg/mL against SA, BS, and EC respectively.
Asunto(s)
Productos Biológicos , Infecciones por Escherichia coli , Antibacterianos/química , Bacillus subtilis , Escherichia coli , Humanos , Pruebas de Sensibilidad Microbiana , Oxepinas/química , Oxepinas/farmacología , Staphylococcus aureusRESUMEN
Liquid chromatography mass spectrometry (LCMS) proteomic analyses have revealed that host proteins are often captured in extracellular virions. These proteins may play a role in viral replication or infectivity and can represent targets for broad-spectrum antiviral agent development. We utilized LCMS to determine the host protein composition of Lassa virus-like particles (LASV VLPs). Multiple host proteins incorporated in LASV VLPs are also incorporated in unrelated viruses, notably ribosomal proteins. We assembled a data set of host proteins incorporated into extracellular viral particles. The frequent incorporation of specific host proteins into viruses of diverse families suggests that interactions of these proteins with viral factors may be important for effective viral replication. Drugs that target virion-associated host proteins could affect the protein in the extracellular virion or the host cell. Compounds that target proteins incorporated into virions with high frequency, but with no known antiviral activity, were assayed in a scalable viral screening platform, and hits were tested in competent viral systems. One of these molecules, GAPDH modulating small molecule CGP 3466B maleate (Omigapil), exhibited a dose-dependent inhibition of HIV, dengue virus, and Zika virus.
Asunto(s)
Antivirales/farmacología , Descubrimiento de Drogas/métodos , Proteómica/métodos , Virión/química , Cromatografía Liquida , Virus del Dengue/efectos de los fármacos , VIH/efectos de los fármacos , Interacciones Huésped-Patógeno , Espectrometría de Masas , Oxepinas/farmacología , Virus Zika/efectos de los fármacosRESUMEN
Eight new diketopiperazine-type alkaloids including four oxepin-containing diketopiperazine-type alkaloids, oxepinamides H-K (1-4), and four 4-quinazolinone alkaloids, puniceloids A-D (5-8), together with two known analogues (9 and 10), were isolated from the culture broth extracts of the deep-sea-derived fungus Aspergillus puniceus SCSIO z021. Their structures were elucidated by spectroscopic analyses, and their absolute configurations were determined by Marfey's method along with comparison of their specific rotations and ECD spectra. The absolute configurations of 4 and 5 were further confirmed by a single-crystal X-ray diffraction analysis. Compounds 1-8 showed significant transcriptional activation of liver X receptor α with EC50 values of 1.7-50 µM, and 7 and 8 were the most potent agonists.
Asunto(s)
Alcaloides/química , Aspergillus/química , Dicetopiperazinas/química , Hongos/química , Receptores X del Hígado/efectos de los fármacos , Oxepinas/química , Piperazinas/química , Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Cristalografía por Rayos X , Dicetopiperazinas/aislamiento & purificación , Dicetopiperazinas/farmacología , Estructura Molecular , Oxepinas/sangre , Oxepinas/aislamiento & purificación , Oxepinas/farmacología , Piperazinas/aislamiento & purificación , Piperazinas/farmacologíaRESUMEN
Four new flavonoids (1-4), a new benzyl benzoate derivative (5), five new oxepinones (6-10), and 14 known compounds (11-24) were isolated from the leaf and twig extracts of Desmos cochinchinensis. Their structures were established by spectroscopic methods. The structure of 1 was also confirmed by X-ray diffraction data. The absolute configurations of 3, 4, and 6-10 were determined from comparisons of their ECD spectra with those of relevant reported compounds. Compounds 1, 2, 6, 8, 10, 12-15, and 17 showed α-glucosidase inhibitory activities with IC50 values ranging from 0.2 to 4.9 µM.
Asunto(s)
Annonaceae/química , Flavonoides/farmacología , Inhibidores de Glicósido Hidrolasas/farmacología , Oxepinas/farmacología , Extractos Vegetales/farmacología , Hojas de la Planta/química , alfa-Glucosidasas/efectos de los fármacos , Flavonoides/química , Inhibidores de Glicósido Hidrolasas/química , Estructura Molecular , Oxepinas/química , Extractos Vegetales/química , Análisis Espectral/métodos , Difracción de Rayos XRESUMEN
Three new quinazoline derivatives (1-3), one new oxepin-containing natural product (4) and four new cyclopenin derivatives (5-7 and 9) have been isolated from an EtOAc extract of the Taiwan Kueishantao hydrothermal vent crab-associated fungus Aspergillus versicolor XZ-4. Their planar structures were established by HRMS, 1D and 2D NMR spectroscopic data analyses. The absolute configurations for compounds 1 and 4 were determined by chiral phase HPLC analysis of their hydrolysis products. The absolute configurations of 2, 3 and 7 were defined mainly by comparison of the quantum chemical TDDFT calculated and the experimental ECD spectra, and the absolute configuration of 5 was deduced from comparison of the optical rotation values reported in the literature. The presence of two atropisomers of 5 was established by NOE analyses. The Ile & Val units in compounds 1-3 allowed the assignment of a new quinazoline skeleton and it's the first time the configuration of isoleucine in the quinazoline skeleton was defined. A series of 7-methoxy cyclopenin derivatives were reported for the first time in this study. The bioevaluation of compounds 5, 7, 8 and 9 revealed inhibitory activities against E. coli at MIC values around 32 µg mL-1.
Asunto(s)
Antibacterianos/farmacología , Aspergillus/química , Productos Biológicos/farmacología , Escherichia coli/efectos de los fármacos , Oxepinas/farmacología , Quinazolinas/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Benzodiazepinonas/química , Benzodiazepinonas/aislamiento & purificación , Benzodiazepinonas/farmacología , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxepinas/química , Oxepinas/aislamiento & purificación , Quinazolinas/química , Quinazolinas/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
Various oxepine and azepine fused N-heterocyclic derivatives were synthesized using a new and one-pot reaction of 2,3-dichloro quinoxaline/pyrazine with 2-(1H-indol-2-yl)phenol/aniline in the presence of 25 mol% FeCl3. The reaction proceeded via C-C bond followed by C-X (X = O or N) bond formation to construct the central 7-membered ring, affording the desired products in good yields. The structure assignment was confirmed by the single crystal X-ray analysis of a synthesized oxepine fused N-heterocycle derivative. Most of the synthesized compounds were found to be promising when tested for their anti-proliferative properties against cervical and breast cancer cell lines.
Asunto(s)
Antineoplásicos/farmacología , Azepinas/farmacología , Cloruros/química , Compuestos Férricos/química , Compuestos Heterocíclicos/farmacología , Indoles/farmacología , Oxepinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Azepinas/síntesis química , Azepinas/química , Catálisis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Humanos , Indoles/química , Células MCF-7 , Modelos Moleculares , Estructura Molecular , Oxepinas/síntesis química , Oxepinas/química , Relación Estructura-ActividadRESUMEN
The phytochemical study of Stereocaulon montagneanum harvested in Sumatra (Indonesia) led to the isolation of 11 known compounds including two metabolites not previously described in the genus Stereocaulon, peristictic acid (8) and menegazziaic acid (10). The complete 1H and 13C NMR spectral assignments of stictic acid derivatives are reported with some revisions. Five depsidones belonging to the stictic acid chemosyndrome were superoxide anion scavengers as potent as ascorbic acid and with no toxicity on two human cell lines.
Asunto(s)
Antioxidantes/farmacología , Depuradores de Radicales Libres/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Líquenes/química , Oxepinas/farmacología , Protectores contra Radiación/farmacología , Superóxidos/metabolismo , Animales , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Línea Celular , Evaluación Preclínica de Medicamentos , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/aislamiento & purificación , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/aislamiento & purificación , Humanos , Indonesia , Queratinocitos/efectos de los fármacos , Queratinocitos/efectos de la radiación , Melanoma Experimental , Ratones , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Oxepinas/química , Oxepinas/aislamiento & purificación , Protectores contra Radiación/química , Protectores contra Radiación/aislamiento & purificación , Solventes , Rayos UltravioletaRESUMEN
The bacterial system for fatty acid biosynthesis (FAS) contains several enzymes whose sequence and structure are highly conserved across a vast array of pathogens. This, coupled with their low homology and difference in organization compared to the equivalent system in humans, makes the FAS pathway an excellent target for antimicrobial drug development. To this end, we have cloned, expressed, and purified the ß-hydroxyacyl-acyl carrier protein dehydratase (FabZ) from both Francisella tularensis (FtFabZ) and Yersinia pestis (YpFabZ). We also solved the crystal structures and performed an enzymatic characterization of both enzymes and several mutant forms of YpFabZ. Additionally, we have discovered two novel inhibitors of FabZ, mangostin and stictic acid, which show similar potencies against both YpFabZ and FtFabZ. Lastly, we selected several compounds from the literature that have been shown to be active against single homologues of FabZ and tested them against both YpFabZ and FtFabZ. These results have revealed clues as to which scaffolds are likely to lead to broad-spectrum antimicrobials targeted against FabZ as well as modifications to existing FabZ inhibitors that may improve potency.
Asunto(s)
Proteínas Bacterianas/química , Francisella tularensis/enzimología , Hidroliasas/química , Modelos Moleculares , Yersinia pestis/enzimología , Sustitución de Aminoácidos , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Biocatálisis , Dominio Catalítico , Cristalografía por Rayos X , Dimerización , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Histidina/química , Hidroliasas/antagonistas & inhibidores , Hidroliasas/genética , Hidroliasas/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Simulación del Acoplamiento Molecular , Peso Molecular , Oxepinas/química , Oxepinas/farmacología , Mutación Puntual , Conformación Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Xantonas/química , Xantonas/farmacologíaRESUMEN
Nicotinic acetylcholine receptors (nAChRs) of parasitic nematodes are required for body movement and are targets of important "classical" anthelmintics like levamisole and pyrantel, as well as "novel" anthelmintics like tribendimidine and derquantel. Four biophysical subtypes of nAChR have been observed electrophysiologically in body muscle of the nematode parasite Oesophagostomum dentatum, but their molecular basis was not understood. Additionally, loss of one of these subtypes (G 35 pS) was found to be associated with levamisole resistance. In the present study, we identified and expressed in Xenopus oocytes, four O. dentatum nAChR subunit genes, Ode-unc-38, Ode-unc-63, Ode-unc-29 and Ode-acr-8, to explore the origin of the receptor diversity. When different combinations of subunits were injected in Xenopus oocytes, we reconstituted and characterized four pharmacologically different types of nAChRs with different sensitivities to the cholinergic anthelmintics. Moreover, we demonstrate that the receptor diversity may be affected by the stoichiometric arrangement of the subunits. We show, for the first time, different combinations of subunits from a parasitic nematode that make up receptors sensitive to tribendimidine and derquantel. In addition, we report that the recombinant levamisole-sensitive receptor made up of Ode-UNC-29, Ode-UNC-63, Ode-UNC-38 and Ode-ACR-8 subunits has the same single-channel conductance, 35 pS and 2.4 ms mean open-time properties, as the levamisole-AChR (G35) subtype previously identified in vivo. These data highlight the flexible arrangements of the receptor subunits and their effects on sensitivity and resistance to the cholinergic anthelmintics; pyrantel, tribendimidine and/or derquantel may still be effective on levamisole-resistant worms.
Asunto(s)
Antihelmínticos/farmacología , Proteínas del Helminto/metabolismo , Indoles/farmacología , Nematodos/metabolismo , Oxepinas/farmacología , Fenilendiaminas/farmacología , Receptores Nicotínicos/metabolismo , Animales , Proteínas del Helminto/genética , Nematodos/genética , Receptores Nicotínicos/genética , Xenopus laevisRESUMEN
Inspired by VUF6884 (7-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine), reported as a dual H1/H4 receptor ligand (pKi: 8.11 (human H1R (hH1R)), 7.55 (human H4R (hH4R))), four known and 28 new oxazepine and related oxepine derivatives were synthesised and pharmacologically characterized at histamine receptors and selected aminergic GPCRs. In contrast to the oxazepine series, within the oxepine series, the new compounds showed high affinity to the hH1R (pKi: 6.8-8.7), but no or moderate affinity to the hH4R (pKi:≤5.3). For one oxepine derivative (1-(2-Chloro-6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4-methylpiperazine), the enantiomers were separated and the R-enantiomer was identified as the eutomer at the hH1R (pKi: 8.83 (R), 7.63 (S)) and the guinea-pig H1R (gpH1R) (pKi: 8.82 (R), 7.41 (S)). Molecular dynamic studies suggest that the tricyclic core of the compounds is bound in a similar mode into the binding pocket, as described for doxepine in the hH1R crystal structure. Moreover, docking studies of all oxepine derivatives at the hH1R indicate that the oxygen and the position of the chlorine in the tricyclic core determines, if the R- or the S-enantiomer is the eutomer. For some of the oxazepines and oxepines the affinity to other aminergic GPCRs is in the same range as to hH1R or hH4R, thus, those compounds have to be classified as dirty drugs. However, one oxazepine derivative (3,7-Dichloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine was identified as dual hH1/h5-HT2A receptor ligand (pKi: 9.23 (hH1R), 8.74 (h5-HT2AR), ≤7 at other analysed GPCRs), whereas one oxepine derivative (1-(3,8-Dichloro-6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4-methylpiperazine) was identified as selective hH1R antagonist (pKi: 8.44 (hH1R), ≤6.7 at other analyzed GPCRs). Thus, the pharmacological results suggest that the oxazepine/oxepine moiety and additionally the chlorine substitution pattern toggles receptor selectivity and specificity.
Asunto(s)
Cloro/química , Oxazepinas/farmacología , Oxepinas/farmacología , Receptor de Serotonina 5-HT2A/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H4/metabolismo , Animales , Células Cultivadas , Cobayas , Humanos , Oxazepinas/química , Oxepinas/química , Unión Proteica/fisiología , Células Sf9 , Relación Estructura-ActividadRESUMEN
This Letter describes an efficient ring-closing metathesis approach to 2-chloro-4-amino-pyrimido[4,5-c]azepines and 2-chloro-4-amino-pyrimido[4,5-c]oxepines. These chlorides were applied to the synthesis of several potent γ-secretase modulators (GSMs).
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Azepinas/farmacología , Oxepinas/farmacología , Pirimidinas/farmacología , Azepinas/síntesis química , Azepinas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Oxepinas/síntesis química , Oxepinas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
The review chronologically considers the main classes of the currently available anthelminthic substances: early anthelmintic compounds, benzimidazoles, imidazolthiazoles, tetrahydropyrimidines, avermectins and milbemycins, and salicylanilides. Great attention is paid to novel substances (emodepside, monepantel, derquantel, tribendimidine) and promising developments. Some aspects of the molecular mechanisms of action of anthelmintics, their resistance, and alternative dehelmintization methods are discussed.
Asunto(s)
Antihelmínticos/clasificación , Cestodos/efectos de los fármacos , Diseño de Fármacos , Nematodos/efectos de los fármacos , Trematodos/efectos de los fármacos , Aminoacetonitrilo/análogos & derivados , Aminoacetonitrilo/síntesis química , Aminoacetonitrilo/farmacología , Animales , Antihelmínticos/síntesis química , Antihelmínticos/farmacología , Productos Biológicos/química , Productos Biológicos/farmacología , Cestodos/fisiología , Infecciones por Cestodos/diagnóstico , Infecciones por Cestodos/tratamiento farmacológico , Infecciones por Cestodos/parasitología , Depsipéptidos/síntesis química , Depsipéptidos/farmacología , Humanos , Indoles/síntesis química , Indoles/farmacología , Medicina Tradicional , Nematodos/fisiología , Infecciones por Nematodos/diagnóstico , Infecciones por Nematodos/tratamiento farmacológico , Infecciones por Nematodos/parasitología , Oxepinas/síntesis química , Oxepinas/farmacología , Fenilendiaminas/síntesis química , Fenilendiaminas/farmacología , Trematodos/fisiología , Infecciones por Trematodos/diagnóstico , Infecciones por Trematodos/tratamiento farmacológico , Infecciones por Trematodos/parasitologíaRESUMEN
Two new dibenz[b,f]oxepins, empetroxepins A and B (1 and 2), and seven known compounds (3-9) were isolated from an extract of the Canadian medicinal plant Empetrum nigrum that significantly inhibited the growth of Mycobacterium tuberculosis H37Ra. The structures of 1 and 2 were established through analysis of NMR and MS data. The antimycobacterial activity of the plant extract was attributed primarily to the presence of two chalcone derivatives (6 and 7) that exhibited selective antimycobacterial activity (IC50 values of 23.8 and 32.8 µM, respectively) in comparison to mammalian (HEK 293) cells (IC50 values of 109 and 249 µM, respectively).
Asunto(s)
Antituberculosos/aislamiento & purificación , Antituberculosos/farmacología , Benzoxepinas/aislamiento & purificación , Benzoxepinas/farmacología , Chalcona/aislamiento & purificación , Chalcona/farmacología , Ericaceae/química , Mycobacterium tuberculosis/efectos de los fármacos , Oxepinas/aislamiento & purificación , Oxepinas/farmacología , Animales , Antituberculosos/química , Benzoxepinas/química , Canadá , Chalcona/química , Células HEK293 , Humanos , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Oxepinas/químicaRESUMEN
Glycyrrhizic acid, glycyrrhetinic acid, and their oxo, ester, lactone, and other derivatives, are known for their anti-inflammatory, anti-oxidant, and hypoglycemic pharmacological activities. In this study, chryseno[2,1-c]oxepin-12-carboxylic acid (MG) was first biosynthesized from glycyrrhizic acid through sequential hydrolysis, oxidation, and esterification using Aspergillus terreus TMZ05-2, providing a novel in vitro biosynthetic pathway for glycyrrhizic acid derivatives. Assessing the influence of fermentation conditions and variation of strains during culture under stress-induction strategies enhanced the final molar yield to 88.3% (5 g/L glycyrrhizic acid). CCK8 assays showed no cytotoxicity and good cell proliferation, and anti-inflammatory experiments demonstrated strong inhibition of NO release (36.3%, low-dose MG vs. model), transcriptional downregulation of classical effective cellular factors tumor necrosis factor-α (TNF-α; 72.2%, low-dose MG vs. model), interleukin-6 (IL-6; 58.3%, low-dose MG vs. model) and interleukin-1ß (IL-1ß; 76.4%, low-dose MG vs. model), and decreased abundance of P-IKK-α, P-IKB-α, and P-P65 proteins, thereby alleviating inflammatory responses through the NF-κB pathway in LPS-induced RAW264.7 cells. The findings provide a reference for the biosynthesis of lactone compounds from medicinal plants.
Asunto(s)
Aspergillus , Ácido Glicirrínico , Oxepinas , Ácido Glicirrínico/farmacología , Oxepinas/farmacología , Transducción de Señal , Ácidos Carboxílicos/farmacología , Antiinflamatorios/farmacología , FN-kappa B/metabolismo , Lactonas/farmacología , Lipopolisacáridos/farmacología , Factor de Necrosis Tumoral alfaRESUMEN
Evolutionary potential of viruses can result in outbreaks of well-known viruses and emergence of novel ones. Pharmacological methods of intervening the reproduction of various less popular, but not less important viruses are not available, as well as the spectrum of antiviral activity for most known compounds. In the framework of chemical biology paradigm, characterization of antiviral activity spectrum of new compounds allows to extend the antiviral chemical space and provides new important structure-activity relationships for data-driven drug discovery. Here we present a primary assessment of antiviral activity of spiro-annulated derivatives of seven-membered heterocycles, oxepane and azepane, in phenotypic assays against viruses with different genomes, virion structures, and genome realization schemes: orthoflavivirus (tick-borne encephalitis virus, TBEV), enteroviruses (poliovirus, enterovirus A71, echovirus 30), adenovirus (human adenovirus C5), hantavirus (Puumala virus). Hit compounds inhibited reproduction of adenovirus C5, the only DNA virus in the studied set, in the yield reduction assay, and did not inhibit reproduction of RNA viruses.
Asunto(s)
Antivirales , Antivirales/farmacología , Antivirales/química , Humanos , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , Oxepinas/química , Oxepinas/farmacología , Animales , Replicación Viral/efectos de los fármacos , FenotipoRESUMEN
We report the design conception, chemical synthesis, and microbiological evaluation of the bridged macrobicyclic antibiotic cresomycin (CRM), which overcomes evolutionarily diverse forms of antimicrobial resistance that render modern antibiotics ineffective. CRM exhibits in vitro and in vivo efficacy against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We show that CRM is highly preorganized for ribosomal binding by determining its density functional theory-calculated, solution-state, solid-state, and (wild-type) ribosome-bound structures, which all align identically within the macrobicyclic subunits. Lastly, we report two additional x-ray crystal structures of CRM in complex with bacterial ribosomes separately modified by the ribosomal RNA methylases, chloramphenicol-florfenicol resistance (Cfr) and erythromycin-resistance ribosomal RNA methylase (Erm), revealing concessive adjustments by the target and antibiotic that permit CRM to maintain binding where other antibiotics fail.
Asunto(s)
Antibacterianos , Hidrocarburos Aromáticos con Puentes , Farmacorresistencia Bacteriana Múltiple , Lincosamidas , Oxepinas , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Eritromicina/química , Eritromicina/farmacología , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Hidrocarburos Aromáticos con Puentes/síntesis química , Hidrocarburos Aromáticos con Puentes/química , Hidrocarburos Aromáticos con Puentes/farmacología , Oxepinas/síntesis química , Oxepinas/química , Oxepinas/farmacología , Lincosamidas/síntesis química , Lincosamidas/química , Lincosamidas/farmacología , Animales , Ratones , Diseño de Fármacos , Ribosomas/químicaRESUMEN
Previously we reported the identification of a new oxepin-containing diketopiperazine-type marine fungal metabolite, named protuboxepin A which showed antiproliferative activity in several cancer cell lines. In this study we elucidated the mechanism by which protuboxepin A induces cancer cell growth inhibition. Here we report that protuboxepin A induced round-up morphology, M phase arrest, and an increase in the subG(1) population in tumor cells in a dose dependent manner. Our investigations revealed that protuboxepin A directly binds to α,ß-tubulin and stabilizes tubulin polymerization thus disrupting microtubule dynamics. This disruption leads to chromosome misalignment and metaphase arrest which induces apoptosis in cancer. Overall, we identified protuboxepin A as a microtubule-stabilizing agent which has a distinctly different chemical structure from previously reported microtubule inhibitors. These results indicate that protuboxepin A has a potential of being a new and effective anti-cancer drug.
Asunto(s)
Antineoplásicos/farmacología , Aspergillus/metabolismo , Emparejamiento Cromosómico/efectos de los fármacos , Metafase/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Oxepinas/farmacología , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptosis/efectos de los fármacos , Organismos Acuáticos/microbiología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Microtúbulos/efectos de los fármacos , Neoplasias/genética , Oxepinas/química , Oxepinas/metabolismo , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismoRESUMEN
Three new depsidones ( 1, 3, and 4), a new diaryl ether ( 5), and a new natural pyrone ( 9) (synthetically known), together with three known depsidones, nidulin ( 6), nornidulin ( 7), and 2-chlorounguinol ( 8), were isolated from the marine-derived fungus ASPERGILLUS UNGUIS CRI282-03. Aspergillusidone C ( 4) showed the most potent aromatase inhibitory activity with the IC (50) value of 0.74 µM, while depsidones 1, 3, 6- 8 inhibited aromatase with IC (50) values of 1.2-11.2 µM. It was found that the structural feature of depsidones, not their corresponding diaryl ether derivatives (e.g. 5), was important for aromatase inhibitory activity. Aspergillusidones A ( 1) and B ( 3) showed radical scavenging activity in the XXO assay with IC (50) values of 16.0 and < 15.6 µM, respectively. Compounds 1 and 3- 7 were mostly inactive or showed only weak cytotoxic activity against HuCCA-1, HepG2, A549, and MOLT-3 cancer cell lines.
Asunto(s)
Inhibidores de la Aromatasa/farmacología , Aspergillus/química , Depsidos/química , Depsidos/farmacología , Depuradores de Radicales Libres/farmacología , Lactonas/farmacología , Oxepinas/química , Animales , Inhibidores de la Aromatasa/química , Inhibidores de la Aromatasa/aislamiento & purificación , Aspergillus/clasificación , Aspergillus/aislamiento & purificación , Secuencia de Bases , Línea Celular Tumoral , Supervivencia Celular , ADN de Hongos/química , ADN de Hongos/genética , ADN Ribosómico/química , ADN Ribosómico/genética , Depsidos/aislamiento & purificación , Ensayos de Selección de Medicamentos Antitumorales , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/aislamiento & purificación , Humanos , Concentración 50 Inhibidora , Lactonas/química , Lactonas/aislamiento & purificación , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Estructura Molecular , Oxepinas/aislamiento & purificación , Oxepinas/farmacología , Poríferos/microbiología , Análisis de Secuencia de ADNRESUMEN
Drug resistance in gastrointestinal nematodes is a severe problem for sheep farmers. With the recent introduction of monepantel (Zolvix®) and of derquantel plus abamectin (Startect®) in New Zealand, two new anthelmintic classes will be available to control gastrointestinal nematodes. While monepantel covers a broad spectrum of nematodes, the efficacy of derquantel is mid-spectrum and limited to a smaller number of species and stages. The combination of derquantel and abamectin allows to enlarge the spectrum and to cover most parasitic nematodes in sheep. However, the question remained open, if the efficacy of the new anthelmintics can be maintained in the presence of severe anthelmintic resistance. The present study investigated the efficacy against adult stages of a multi-resistant Haemonchus contortus isolate. While monepantel resulted in 100 % elimination, derquantel in combination with abamectin resulted in efficacies <95 % (faecal egg counts and worm counts).