RESUMEN
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
The synthesis of 2,2-dimethyloxepane frameworks based on the 7-endo-trig cyclization of ene-diol using a catalytic amount of metal catalysts (Au, Ag) or Brønsted acid (TfOH) has been developed. Also, the spiro-type dioxabicyclic products were also derived from the diene-diols. For the condition using metal catalysts, the cyclization selectively reacted between the 1,1,3-trisubstituted alkenes and alcohols to form the 2,2-dimethyloxepane frameworks. On the other hand, the TfOH reacted with not only the 1,1,2-trisubstituted alkene, but also the 1-substituted and 1,2-disubstituted alkenes providing the corresponding cyclic ethers, which is quite different from the conditions of the metal catalysts.
Asunto(s)
Oro/química , Mesilatos/química , Oxepinas/síntesis química , Plata/química , Catálisis , Ciclización , Estructura Molecular , Oxepinas/químicaRESUMEN
A gram-scale synthesis of iboxamycin, an antibiotic candidate bearing a fused bicyclic amino acid residue, is presented. A pivotal transformation in the route involves an intramolecular hydrosilylation-oxidation sequence to set the ring-fusion stereocenters of the bicyclic scaffold. Other notable features of the synthesis include a high-yielding, highly diastereoselective alkylation of a pseudoephenamine amide, a convergent sp3-sp2 Negishi coupling, and a one-pot transacetalization-reduction reaction to form the target compound's oxepane ring. Implementation of this synthetic strategy has provided ample quantities of iboxamycin to allow for its in vivo profiling in murine models of infection.
Asunto(s)
Antibacterianos/síntesis química , Oxepinas/síntesis química , Piranos/síntesis química , Antibacterianos/química , Cristalografía por Rayos X , Modelos Moleculares , Conformación Molecular , Oxepinas/química , Piranos/química , EstereoisomerismoRESUMEN
A practical convergent synthesis of PI3K inhibitor GDC-0908 (1) is described. The process features a dihydrobenzothienooxepine formation via palladium-catalyzed intramolecular direct C-H arylation and a Negishi coupling to construct the key C-C bonds. We further developed a general synthesis of dihydrobenzothienooxepines in good to excellent yields via palladium-catalyzed intramolecular direct C-H arylation, which tolerates both electronically and sterically diverse substituents on the phenyl ring.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Oxepinas/envenenamiento , Paladio/química , Fosfatidilinositol 3-Quinasas/metabolismo , Catálisis , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Oxepinas/síntesis química , Oxepinas/químicaRESUMEN
BACKGROUND: Stilbenes, 1,2-diphenylethen derivatives, including resveratrol and combretastatins, show anticancer features especially against tumor angiogenesis. Fosbretabulin, CA-4, in combination with carboplatin, is in the last stages of clinical tests as an inhibitor of thyroid cancer. The mode of action of these compounds involves suppression of angiogenesis through interfering with tubulin (de)polymerization. OBJECTIVE: We have previously synthesized five E-2-hydroxystilbenes and seven dibenzo [b,f]oxepins in Z configuration, with methyl or nitro groups at varied positions. The aim of the present work was to evaluate the anticancer activity and molecular mechanism(s) of action of these compounds. RESULTS: Two healthy, EUFA30 and HEK293, and two cancerous, HeLa and U87, cell lines were treated with four newly synthetized stilbenes and seven oxepins. Two of these compounds, JJR5 and JJR6, showed the strongest cytotoxic effect against cancerous cells tested and these two were selected for further investigations. They induced apoptosis with sub-G1 or S cell cycle arrest and PARP cleavage, with no visible activation of caspases 3 and 7. Proteomic differential analysis of stilbene-treated cells led to the identification of proteins involved almost exclusively in cell cycle management, apoptosis, DNA repair and stress response, e.g. oxidative stress. CONCLUSION: Among the newly synthesized stilbene derivatives, we selected two as potent anticancer compounds triggering late apoptosis/necrosis in cancerous cells through sub-G1 phase cell cycle arrest. They changed cyclin expression, induced DNA repair mechanisms, enzymes involved in apoptosis and oxidative stress response. Compounds JJR5 and JJR6 can be a base for structure modification(s) to obtain even more active derivatives.
Asunto(s)
Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales/métodos , Oxepinas/farmacología , Estilbenos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Apoptosis/efectos de los fármacos , Sitios de Unión , Ciclinas/metabolismo , Reparación del ADN/efectos de los fármacos , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Células HEK293 , Células HeLa , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxepinas/síntesis química , Oxepinas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Estilbenos/síntesis química , Estilbenos/metabolismo , Tubulina (Proteína)/metabolismoRESUMEN
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
Polymers prepared by chemical vapor deposition (CVD) polymerization have found broad acceptance in research and industrial applications. However, their intrinsic lack of degradability has limited wider applicability in many areas, such as biomedical devices or regenerative medicine. Herein, we demonstrate, for the first time, a backbone-degradable polymer directly synthesized via CVD. The CVD co-polymerization of [2.2]para-cyclophanes with cyclic ketene acetals, specifically 5,6-benzo-2-methylene-1,3-dioxepane (BMDO), results in well-defined, hydrolytically degradable polymers, as confirmed by FTIR spectroscopy and ellipsometry. The degradation kinetics are dependent on the ratio of ketene acetals to [2.2]para-cyclophanes as well as the hydrophobicity of the films. These coatings address an unmet need in the biomedical polymer field, as they provide access to a wide range of reactive polymer coatings that combine interfacial multifunctionality with degradability.
Asunto(s)
Acetales/química , Técnicas de Química Sintética/métodos , Éteres Cíclicos/química , Etilenos/química , Cetonas/química , Piperidinas/química , Polimerizacion , Polímeros/química , Acetales/síntesis química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Ciclización , Éteres Cíclicos/síntesis química , Etilenos/síntesis química , Cetonas/síntesis química , Oxepinas/síntesis química , Oxepinas/química , Piperidinas/síntesis química , Polímeros/síntesis química , VolatilizaciónRESUMEN
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
An efficient, seven-step synthesis of carbohydrate based oxepines is reported using per-O-acetyl septanoses as key intermediates. The scope of the synthesis was evaluated by varying both the pyranose starting materials and protecting groups incorporated into the oxepine products. The practicality of the method make it amenable to scale up as demonstrated by the gram-scale synthesis of the d-glucose derived oxepine.
Asunto(s)
Carbohidratos/química , Dioxolanos/química , Cetonas/química , Oxepinas/síntesis química , Catálisis , Cristalografía por Rayos X , Espectroscopía de Resonancia Magnética , Estructura Molecular , Oxepinas/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
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
New enantiomerically pure 1,2,4-trioxepanes 10a,b/11a,b were synthesized from D-glucose. Their conformational behavior was studied by low-temperature NMR and substantiated by DFT calculations. On evaluation of in vitro antimalarial activity, the adamantyl derivative 11b showed IC50 values in the low micromolar range, particularly against the W2 chloroquine-resistant Plasmodium falciparum strain (IC50 = 0.15 ± 0.12 µM).
Asunto(s)
Adamantano/síntesis química , Adamantano/farmacología , Antimaláricos/síntesis química , Glucosa/química , Oxepinas/síntesis química , Adamantano/química , Antimaláricos/química , Antimaláricos/farmacología , Cloroquina/farmacología , Relación Dosis-Respuesta a Droga , Conformación Molecular , Estructura Molecular , Oxepinas/química , Oxepinas/farmacología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/genética , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis of the sesquiterpene endoperoxide natural product 10,12-peroxycalamenene has been achieved. Featured transformations include an intramolecular Heck reaction to build the fused bicyclic core and a cobalt-catalyzed peroxidation to install the peroxide functional group. The final step involved an SN1-type ring closure catalyzed by DDQ to construct the 1,2-dioxepane ring.
Asunto(s)
Oxepinas/síntesis química , Sesquiterpenos/síntesis química , Ciclización , Estructura Molecular , Oxepinas/química , Sesquiterpenos/química , EstereoisomerismoRESUMEN
Herein we suggest an approach to oxygenated bicyclic amino acids based on an aza-Cope-Mannich rearrangement. Seven distinct amino acid scaffolds analogous to the natural products were prepared on a gram scale with precise control of stereochemistry. Successful implementation of our strategy resulted in the formal synthesis of acetylaranotin.
Asunto(s)
Aminoácidos/química , Compuestos Aza/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Oxepinas/síntesis química , Prolina/química , Compuestos Aza/química , Catálisis , Estructura Molecular , Oxepinas/químicaRESUMEN
Oxepanes are found in a wide range of natural products; however, they are challenging synthetic targets due to enthalpic and entropic barriers. Organocatalytic oxa-conjugate addition reactions promoted by the gem-disubstituent (Thorpe-Ingold) effect stereoselectively provided α,α'-trans-oxepanes. In addition, the potential of an organocatalytic tandem oxa-conjugate addition/α-oxidation was demonstrated in a rapid generation of molecular complexity. These organocatalytic oxa-conjugate addition reactions would provide powerful tools for the synthesis of natural products that contain highly functionalized oxepanes.
Asunto(s)
Productos Biológicos/síntesis química , Oxepinas/síntesis química , Productos Biológicos/química , Catálisis , Estructura Molecular , Oxepinas/química , Oxidación-ReducciónRESUMEN
The enantioselective formal synthesis of (-)-isolaurepinnacin and (+)-rogioloxepane A has been achieved. The key steps are an intermolecular Nicholas reaction with a ß-hydroxy-γ-lactone as the nucleophile, to form branched linear ethers, and an olefin ring-closing metathesis to obtain the oxepene core.
Asunto(s)
Lactonas/química , Oxepinas/síntesis química , Oxepinas/química , EstereoisomerismoRESUMEN
A highly regioselective cascade synthesis of 2,3-dihydrobenzodioxepinone from 2-bromophenols and epoxides has been developed. The reactions go through nucleophilic ring-opening of epoxides and subsequent palladium-catalyzed intramolecular alkoxylcarbonylation.
Asunto(s)
Compuestos Epoxi/química , Éteres Cíclicos/síntesis química , Oxepinas/síntesis química , Paladio/química , Fenoles/química , Catálisis , Cristalografía por Rayos X , Éteres Cíclicos/química , Conformación Molecular , Oxepinas/química , EstereoisomerismoRESUMEN
In this report a short and efficient synthesis of the dibenz[b,f]oxepin framework through intramolecular SNAr and McMurry reactions is described. The diaryl ethers required for the McMurry reaction have been obtained in good yields under microwave-assisted conditions of the reaction of salicylaldehydes with fluorobenzaldehydes without catalysts. Application of an intramolecular McMurry reaction to the synthesized diarylethers using TiCl4/Zn in THF gave the target dibenzo[b,f]oxepin system in 53%-55% yields.
Asunto(s)
Oxepinas/síntesis química , Técnicas Químicas Combinatorias , Microondas , Estructura Molecular , Oxepinas/químicaRESUMEN
A three-step sequence to access functionalized 4,5-dihydrooxepines from cyclohexenones has been developed. This approach features a regioselective Baeyer-Villiger oxidation and subsequent functionalization via the corresponding enol phosphate intermediate.
Asunto(s)
Ciclohexanonas/química , Oxepinas/síntesis química , Catálisis , Técnicas Químicas Combinatorias , Estructura Molecular , Oxepinas/química , Oxidación-Reducción , EstereoisomerismoRESUMEN
The key step in this total synthesis of (-)-acetylaranotin is the efficient formation of the characteristic dihydrooxepine ring from cyclohexenone through an unusual vinylogous Rubottom oxidation and a regioselective Baeyer-Villiger oxidation. (-)-Acetylaranotin is obtained in 22 steps from commercially available L-Cbz-tyrosine (Cbz=benzyloxycarbonyl).
Asunto(s)
Oxepinas/síntesis química , Ciclohexenos/química , Oxepinas/química , Oxidación-Reducción , Piperazina , Piperazinas/química , EstereoisomerismoRESUMEN
Prins cyclization of bis-homoallylic alcohols with aldehydes catalyzed by iron(III) salts shows excellent cis selectivity and yields to form 2,7-disubstituted oxepanes. The iron(III) is able to catalyze this process with unactivated olefins. This cyclization was used as the key step in the shortest total synthesis of (+)-isolaurepan.