RESUMO
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.
Assuntos
Antibacterianos , Hidrocarbonetos Aromáticos com Pontes , Farmacorresistência Bacteriana Múltipla , Lincosamidas , Oxepinas , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Eritromicina/química , Eritromicina/farmacologia , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Oxepinas/síntese química , Oxepinas/química , Oxepinas/farmacologia , Lincosamidas/síntese química , Lincosamidas/química , Lincosamidas/farmacologia , Animais , Camundongos , Desenho de Fármacos , Ribossomos/químicaRESUMO
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.
Assuntos
Ouro/química , Mesilatos/química , Oxepinas/síntese química , Prata/química , Catálise , Ciclização , Estrutura Molecular , Oxepinas/químicaRESUMO
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.
Assuntos
Antibacterianos/síntese química , Oxepinas/síntese química , Piranos/síntese química , Antibacterianos/química , Cristalografia por Raios X , Modelos Moleculares , Conformação Molecular , Oxepinas/química , Piranos/química , EstereoisomerismoRESUMO
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.
Assuntos
Inibidores Enzimáticos/farmacologia , Oxepinas/intoxicação , Paládio/química , Fosfatidilinositol 3-Quinases/metabolismo , Catálise , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Oxepinas/síntese química , Oxepinas/químicaRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Oxepinas/farmacologia , Estilbenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação , Ciclinas/metabolismo , Reparo do DNA/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxepinas/síntese química , Oxepinas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Estilbenos/síntese química , Estilbenos/metabolismo , Tubulina (Proteína)/metabolismoRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Azepinas/farmacologia , Cloretos/química , Compostos Férricos/química , Compostos Heterocíclicos/farmacologia , Indóis/farmacologia , Oxepinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Azepinas/síntese química , Azepinas/química , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Indóis/química , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Oxepinas/síntese química , Oxepinas/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Acetais/química , Técnicas de Química Sintética/métodos , Éteres Cíclicos/química , Etilenos/química , Cetonas/química , Piperidinas/química , Polimerização , Polímeros/química , Acetais/síntese química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Ciclização , Éteres Cíclicos/síntese química , Etilenos/síntese química , Cetonas/síntese química , Oxepinas/síntese química , Oxepinas/química , Piperidinas/síntese química , Polímeros/síntese química , VolatilizaçãoRESUMO
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.
Assuntos
Anti-Helmínticos/classificação , Cestoides/efeitos dos fármacos , Desenho de Fármacos , Nematoides/efeitos dos fármacos , Trematódeos/efeitos dos fármacos , Aminoacetonitrila/análogos & derivados , Aminoacetonitrila/síntese química , Aminoacetonitrila/farmacologia , Animais , Anti-Helmínticos/síntese química , Anti-Helmínticos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Cestoides/fisiologia , Infecções por Cestoides/diagnóstico , Infecções por Cestoides/tratamento farmacológico , Infecções por Cestoides/parasitologia , Depsipeptídeos/síntese química , Depsipeptídeos/farmacologia , Humanos , Indóis/síntese química , Indóis/farmacologia , Medicina Tradicional , Nematoides/fisiologia , Infecções por Nematoides/diagnóstico , Infecções por Nematoides/tratamento farmacológico , Infecções por Nematoides/parasitologia , Oxepinas/síntese química , Oxepinas/farmacologia , Fenilenodiaminas/síntese química , Fenilenodiaminas/farmacologia , Trematódeos/fisiologia , Infecções por Trematódeos/diagnóstico , Infecções por Trematódeos/tratamento farmacológico , Infecções por Trematódeos/parasitologiaRESUMO
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.
Assuntos
Carboidratos/química , Dioxolanos/química , Cetonas/química , Oxepinas/síntese química , Catálise , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oxepinas/química , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
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).
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Azepinas/farmacologia , Oxepinas/farmacologia , Pirimidinas/farmacologia , Azepinas/síntese química , Azepinas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Oxepinas/síntese química , Oxepinas/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
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).
Assuntos
Adamantano/síntese química , Adamantano/farmacologia , Antimaláricos/síntese química , Glucose/química , Oxepinas/síntese química , Adamantano/química , Antimaláricos/química , Antimaláricos/farmacologia , Cloroquina/farmacologia , Relação Dose-Resposta a Droga , Conformação Molecular , Estrutura Molecular , Oxepinas/química , Oxepinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Oxepinas/síntese química , Sesquiterpenos/síntese química , Ciclização , Estrutura Molecular , Oxepinas/química , Sesquiterpenos/química , EstereoisomerismoRESUMO
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.
Assuntos
Aminoácidos/química , Compostos Aza/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Oxepinas/síntese química , Prolina/química , Compostos Aza/química , Catálise , Estrutura Molecular , Oxepinas/químicaRESUMO
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.
Assuntos
Produtos Biológicos/síntese química , Oxepinas/síntese química , Produtos Biológicos/química , Catálise , Estrutura Molecular , Oxepinas/química , OxirreduçãoRESUMO
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.
Assuntos
Lactonas/química , Oxepinas/síntese química , Oxepinas/química , EstereoisomerismoRESUMO
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.
Assuntos
Compostos de Epóxi/química , Éteres Cíclicos/síntese química , Oxepinas/síntese química , Paládio/química , Fenóis/química , Catálise , Cristalografia por Raios X , Éteres Cíclicos/química , Conformação Molecular , Oxepinas/química , EstereoisomerismoRESUMO
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.
Assuntos
Oxepinas/síntese química , Técnicas de Química Combinatória , Micro-Ondas , Estrutura Molecular , Oxepinas/químicaRESUMO
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.
Assuntos
Cicloexanonas/química , Oxepinas/síntese química , Catálise , Técnicas de Química Combinatória , Estrutura Molecular , Oxepinas/química , Oxirredução , EstereoisomerismoRESUMO
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).
Assuntos
Oxepinas/síntese química , Cicloexenos/química , Oxepinas/química , Oxirredução , Piperazina , Piperazinas/química , EstereoisomerismoRESUMO
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.