RESUMEN
The C-terminal to LisH (CTLH) complex is a ubiquitin ligase complex that recognizes substrates with Pro/N-degrons via its substrate receptor Glucose-Induced Degradation 4 (GID4), but its function and substrates in humans remain unclear. Here, we report PFI-7, a potent, selective and cell-active chemical probe that antagonizes Pro/N-degron binding to human GID4. Use of PFI-7 in proximity-dependent biotinylation and quantitative proteomics enabled the identification of GID4 interactors and GID4-regulated proteins. GID4 interactors are enriched for nucleolar proteins, including the Pro/N-degron-containing RNA helicases DDX21 and DDX50. We also identified a distinct subset of proteins whose cellular levels are regulated by GID4 including HMGCS1, a Pro/N-degron-containing metabolic enzyme. These data reveal human GID4 Pro/N-degron targets regulated through a combination of degradative and nondegradative functions. Going forward, PFI-7 will be a valuable research tool for investigating CTLH complex biology and facilitating development of targeted protein degradation strategies that highjack CTLH E3 ligase activity.
Asunto(s)
Unión Proteica , Humanos , Proteolisis , Células HEK293 , Sondas Moleculares/química , Sondas Moleculares/metabolismo , ARN Helicasas DEAD-box/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Degrones , Receptores de Interleucina-17RESUMEN
We have developed a novel chemical handle (PFI-E3H1) and a chemical probe (PFI-7) as ligands for the Gid4 subunit of the human E3 ligase CTLH degradation complex. Through an efficient initial hit-ID campaign, structure-based drug design (SBDD) and leveraging the sizeable Pfizer compound library, we identified a 500 nM ligand for this E3 ligase through file screening alone. Further exploration identified a vector that is tolerant to addition of a linker for future chimeric molecule design. The chemotype was subsequently optimized to sub-100 nM Gid4 binding affinity for a chemical probe. These novel tools, alongside the suitable negative control also identified, should enable the interrogation of this complex human E3 ligase macromolecular assembly.
RESUMEN
By analyzing data sets of replicate DNA-Encoded Library (DEL) selections, an approach for estimating the noise level of the experiment has been developed. Using a logarithm transformation of the number of counts associated with each compound and a subset of compounds with the highest number of counts, it is possible to assess the quality of the data through normalizing the replicates and use this same data to estimate the noise in the experiment. The noise level is seen to be dependent on sequencing depth as well as specific selection conditions. The noise estimation is independent of any cutoff used to remove low frequency compounds from the data analysis. The removal of compounds with only 1-5 read counts greatly reduces some of the challenges encountered in DEL data analysis as it can reduce the data set by greater than 100-fold without impacting the interpretation of the results.
Asunto(s)
ADN , Bibliotecas de Moléculas Pequeñas , Análisis de Datos , IncertidumbreRESUMEN
The ability to predict chemical structure from DNA sequence has to date been a necessary cornerstone of DNA-encoded library technology. DNA-encoded libraries (DELs) are typically screened by immobilized affinity selection and enriched library members are identified by counting the number of times an individual compound's sequence is observed in the resultant dataset. Those with high signal reads (DEL hits) are subsequently followed up through off-DNA synthesis of the predicted small molecule structures. However, hits followed-up in this manner often fail to translate to confirmed ligands. To address this low conversion rate of DEL hits to off-DNA ligands, we have developed an approach that eliminates the reliance on chemical structure prediction from DNA sequence. Here we describe our method of combining non-combinatorial resynthesis on-DNA following library procedures as a rapid means to assess the probable molecules attached to the DNA barcode. Furthermore, we apply our Bead-Assisted Ligand Isolation Mass Spectrometry (BALI-MS) technique to identify the true binders found within the mixtures of on-DNA synthesis products. Finally, we describe a Normalized Enrichment (NE) metric that allows for the quantitative assessment of affinity selection in these studies. We exemplify how this combined approach enables the identification of putative hit matter against a clinically relevant therapeutic target bisphosphoglycerate mutase, BPGM.
Asunto(s)
ADN/química , Descubrimiento de Drogas , Biblioteca de Genes , Espectrometría de Masas/métodos , Técnicas Químicas Combinatorias , Ligandos , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Over the past 20 years, the toolbox for discovering small-molecule therapeutic starting points has expanded considerably. Pharmaceutical researchers can now choose from technologies that, in addition to traditional high-throughput knowledge-based and diversity screening, now include the screening of fragment and fragment-like libraries, affinity selection mass spectrometry, and selection against DNA-encoded libraries (DELs). Each of these techniques has its own unique combination of advantages and limitations that makes them more, or less, suitable for different target classes or discovery objectives, such as desired mechanism of action. Layered on top of this are the constraints of the drug-hunters themselves, including budgets, timelines, and available platform capacity; each of these can play a part in dictating the hit identification strategy for a discovery program. In this article, we discuss some of the factors that we use to govern our building of a hit identification roadmap for a program and describe the increasing role that DELs are playing in our discovery strategy. Furthermore, we share our learning during our initial exploration of DEL and highlight the approaches we have evolved to maximize the value returned from DEL selections. Topics addressed include the optimization of library design and production, reagent validation, data analysis, and hit confirmation. We describe how our thinking in these areas has led us to build a DEL platform that has begun to deliver tractable matter to our global discovery portfolio.
Asunto(s)
Descubrimiento de Drogas/métodos , Biblioteca de Genes , Bibliotecas de Moléculas Pequeñas , Descubrimiento de Drogas/normas , HumanosRESUMEN
Heterobifunctional chimeric degraders are a class of ligands that recruit target proteins to E3 ubiquitin ligases to drive compound-dependent protein degradation. Advancing from initial chemical tools, protein degraders represent a mechanism of growing interest in drug discovery. Critical to the mechanism of action is the formation of a ternary complex between the target, degrader and E3 ligase to promote ubiquitination and subsequent degradation. However, limited insights into ternary complex structures exist, including a near absence of studies on one of the most widely co-opted E3s, cellular inhibitor of apoptosis 1 (cIAP1). In this work, we use a combination of biochemical, biophysical and structural studies to characterize degrader-mediated ternary complexes of Bruton's tyrosine kinase and cIAP1. Our results reveal new insights from unique ternary complex structures and show that increased ternary complex stability or rigidity need not always correlate with increased degradation efficiency.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/genética , Proteínas Inhibidoras de la Apoptosis/genética , Cromatografía en Gel , Reactivos de Enlaces Cruzados , Humanos , Cinética , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular , Conformación Proteica , Proteolisis , Espectrometría de Masa por Ionización de Electrospray , Ubiquitina-Proteína Ligasas , Ubiquitinación , Difracción de Rayos XRESUMEN
DNA-encoded chemical library (DECL) synthesis must occur in aqueous media under conditions that preserve the integrity of the DNA encoding tag. While the identification of "DNA-compatible" reaction conditions is critical for the development of DECL designs that explore previously inaccessible chemical space, reports measuring such compatibility have been largely restricted to methods that do not faithfully capture the impact of reaction conditions on DNA fidelity in solution phase. Here we report a comprehensive methodology that uses soluble DNA substrates that exactly recapitulate DNA's exposure to the chemically reactive species of DECL synthesis. This approach includes the assessment of chemical fidelity (reaction yield and purity), encoding fidelity (ligation efficiency), and readability (DNA compatibility), revealing the fate of the DNA tag during DECL chemistry from a single platform.
Asunto(s)
ADN/química , Bibliotecas de Moléculas Pequeñas/síntesis química , Técnicas Químicas Combinatorias , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/química , SolucionesRESUMEN
Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Carbamatos/síntesis química , Carbamatos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Monoacilglicerol Lipasas/antagonistas & inhibidores , Neuritis/tratamiento farmacológico , Amidohidrolasas/antagonistas & inhibidores , Animales , Ácidos Araquidónicos/metabolismo , Biomarcadores , Química Encefálica/efectos de los fármacos , Perros , Diseño de Fármacos , Descubrimiento de Drogas , Endocannabinoides/metabolismo , Glicéridos/metabolismo , Humanos , Macaca mulatta , Modelos Moleculares , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Inhibition of the sodium-coupled citrate transporter (NaCT or SLC13A5) has been proposed as a new therapeutic approach for prevention and treatment of metabolic diseases. In a previous report, we discovered dicarboxylate 1a (PF-06649298) which inhibits the transport of citrate in in vitro and in vivo settings via a specific interaction with NaCT. Herein, we report the optimization of this series leading to 4a (PF-06761281), a more potent inhibitor with suitable in vivo pharmacokinetic profile for assessment of in vivo pharmacodynamics. Compound 4a was used to demonstrate dose-dependent inhibition of radioactive [(14)C]citrate uptake in liver and kidney in vivo, resulting in modest reductions in plasma glucose concentrations.
Asunto(s)
Citratos/metabolismo , Malatos/química , Malatos/farmacología , Fenilbutiratos/química , Fenilbutiratos/farmacología , Piridinas/química , Piridinas/farmacología , Simportadores/antagonistas & inhibidores , Animales , Transporte Biológico/efectos de los fármacos , Glucemia/metabolismo , Citratos/farmacocinética , Relación Dosis-Respuesta a Droga , Células HEK293 , Hepatocitos/efectos de los fármacos , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Malatos/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Estructura Molecular , Fenilbutiratos/administración & dosificación , Piridinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Simportadores/metabolismoRESUMEN
A high-throughput phenotypic screen for novel antibacterial agents led to the discovery of a novel pyrazolopyrimidinedione, PPD-1, with preferential activity against methicillin-resistant Staphylococcus aureus (MRSA). Resistance mapping revealed the likely target of inhibition to be lysyl tRNA synthetase (LysRS). Preliminary structure-activity relationship (SAR) studies led to an analog, PPD-2, which gained Gram-negative antibacterial activity at the expense of MRSA activity and resistance to this compound mapped to prolyl tRNA synthetase (ProRS). These targets of inhibition were confirmed in vitro, with PPD-1 showing IC50s of 21.7 and 35 µM in purified LysRS and ProRS enzyme assays, and PPD-2, 151 and 0.04 µM, respectively. The highly attractive chemical properties of these compounds combined with intriguing preliminary SAR suggest that further exploration of this compelling novel series is warranted.
Asunto(s)
Aminoacil-ARNt Sintetasas/antagonistas & inhibidores , Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Diseño de Fármacos , Descubrimiento de Drogas , Pirazoles/farmacología , Pirimidinonas/farmacología , Aminoacil-ARNt Sintetasas/genética , Aminoacil-ARNt Sintetasas/metabolismo , Antibacterianos/síntesis química , Antibacterianos/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Farmacorresistencia Bacteriana , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Escherichia coli/crecimiento & desarrollo , Proteínas de Escherichia coli/antagonistas & inhibidores , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Ensayos Analíticos de Alto Rendimiento , Lisina-ARNt Ligasa/antagonistas & inhibidores , Lisina-ARNt Ligasa/genética , Lisina-ARNt Ligasa/metabolismo , Resistencia a la Meticilina , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/enzimología , Staphylococcus aureus Resistente a Meticilina/crecimiento & desarrollo , Pruebas de Sensibilidad Microbiana , Neisseria gonorrhoeae/efectos de los fármacos , Neisseria gonorrhoeae/enzimología , Neisseria gonorrhoeae/crecimiento & desarrollo , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Pseudomonas aeruginosa/crecimiento & desarrollo , Pirazoles/síntesis química , Pirazoles/química , Pirimidinonas/síntesis química , Pirimidinonas/química , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Aminoacilación de ARN de Transferencia/efectos de los fármacosRESUMEN
UNLABELLED: The problem of multidrug resistance in serious Gram-negative bacterial pathogens has escalated so severely that new cellular targets and pathways need to be exploited to avoid many of the preexisting antibiotic resistance mechanisms that are rapidly disseminating to new strains. The discovery of small-molecule inhibitors of LpxC, the enzyme responsible for the first committed step in the biosynthesis of lipid A, represents a clinically unprecedented strategy to specifically act against Gram-negative organisms such as Pseudomonas aeruginosa and members of the Enterobacteriaceae. In this report, we describe the microbiological characterization of LpxC-4, a recently disclosed inhibitor of this bacterial target, and demonstrate that its spectrum of activity extends to several of the pathogenic species that are most threatening to human health today. We also show that spontaneous generation of LpxC-4 resistance occurs at frequencies comparable to those seen with marketed antibiotics, and we provide an in-depth analysis of the mechanisms of resistance utilized by target pathogens. Interestingly, these isolates also served as tools to further our understanding of the regulation of lipid A biosynthesis and enabled the discovery that this process occurs very distinctly between P. aeruginosa and members of the Enterobacteriaceae. Finally, we demonstrate that LpxC-4 is efficacious in vivo against multiple strains in different models of bacterial infection and that the major first-step resistance mechanisms employed by the intended target organisms can still be effectively treated with this new inhibitor. IMPORTANCE: New antibiotics are needed for the effective treatment of serious infections caused by Gram-negative pathogens, and the responsibility of identifying new drug candidates rests squarely on the shoulders of the infectious disease community. The limited number of validated cellular targets and approaches, along with the increasing amount of antibiotic resistance that is spreading throughout the clinical environment, has prompted us to explore the utility of inhibitors of novel targets and pathways in these resistant organisms, since preexisting target-based resistance should be negligible. Lipid A biosynthesis is an essential process for the formation of lipopolysaccharide, which is a critical component of the Gram-negative outer membrane. In this report, we describe the in vitro and in vivo characterization of novel inhibitors of LpxC, an enzyme whose activity is required for proper lipid A biosynthesis, and demonstrate that our lead compound has the requisite attributes to warrant further consideration as a novel antibiotic.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Lípido A/biosíntesis , Pseudomonas aeruginosa/metabolismo , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Animales , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Femenino , Eliminación de Gen , Concentración 50 Inhibidora , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/metabolismo , Lipopolisacáridos/metabolismo , Ratones , Ratones Endogámicos C3H , Pruebas de Sensibilidad Microbiana , Complejos Multienzimáticos/genética , Complejos Multienzimáticos/metabolismo , Pseudomonas aeruginosa/efectos de los fármacos , Regulación hacia ArribaRESUMEN
The synthesis and antibacterial activity of heterocyclic methylsulfone hydroxamates is presented. Compounds in this series are potent inhibitors of the LpxC enzyme, a key enzyme involved in the production of lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria. SAR evaluation of compounds in this series revealed analogs with potent antibacterial activity against challenging Gram-negative species such as Pseudomonas aeruginosa and Klebsiella pneumoniae.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/química , Inhibidores Enzimáticos/química , Bacterias Gramnegativas/efectos de los fármacos , Ácidos Hidroxámicos/química , Amidohidrolasas/metabolismo , Antibacterianos/síntesis química , Antibacterianos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/química , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Klebsiella pneumoniae/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Relación Estructura-Actividad , Sulfonas/químicaRESUMEN
UNLABELLED: New treatments are needed for extensively drug-resistant (XDR) Gram-negative bacilli (GNB), such as Acinetobacter baumannii. Toll-like receptor 4 (TLR4) was previously reported to enhance bacterial clearance of GNB, including A. baumannii. However, here we have shown that 100% of wild-type mice versus 0% of TLR4-deficient mice died of septic shock due to A. baumannii infection, despite having similar tissue bacterial burdens. The strain lipopolysaccharide (LPS) content and TLR4 activation by extracted LPS did not correlate with in vivo virulence, nor did colistin resistance due to LPS phosphoethanolamine modification. However, more-virulent strains shed more LPS during growth than less-virulent strains, resulting in enhanced TLR4 activation. Due to the role of LPS in A. baumannii virulence, an LpxC inhibitor (which affects lipid A biosynthesis) antibiotic was tested. The LpxC inhibitor did not inhibit growth of the bacterium (MIC>512 µg/ml) but suppressed A. baumannii LPS-mediated activation of TLR4. Treatment of infected mice with the LpxC inhibitor enhanced clearance of the bacteria by enhancing opsonophagocytic killing, reduced serum LPS concentrations and inflammation, and completely protected the mice from lethal infection. These results identify a previously unappreciated potential for the new class of LpxC inhibitor antibiotics to treat XDR A. baumannii infections. Furthermore, they have far-reaching implications for pathogenesis and treatment of infections caused by GNB and for the discovery of novel antibiotics not detected by standard in vitro screens. IMPORTANCE: Novel treatments are needed for infections caused by Acinetobacter baumannii, a Gram-negative bacterium that is extremely antibiotic resistant. The current study was undertaken to understand the immunopathogenesis of these infections, as a basis for defining novel treatments. The primary strain characteristic that differentiated virulent from less-virulent strains was shedding of Gram-negative lipopolysaccharide (LPS) during growth. A novel class of antibiotics, called LpxC inhibitors, block LPS synthesis, but these drugs do not demonstrate the ability to kill A. baumannii in vitro. We found that an LpxC inhibitor blocked the ability of bacteria to activate the sepsis cascade, enhanced opsonophagocytic killing of the bacteria, and protected mice from lethal infection. Thus, an entire new class of antibiotics which is already in development has heretofore-unrecognized potential to treat A. baumannii infections. Furthermore, standard antibiotic screens based on in vitro killing failed to detect this treatment potential of LpxC inhibitors for A. baumannii infections.
Asunto(s)
Infecciones por Acinetobacter/inmunología , Infecciones por Acinetobacter/patología , Acinetobacter baumannii/inmunología , Acinetobacter baumannii/patogenicidad , Amidohidrolasas/antagonistas & inhibidores , Fagocitosis , Infecciones por Acinetobacter/mortalidad , Acinetobacter baumannii/enzimología , Animales , Inflamación/inmunología , Inflamación/patología , Lipopolisacáridos/inmunología , Lipopolisacáridos/toxicidad , Ratones , Ratones Noqueados , Sepsis/inmunología , Sepsis/mortalidad , Sepsis/patología , Análisis de Supervivencia , Receptor Toll-Like 4/deficiencia , Receptor Toll-Like 4/metabolismo , VirulenciaRESUMEN
The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Bacterias Gramnegativas/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Ácidos Hidroxámicos/síntesis química , Piridonas/síntesis química , Ácidos Sulfónicos/síntesis química , Animales , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Cristalografía por Rayos X , Humanos , Ácidos Hidroxámicos/farmacocinética , Ácidos Hidroxámicos/farmacología , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Piridonas/farmacocinética , Piridonas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Ácidos Sulfónicos/farmacocinética , Ácidos Sulfónicos/farmacologíaRESUMEN
In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Compuestos de Bifenilo/síntesis química , Ácidos Hidroxámicos/síntesis química , Éteres Fenílicos/síntesis química , Infecciones por Pseudomonas/tratamiento farmacológico , Sulfuros/síntesis química , Sulfonas/síntesis química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Dominio Catalítico , Cristalografía por Rayos X , Farmacorresistencia Bacteriana , Enlace de Hidrógeno , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Ratones , Modelos Moleculares , Conformación Molecular , Éteres Fenílicos/química , Éteres Fenílicos/farmacología , Pseudomonas aeruginosa , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfuros/química , Sulfuros/farmacología , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
An efficient method was developed for the synthesis of 2-methylene-4-substituted ethyl butyrates via cyclopropyl opening followed by a Wittig reaction. The desired products were formed in a two-step, one-pot reaction sequence. Alternatively, the key intermediate ylide 2 was isolable and could be stored under oxygen-free conditions and subsequently utilized. A variety of nucleophiles were found to open the commercially available cyclopropane 1. The resulting ylide reacted with aldehydes to provide E-olefinic products.
Asunto(s)
Boratos/química , Compuestos Organofosforados/química , Aldehídos/química , Ciclización , Estructura MolecularRESUMEN
A series of benzyl phenyl ethers (BPEs) is described that displays potent inhibition of bacterial phenylalanyl-tRNA synthetase. The synthesis, SAR, and select ADMET data are provided.
Asunto(s)
Bacterias/enzimología , Química Farmacéutica/métodos , Éteres Fenílicos/química , Fenilalanina-ARNt Ligasa/química , Adenosina Trifosfato/química , Antibacterianos/química , Antibacterianos/farmacología , Antiinfecciosos/química , Antiinfecciosos/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Concentración 50 Inhibidora , Modelos Químicos , Relación Estructura-ActividadRESUMEN
The tandem [4+2]/[3+2] cycloaddition of nitroalkenes has been employed in the synthesis of 1-azafenestranes, molecules of theoretical interest because of planarizing distortion of their central carbon atoms. The synthesis of c,c,c,c-[5.5.5.5]-1-azafenestrane was completed in good yield from a substituted nitrocyclopentene, and its borane adduct was analyzed through X-ray crystallography, which showed a moderate distortion from ideal tetrahedral geometry. The syntheses of two members of the [4.5.5.5] family of 1-azafenestranes are also reported, including one with a trans fusion at a bicyclic ring junction which brings about considerable planarization of one of the central angles (16.8 degrees deviation from tetrahedral geometry). While investigating the [4.5.5.5]-1-azafenestranes, a novel dyotropic rearrangement that converts nitroso acetals into tetracyclic aminals was discovered. Through conformational analysis, a means to prevent this molecular reorganization was formulated and realized experimentally with the use of a bulky vinyl ether in the key [4+2] cycloaddition reaction. Finally, DFT calculations on relative strain energy for the 1-azafenestranes, as well as their predicted central angles, are disclosed.
Asunto(s)
Compuestos Aza/síntesis química , Compuestos Bicíclicos con Puentes/síntesis química , Ciclopropanos/química , Compuestos Policíclicos/química , Compuestos Aza/química , Compuestos Bicíclicos con Puentes/química , Cristalografía por Rayos X , Ciclización , Modelos Moleculares , Conformación Molecular , EstereoisomerismoRESUMEN
A general synthesis of a new type of heterodiene, the N-vinyl nitrone, is described. The synthetic sequence begins with the conjugate addition of benzeneselenol to nitroalkenes (in turn derived from Henry reaction of an aldehyde and a nitroalkane) to provide 2-selenenylnitroalkenes. These selenonitroalkanes are reduced to the corresponding hydroxylamines which are combined with aldehydes to form nitrones. The phenylselenenyl-containing nitrones are then oxidized to selenoxides which undergo syn-selenoxide elimination to provide N-vinyl nitrones. Three X-ray crystal structures of substituted N-vinyl nitrones were obtained. In addition, the first [4+2] cycloaddition of an N-vinyl nitrone is reported.