RESUMEN
Orexinergic neurons are critically involved in regulating arousal, wakefulness, and appetite. Their dysfunction has been associated with sleeping disorders, and non-peptide drugs are currently being developed to treat insomnia and narcolepsy. Yet, no light-regulated agents are available to reversibly control their activity. To meet this need, a photoswitchable peptide analogue of the endogenous neuroexcitatory peptide orexin-B was designed, synthesized, and tested in vitro and in vivo. This compound - photorexin - is the first photo-reversible ligand reported for orexin receptors. It allows dynamic control of activity in vitro (including almost the same efficacy as orexin-B, high nanomolar potency, and subtype selectivity to human OX2 receptors) and in vivo in zebrafish larvae by direct application in water. Photorexin induces dose- and light-dependent changes in locomotion and a reduction in the successive induction reflex that is associated with sleep behavior. Molecular dynamics calculations indicate that trans and cis photorexin adopt similar bent conformations and that the only discriminant between their structures and activities is the positioning of the N-terminus. This, in the case of the more active trans isomer, points towards the OX2 N-terminus and extra-cellular loop 2, a region of the receptor known to be involved in ligand binding and recognition consistent with a "message-address" system. Thus, our approach could be extended to several important families of endogenous peptides, such as endothelins, nociceptin, and dynorphins among others, that bind to their cognate receptors through a similar mechanism: a "message" domain involved in receptor activation and signal transduction, and an "address" sequence for receptor occupation and improved binding affinity.
Asunto(s)
Luz , Receptores de Orexina , Orexinas , Pez Cebra , Receptores de Orexina/metabolismo , Receptores de Orexina/química , Animales , Orexinas/metabolismo , Humanos , Locomoción/efectos de los fármacos , Simulación de Dinámica Molecular , Larva/metabolismo , Larva/efectos de los fármacos , Células HEK293 , LigandosRESUMEN
A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment.
Asunto(s)
Antineoplásicos , Fibroblastos Asociados al Cáncer , Neoplasias Colorrectales , Humanos , Fibroblastos Asociados al Cáncer/patología , Oxaliplatino/farmacología , Distribución Tisular , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Microambiente Tumoral , Fibroblastos/patología , Línea Celular TumoralRESUMEN
The relative success of platinum (Pt)-based chemotherapy comes at the cost of severe adverse side effects and is associated with a high risk of pro-oncogenic activation in the tumor microenvironment. Here, we report the synthesis of C-POC, a novel Pt(IV) cell-penetrating peptide conjugate showing a reduced impact against nonmalignant cells. In vitro and in vivo evaluation using patient-derived tumor organoids and laser ablation inductively coupled plasma mass spectrometry indicates that C-POC maintains robust anticancer efficacy while displaying diminished accumulation in healthy organs and reduced adverse toxicity compared to the standard Pt-based therapy. Likewise, C-POC uptake is significantly lowered in the noncancerous cells populating the tumor microenvironment. This results in the downregulation of versican, a biomarker of metastatic spreading and chemoresistance that we found upregulated in patients treated with standard Pt-based therapy. Altogether, our findings underscore the importance of considering the off-target impact of anticancer treatment on normal cells to improve drug development and patient care.
Asunto(s)
Antineoplásicos , Platino (Metal) , Humanos , Platino (Metal)/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Péptidos/farmacología , Péptidos/uso terapéutico , Línea Celular TumoralRESUMEN
Peptides are a rapidly growing class of therapeutics with various advantages over traditional small molecules, especially for targeting difficult protein-protein interactions. However, current structure-based methods are largely limited to natural peptides and are not suitable for designing bioactive cyclic topologies that go beyond natural l-amino acids. Here, we report a generalizable framework that exploits the computational power of Rosetta, in terms of large-scale backbone sampling, side-chain composition and energy scoring, to design heterochiral cyclic peptides that bind to a protein surface of interest. To showcase the applicability of our approach, we developed two new inhibitors (PD-i3 and PD-i6) of programmed cell death 1 (PD-1), a key immune checkpoint in oncology. A comprehensive biophysical evaluation was performed to assess their binding to PD-1 as well as their blocking effect on the endogenous PD-1/PD-L1 interaction. Finally, NMR elucidation of their in-solution structures confirmed our de novo design approach.
RESUMEN
Despite the widespread use of antibodies in clinical applications, the precise molecular mechanisms underlying antibody-antigen (Ab-Ag) interactions are often poorly understood. In this study, we exploit the technical features of a typical surface plasmon resonance (SPR) biosensor to dissect the kinetic and thermodynamic components that govern the binding of single-domain Ab or nanobodies to their target antigen, epidermal growth factor (EGF), a key oncogenic protein that is involved in tumour progression. By carefully tuning the experimental conditions and transforming the kinetic data into equilibrium constants, we reveal the complete picture of binding thermodynamics, including the energetics of the complex-formation transition state. This approach, performed using an experimentally simple and high-throughput setup, is expected to facilitate mechanistic studies of Ab-based therapies and, importantly, promote the rational development of new biological drugs with suitable properties.
RESUMEN
Epidermal growth factor receptor (EGFR) inhibitors were among the first type of targeted agents discovered in cancer and currently constitute the standard of care for a wide range of lung and colon malignancies. However, the therapeutic progress achieved with these drugs has been accompanied by the identification of an ever-increasing number of acquired resistance mechanisms that inevitably appear in nearly all patients. Increased knowledge on EGFR biochemistry, cellular crosstalk, and resistance pathways provides an opportunity to establish effective combination therapies and discover novel-acting inhibitors that prevent or overcome therapeutic resistance. One such strategy is the selective blockade of circulating growth factors such as EGF. In this review, we address the uses and limitations of approved EGFR inhibitors and explore the potential of drug combinations and new third avenues to block the activation of the EGFR.
Asunto(s)
Receptores ErbB/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Animales , Ensayos Clínicos como Asunto , Factor de Crecimiento Epidérmico/antagonistas & inhibidores , Factor de Crecimiento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Humanos , Terapia Molecular Dirigida , Neoplasias/enzimología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
The epidermal growth factor (EGF) pathway, being overactive in a number of cancers, is a good target for clinical therapy. Although several drugs targeting the EGF receptor (EGFR) are on the market, tumours acquire resistance very rapidly. As an alternative, small molecules and peptides targeting EGF have been developed, although with moderate success. Herein, we report the use of mirror-image phage display technology to discover protease-resistant peptides with the capacity to inhibit the EGF-EGFR interaction. After the chemical synthesis of the enantiomeric protein d-EGF, two phage-display peptide libraries were used to select binding sequences. The d versions of these peptides bound to natural EGF, as confirmed by surface acoustic waves (SAWs). High-field NMR spectroscopy showed that the best EGF binder, d-PI_4, interacts preferentially with an EGF region that partially overlaps with the receptor binding interface. Importantly, we also show that d-PI_4 efficiently disrupts the EGF-EGFR interaction. This methodology represents a straightforward approach to find new protease-resistant peptides with potential applications in cancer therapy.
Asunto(s)
Factor de Crecimiento Epidérmico/antagonistas & inhibidores , Receptores ErbB/antagonistas & inhibidores , Biblioteca de Péptidos , Péptidos/farmacología , Secuencia de Aminoácidos , Factor de Crecimiento Epidérmico/síntesis química , Factor de Crecimiento Epidérmico/química , Receptores ErbB/química , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Péptidos/síntesis química , Péptidos/químicaRESUMEN
Our laboratory has recently identified two nanobodies (small antibodies produced by camelids)-Nb1 and Nb6-that bind efficiently to epithelial growth factor (EGF) and inhibit its ability to activate its receptor (EGFR). Because of the relevance of the EGF/EGFR axis as a target in oncology, these new nanobodies have promising therapeutic potential. This article, however, is focused on another feature of these nanobodies: their distinct thermodynamic signatures. Nb1 binds to EGF through an entropy-driven mechanism whereas Nb6 binds to this factor under enthalpic control. We discuss the advantages and disadvantages of each mechanism in the contexts of traditional medical chemistry (small-molecule drugs) and also of biological drugs. In this latter case, the implications in terms of selectivity are far from being clearly established and further experimental data are required. Their monomeric natures, high stability, and ease of recombinant production make nanobodies ideally suited for thermodynamic studies. Moreover, nanobodies, thanks to their simpler structures in comparison with conventional antibodies, might provide better understanding of the structural basis of the thermodynamic parameters of antigen recognition.
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Entropía , Anticuerpos/inmunología , Antígenos/inmunología , Modelos Moleculares , Dominios Proteicos , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
Venoms have recently emerged as a promising field in drug discovery due to their good selectivity and affinity for a wide range of biological targets. Among their multiple potential applications, venoms are a rich source of blood-brain barrier (BBB) peptide shuttles. We previously described a short nontoxic derivative of apamin, MiniAp-4, which can transport a wide range of cargoes across the BBB. Here, we have studied the conformation of the proline residue of a range of MiniAp-4 analogues by high-field NMR techniques, with the aim to identify whether there is a direct relation between the cis/trans population and a range of features, such as the capacity to transport molecules across a human-based cellular model and stability in various media. The most promising candidate showed improved transport properties for a relevant small fluorophore.
Asunto(s)
Apamina/metabolismo , Barrera Hematoencefálica/metabolismo , Prolina/metabolismo , Apamina/química , Apamina/aislamiento & purificación , Transporte Biológico , Barrera Hematoencefálica/química , Células Cultivadas , Humanos , Resonancia Magnética Nuclear Biomolecular , Prolina/química , Conformación Proteica , EstereoisomerismoRESUMEN
Progress in drug delivery is hampered by a lack of efficient strategies to target drugs with high specificity and precise spatiotemporal regulation. The remote control of nanoparticles and drugs with light allows regulation of their action site and dosage. Peptide-based drugs are highly specific, non-immunogenic, and can be designed to cross the plasma membrane. In order to combine target specificity and remote control of drug action, here we describe a versatile strategy based on a generalized template to design nanoswitchable peptides that modulate protein-protein interactions upon light activation. This approach is demonstrated to promote photomodulation of two important targets involved in apoptosis (the interactions Bcl-xL-Bak and MDM2-p53), but can be also applied to a large pool of therapeutically relevant protein-protein interactions mediated by α-helical motifs. The template can be adjusted using readily available information about hot spots (residues contributing most to the binding energy) at the protein-protein interface of interest.
Asunto(s)
Apoptosis/efectos de los fármacos , Nanoestructuras/química , Péptidos/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Péptidos/química , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/metabolismo , Proteína Destructora del Antagonista Homólogo bcl-2/antagonistas & inhibidores , Proteína Destructora del Antagonista Homólogo bcl-2/química , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Proteína bcl-X/antagonistas & inhibidores , Proteína bcl-X/química , Proteína bcl-X/metabolismoRESUMEN
The present study aims to develop chlorotoxin (CTX), from Giant Yellow Israeli scorpion venom, as a new BBB-shuttle. Minimised versions of CTX were prepared to reduce its complexity while enhancing its BBB-shuttle capacity and preserving its protease-resistance. MiniCTX3, a monocyclic lactam-bridge peptidomimetic, was capable of transporting nanoparticles across endothelial cell monolayers. Our results reveal animal venoms as an outstanding source of new families of BBB-shuttles.
Asunto(s)
Barrera Hematoencefálica/metabolismo , Células Endoteliales/metabolismo , Nanopartículas/química , Peptidomiméticos/metabolismo , Venenos de Escorpión/metabolismo , Animales , Transporte Biológico , Barrera Hematoencefálica/química , Células Endoteliales/química , Peptidomiméticos/síntesis química , Peptidomiméticos/química , Venenos de Escorpión/síntesis química , Venenos de Escorpión/química , Escorpiones/químicaRESUMEN
Objectives: Preventing bacterial contact with host cells can provide an additional approach to tackling MDR Acinetobacter baumannii. Recently, we identified AOA-2 as a potential blocker of A. baumannii outer membrane protein A without presenting bactericidal activity. Here, we aimed to study whether AOA-2 can increase the activity of colistin against colistin-resistant A. baumannii in vitro and in vivo. Methods: Reference and clinical A. baumannii strains susceptible and resistant to colistin (CST-S and CST-R) were used. Microdilution and time-kill curve assays were performed to determine the synergy between AOA-2 and colistin. SDS-PAGE assays with CST-S and CST-R outer membrane proteins and MALDI-TOF-TOF (MS-MS/MS) analysis were performed to determine the AOA-2 and colistin synergy mechanism. In a murine peritoneal sepsis model, the therapeutic efficacy of AOA-2 (10 mg/kg/24 h) in combination with a sub-optimal dose of colistin (10 mg/kg/24 h) against CST-R was evaluated by determining the bacterial load in tissues and blood, and mouse survival. Results: We showed that AOA-2 increased the in vitro colistin susceptibility of reference and clinical CST-S and CST-R strains. This combination also enhanced their killing activity after 24 h of drug exposure. This synergy is mediated by the overexpression of Omp25. In vivo, the combination of AOA-2 with colistin significantly reduced the bacterial load in tissues and blood, and increased mouse survival, compared with colistin monotherapy. Conclusions: We identified a novel class of antimicrobial agents that has proven to be effective in combination with colistin in an experimental model of severe infection by CST-R A. baumannii.
Asunto(s)
Infecciones por Acinetobacter/microbiología , Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/farmacología , Proteínas de la Membrana Bacteriana Externa/antagonistas & inhibidores , Colistina/farmacología , Sinergismo Farmacológico , Inhibidores Enzimáticos/farmacología , Infecciones por Acinetobacter/tratamiento farmacológico , Animales , Antibacterianos/administración & dosificación , Colistina/administración & dosificación , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/administración & dosificación , Femenino , Ratones Endogámicos C57BL , Pruebas de Sensibilidad Microbiana , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Resultado del TratamientoRESUMEN
One of the hallmarks of cancer is the overproduction of growth factors such as EGF. Despite the clinical success achieved by EGFR-targeted therapies, their long-term efficacy is compromised by the onset of drug-resistant mutations. To address this issue, a family of camelid-derived single-domain antibodies (Nbs) were generated, obtaining the first direct EGF inhibitors that prevent EGFR phosphorylation and pathway activation through this new mechanism of action. The two best Nbs were subjected to a detailed investigation of their interaction mechanism that revealed important differences in their binding kinetics and equilibrium thermodynamics. These distinct behaviors at the biophysical level translate into an equally efficient inhibition of the cellular EGFR phosphorylation, thus proving the efficacy of these Nbs to turn off the initiation of this key oncogenic pathway in cancer cells.
Asunto(s)
Anticuerpos de Dominio Único/inmunología , Secuencia de Aminoácidos , Activación Enzimática , Factor de Crecimiento Epidérmico/administración & dosificación , Receptores ErbB/inmunología , Humanos , Fosforilación , Anticuerpos de Dominio Único/químicaRESUMEN
In cancer, proliferation of malignant cells is driven by overactivation of growth-signalling mechanisms, such as the epidermal growth factor receptor (EGFR) pathway. Despite its therapeutic relevance, the EGF-EGFR interaction has remained elusive to inhibition by synthetic molecules, mostly as a result of its large size and lack of binding pockets and cavities. Designed peptides, featuring cyclic motifs and other structural constraints, have the potential to modulate such challenging protein-protein interactions (PPIs). Herein, we present the structure-based design of a series of bicyclic constrained peptides that mimic an interface domain of EGFR and inhibit the EGF-EGFR interaction by targeting the smaller partner (i.e., EGF). This design process was guided by the integrated use of inâ silico methods and biophysical techniques, such as NMR spectroscopy and surface acoustic wave. The best analogues were able to reduce selectively the viability of EGFR+ human cancer cells. In addition to their efficacy, these bicyclic peptides are endowed with exceptional stability and metabolic resistance-two features that make them suitable candidates for in vivo applications.
Asunto(s)
Factor de Crecimiento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Péptidos Cíclicos/metabolismo , Secuencia de Aminoácidos , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Dicroismo Circular , Diseño de Fármacos , Factor de Crecimiento Epidérmico/química , Receptores ErbB/química , Humanos , Ligandos , Simulación de Dinámica Molecular , Resonancia Magnética Nuclear Biomolecular , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Dominios y Motivos de Interacción de Proteínas/efectos de los fármacos , Estabilidad Proteica , Alineación de SecuenciaRESUMEN
Preventing the adhesion of pathogens to host cells provides an innovative approach to tackling multidrug-resistant bacteria. In this regard, the identification of outer membrane protein A (OmpA) as a key bacterial virulence factor has been a major breakthrough. The use of virtual screening helped us to identify a cyclic hexapeptide AOA-2 that inhibits the adhesion of Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli to host cells and the formation of biofilm, thereby preventing the development of infection in vitro and in a murine sepsis peritoneal model. Inhibition of OmpA offers a strategy as monotherapy to address the urgent need for treatments for infections caused by Gram-negative bacilli.
Asunto(s)
Infecciones por Acinetobacter/inmunología , Acinetobacter baumannii/fisiología , Células Epiteliales Alveolares/fisiología , Adhesión Bacteriana/efectos de los fármacos , Proteínas de la Membrana Bacteriana Externa/antagonistas & inhibidores , Infecciones por Escherichia coli/inmunología , Escherichia coli/fisiología , Péptidos/metabolismo , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/fisiología , ARN Helicasas/metabolismo , Sepsis/inmunología , Factores de Virulencia/antagonistas & inhibidores , Infecciones por Acinetobacter/tratamiento farmacológico , Animales , Antibacterianos/uso terapéutico , Biopelículas , Línea Celular , ADN Helicasas , Modelos Animales de Enfermedad , Infecciones por Escherichia coli/tratamiento farmacológico , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Enzimas Multifuncionales , Péptidos/genética , Péptidos/uso terapéutico , Infecciones por Pseudomonas/tratamiento farmacológico , ARN Helicasas/genética , ARN Helicasas/uso terapéuticoRESUMEN
Ion mobility mass spectrometry (IMMS) is a biophysical technique that allows the separation of isobaric species on the basis of their size and shape. The high separation capacity, sensitivity and relatively fast time scale measurements confer IMMS great potential for the study of proteins in slow (µs-ms) conformational equilibrium in solution. However, the use of this technique for examining dynamic proteins is still not generalized. One of the major limitations is the instability of protein ions in the gas phase, which raises the question as to what extent the structures detected reflect those in solution. Here, we addressed this issue by analyzing the conformational landscape of prolyl oligopeptidase (POP) - a model of a large dynamic enzyme in the µs-ms range - by native IMMS and compared the results obtained in the gas phase with those obtained in solution. In order to interpret the experimental results, we used theoretical simulations. In addition, the stability of POP gaseous ions was explored by charge reduction and collision-induced unfolding experiments. Our experiments disclosed two species of POP in the gas phase, which correlated well with the open and closed conformations in equilibrium in solution; moreover, a gas-phase collapsed form of POP was also detected. Therefore, our findings not only support the potential of IMMS for the study of multiple co-existing conformations of large proteins in slow dynamic equilibrium in solution but also stress the need for careful data analysis to avoid artifacts. Copyright © 2016 John Wiley & Sons, Ltd.
Asunto(s)
Serina Endopeptidasas/química , Animales , Gases/química , Iones/química , Espectrometría de Masas/métodos , Modelos Moleculares , Prolil Oligopeptidasas , Conformación Proteica , PorcinosRESUMEN
The modulation of protein-protein interactions (PPIs) is emerging as a highly promising tool to fight diseases. However, whereas an increasing number of compounds are able to disrupt peptide-mediated PPIs efficiently, the inhibition of domain-domain PPIs appears to be much more challenging. Herein, we report our results related to the interaction between vascular endothelial growth factor (VEGF) and its receptor (VEGFR). The VEGF-VEGFR interaction is a typical domain-domain PPI that is highly relevant for the treatment of cancer and some retinopathies. Our final goal was to identify ligands able to bind VEGF at the region used by the growth factor to interact with its receptor. We undertook an extensive study, combining a variety of experimental approaches, including NMR-spectroscopy-based screening of small organic fragments, peptide libraries, and medicinal plant extracts. The key feature of the successful ligands that emerged from this study was their capacity to expose hydrophobic functional groups able to interact with the hydrophobic hot spots at the interacting VEGF surface patch.
Asunto(s)
Productos Biológicos/farmacología , Oligopéptidos/farmacología , Fragmentos de Péptidos/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Sitios de Unión/efectos de los fármacos , Productos Biológicos/síntesis química , Productos Biológicos/química , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Modelos Moleculares , Oligopéptidos/síntesis química , Oligopéptidos/química , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/química , Biblioteca de Péptidos , Unión Proteica/efectos de los fármacos , Receptores de Factores de Crecimiento Endotelial Vascular/química , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Relación Estructura-Actividad , Factor A de Crecimiento Endotelial Vascular/químicaRESUMEN
Synthetically useful aminodioximes are prepared via a novel three-component reaction among Z-chlorooximes, isocyanides, and hydroxylamines by exploiting the preferential attack of isocyanides to nitrile N-oxides via a [3 + 1] cycloaddition reaction. The results of quantum mechanical studies of the reaction mechanism are also discussed. Furthermore, the one-pot conversion of aminodioximes to 1,2,3-oxadiazole-5-amines via Mitsunobu-Beckmann rearrangement is reported for the first time.
RESUMEN
A library of 41 aryloxyimino amides was prepared via solution phase parallel synthesis by extending the multicomponent reaction of (Z)-chlorooximes and isocyanides to the use of electron-deficient phenols. The resulting aryloxyiminoamide derivatives can be used as intermediates for the synthesis of benzo[d]isoxazole-3-carboxamides, dramatically reducing the number of synthetic steps required by other methods reported in literature.
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Amidas/síntesis química , Técnicas Químicas Combinatorias/métodos , Cianuros/química , Oximas/química , Fenoles/química , Amidas/química , Cianuros/síntesis química , Halogenación , Hidrocarburos Aromáticos/síntesis química , Hidrocarburos Aromáticos/química , Oximas/síntesis química , Fenoles/síntesis químicaRESUMEN
A novel one-pot multicomponent synthesis of α-aminocarbonyl N-acylhydrazones starting from readily available hydrazonoyl chlorides, isocyanides, and carboxylic acids is reported. The strategy exploits the ability of the carboxylic acid as a third component to suppress all competing reactions between nitrile imines and isocyanides, channeling the course of the reaction toward the formation of this novel class of compounds.