RESUMEN
A simple Ugi tetrazole multicomponent reaction allows the synthesis of a novel macrocyclic cyclen derivative with four appendant tetrazole arms in just two steps in excellent yields. This ligand, called TEMDO, turns out to have a high complexation affinity with lanthanoid metals. Here we describe the design, synthesis, solid-state structure, binding constant, and some MRI applications of the Gd-TEMDO complex as the first example of a congeneric family of oligo-amino tetrazoles.
Asunto(s)
Gadolinio/química , Compuestos Heterocíclicos/síntesis química , Compuestos Organometálicos/síntesis química , Tetrazoles/síntesis química , Medios de Contraste/química , Ciclamas , Compuestos Heterocíclicos/química , Ligandos , Imagen por Resonancia Magnética , Estructura Molecular , Compuestos Organometálicos/química , Tetrazoles/químicaRESUMEN
Lipoxygenases catalyze the oxidation of unsaturated fatty acids, such as linoleic acid, which play a crucial role in inflammatory responses. Selective inhibitors may provide a new therapeutic approach for inflammatory diseases. In this study, we describe the identification of a novel soybean lipoxygenase-1 (SLO-1) inhibitor and a potato 5-lipoxygenase (5-LOX) activator from a screening of a focused compound collection around the natural product anacardic acid. The natural product anacardic acid inhibits SLO-1 with an IC(50) of 52 µM, whereas the inhibitory potency of the novel mixed type inhibitor 23 is fivefold enhanced. In addition, another derivative (21) caused non-essential activation of potato 5-LOX. This suggests the presence of an allosteric binding site that regulates the lipoxygenase activity.
Asunto(s)
Ácidos Anacárdicos/química , Araquidonato 5-Lipooxigenasa/metabolismo , Inhibidores de la Lipooxigenasa/farmacología , Lipooxigenasa/metabolismo , Salicilatos/farmacología , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/química , Estructura Molecular , Salicilatos/síntesis química , Salicilatos/química , Solanum tuberosum/enzimología , Glycine max/enzimología , Relación Estructura-ActividadRESUMEN
Several lines of evidence indicate that histone acetyltransferases (HATs) are novel drug targets for treatment of diseases like, for example, cancer and inflammation. The natural product anacardic acid is a starting point for development of small molecule inhibitors of the histone acetyltransferase (HAT) p300/CBP associated factor (PCAF). In order to optimize the inhibitory potency, a binding model for PCAF inhibition by anacardic acid was proposed and new anacardic acid derivatives were designed. Ten new derivatives were synthesized using a novel synthetic route. One compound showed a twofold improved inhibitory potency for the PCAF HAT activity and a twofold improved inhibition of histone acetylation in HEP G2 cells.
Asunto(s)
Ácidos Anacárdicos/química , Ácidos Anacárdicos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Histona Acetiltransferasas/antagonistas & inhibidores , Histona Acetiltransferasas/metabolismo , Células Hep G2 , Histona Acetiltransferasas/química , Humanos , Inflamación/tratamiento farmacológico , Modelos MolecularesRESUMEN
Imidazo[1,2-a]pyridine is a well-known scaffold in many marketed drugs, such as Zolpidem, Minodronic acid, Miroprofen and DS-1 and it also serves as a broadly applied pharmacophore in drug discovery. The scaffold revoked a wave of interest when Groebke, Blackburn and Bienaymé reported independently a new three component reaction resulting in compounds with the imidazo[1,2-a]-heterocycles as a core structure. During the course of two decades the Groebke Blackburn Bienaymé (GBB-3CR) reaction has emerged as a very important multicomponent reaction (MCR), resulting in over a hundred patents and a great number of publications in various fields of interest. Now two compounds derived from GBB-3CR chemistry received FDA approval. To celebrate the first 20 years of GBB-chemistry, we present an overview of the chemistry of the GBB-3CR, including an analysis of each of the three starting material classes, solvents and catalysts. Additionally, a list of patents and their applications and a more in-depth summary of the biological targets that were addressed, including structural biology analysis, is given.
RESUMEN
A three step synthesis of N-unsubstituted tetrazolo γ- and δ-lactams involving a key Ugi-4CR is presented. The compounds, otherwise difficult to access, are conveniently synthesized in overall good yields by our route. PDB analysis of the N-unsubstituted γ- and δ-lactam fragment reveals a strongly tri-directional hydrogen bond donor acceptor interaction with the amino acids of the binding sites.
RESUMEN
On the basis of our recently resolved first cocrystal structure of Mdm4 in complex with a small molecule inhibitor (PDB ID 3LBJ ), we devised an approach for the generation of potential Mdm4 selective ligands. We performed the Ugi four-component reaction (Ugi-4CR) in 96-well plates with an indole fragment, which is specially designed to mimic Trp23, a key amino acid for the interaction between p53 and Mdm4. Generally the reaction yielded mostly precipitates collected by 96-well filter plates. The best hit compound was found to be active and selective for Mdm4 (Ki=5 µM, 10-fold stronger than Mdm2). This initial hit may serve as the starting point for designing selective p53-Mdm4 inhibitor with higher affinity.
Asunto(s)
Peptidomiméticos/química , Peptidomiméticos/farmacología , Mapas de Interacción de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Descubrimiento de Drogas , Humanos , Ligandos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The role of tritylamine is introduced as a convenient ammonia substitute in the Ugi tetrazole synthesis. Fifteen examples and their mild cleavage products are described in satisfactory to good yields. N-Unsubstituted α-aminotetrazoles are important compounds with annotated biological activities, and the described two-step synthesis provided an alternative route to otherwise difficult to access derivatives.