RESUMEN
Significant inhibition of Aurora B was achieved by the synthesis of simplified fragments of benzosceptrins and oroidin belonging to the marine pyrrole-2-aminoimidazoles metabolites isolated from sponges. Evaluation of kinase inhibition enabled the discovery of a synthetically accessible rigid acetylenic structural analogue EL-228 (1), whose structure could be optimized into the potent CJ2-150 (37). Here we present the synthesis of new inhibitors of Aurora B kinase, which is an important target for cancer therapy through mitosis regulation. The biologically oriented synthesis yielded several nanomolar inhibitors. The optimized compound CJ2-150 (37) showed a non-ATP competitive allosteric mode of action in a mixed-type inhibition for Aurora B kinase. Molecular docking identified a probable binding mode in the allosteric site "F" and highlighted the key interactions with the protein. We describe the improvement of the inhibitory potency and specificity of the novel scaffold as well as the characterization of the mechanism of action.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Aurora Quinasa B/antagonistas & inhibidores , Poríferos/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Adenosina Trifosfato/metabolismo , Regulación Alostérica , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Mitosis/efectos de los fármacos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
With the aim to develop new chemical tools based on simplified natural metabolites to help deciphering the molecular mechanism of necroptosis, simplified benzazole fragments including 2-aminobenzimidazole and the 2-aminobenzothiazole analogs were prepared during the synthesis of the marine benzosceptrin B. Conpounds inhibiting the RIPK1 protein kinase were discovered. A library of 54 synthetic analogs were prepared and evaluated through a phenotypic screen using the inhibition of the necrotic cell death induced by TNF-α in human Jurkat T cells deficient for the FADD protein. This article reports the design, synthesis and biological evaluation of a series of 2-aminobenzazoles on the necroptotic cell death through the inhibition of RIPK1 protein kinase. The 2-aminobenzimidazole and 2-aminobenzothiazole platforms presented herein can serve as novel chemical tools to study the molecular regulation of necroptosis and further develop lead drug candidates for chronic pathologies involving necroptosis.
Asunto(s)
Imidazoles/farmacología , Necroptosis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/farmacología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidores , Sitios de Unión , Diseño de Fármacos , Proteína de Dominio de Muerte Asociada a Fas/deficiencia , Humanos , Imidazoles/síntesis química , Imidazoles/metabolismo , Células Jurkat , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Pirroles/síntesis química , Pirroles/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/química , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Relación Estructura-ActividadRESUMEN
By comparing imatinib-sensitive and -resistant chronic myeloid leukemia (CML) cell models, we investigated the molecular mechanisms by which tetrahydrobenzimidazole derivative TMQ0153 triggered caspase-dependent apoptosis at low concentrations accompanied by loss of mitochondrial membrane potential (MMP) and increase of cytosolic free Ca2+ levels. Interestingly, at higher concentrations, TMQ0153 induced necroptotic cell death with accumulation of ROS, both preventable by N-acetyl-L-cysteine (NAC) pretreatment. At necroptosis-inducing concentrations, we observed increased ROS and decreased ATP and GSH levels, concomitant with protective autophagy induction. Inhibitors such as bafilomycin A1 (baf-A1) and siRNA against beclin 1 abrogated autophagy, sensitized CML cells against TMQ0153 and enhanced necroptotic cell death. Importantly, TMQ153-induced necrosis led to cell surface exposure of calreticulin (CRT) and ERp57 as well as the release of extracellular ATP and high mobility group box (HMGB1) demonstrating the capacity of this compound to release immunogenic cell death (ICD) markers. We validated the anti-cancer potential of TMQ0153 by in vivo inhibition of K562 microtumor formation in zebrafish. Taken together, our findings provide evidence that cellular stress and redox modulation by TMQ0153 concentration-dependently leads to different cell death modalities including controlled necrosis in CML cell models.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Bencimidazoles/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Necroptosis/efectos de los fármacos , Animales , Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Metabolismo Energético/efectos de los fármacos , Regulación Leucémica de la Expresión Génica , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Pez CebraRESUMEN
Molecular iodine is shown to be an excellent catalyst for aerobic oxidative α,ß-diamination of cyclohexanones with 2-aminopyrimidine/2-aminopyridines. This α,ß-C-H functionalization is remarkable for its simplicity in both substrates and conditions, involving one and a half oxygen molecules and releasing three water molecules as the only byproduct. In addition, the functionalized products including protected 2-aminoimidazoles introduced without aromatization can serve as useful building blocks for natural product synthesis and medicinal chemistry.
RESUMEN
Elements as feedstocks for organic synthesis, the trio of metallic iron, molecular iodine, and dioxygen, were found to be an excellent tool for oxidative regioselective diamination of conjugated enones with 2-aminopyrimidine (a guanidine surrogate) and 2-aminopyridines leading to unaromatized coupled products in moderate to good yields.
Asunto(s)
Aminopiridinas/química , Ciclohexanonas/química , Hierro/química , Pirimidinas/química , Aminación , Catálisis , Técnicas de Química Sintética , Cristalografía por Rayos X , Conformación Molecular , Estructura Molecular , Oxidación-Reducción , Oxígeno/químicaRESUMEN
A wide range of 2-aroylbenzothiazoles 3 including some pharmacologically relevant derivatives can be obtained in high yields by simply heating o-halonitrobenzenes 1, acetophenones 2, elemental sulfur, and N-methylmorpholine. This three-component nitro methyl coupling was found to occur in an excellent atom-, step-, and redox-efficient manner in which elemental sulfur played the role of nucleophile building block and redox moderating agent to fulfill electronic requirements of the global reaction.
Asunto(s)
Acetofenonas/química , Benzotiazoles/síntesis química , Nitrobencenos/química , Azufre/química , Benzotiazoles/química , Benzotiazoles/farmacología , Estructura Molecular , Morfolinas/química , Oxidación-ReducciónRESUMEN
The disproportionation of elemental sulfur at moderate temperatures is investigated in the redox condensation involving o-halonitrobenzenes 1 and benzylamines 2. As a redox moderator, elemental sulfur plays the dual role of both electron donor and acceptor, generating its lowest and highest oxidation states: S(-2) (sulfide equivalent) in benzothiazole 3 and S(+6) (sulfate equivalent) in sulfamate 4, and filling the electron gap of the global redox condensation process. Along with this process, a cascade of reactions of reduction of the nitro group of 1, oxidation of the aminomethyl group of 2, metal-free aromatic halogen substitution, and condensation finally led to 2-arylbenzothiazoles 3.
RESUMEN
Oxidative nucleophilic addition of ethylenediamine and guanidine derivatives to pyrrole-amino acid diketopiperazines was shown to provide substituted 5,6-dihydro-2(1H)-piperazinones, quinoxalinones, and 2-aminoimidazolones. On the basis of this methodology, a concise approach to natural products didebromohamacanthin A and demethylaplysinopsine has been demonstrated.
Asunto(s)
Aminoácidos/química , Dicetopiperazinas/química , Etilenodiaminas/química , Guanidina/química , Alcaloides Indólicos/síntesis química , Pirroles/química , Alcaloides Indólicos/química , Estructura Molecular , Oxidación-Reducción , EstereoisomerismoRESUMEN
A new strategy for the synthesis of 2-aminobenzimidazol-6-ols via a reaction of quinones with guanidine derivatives is reported. Sequential application of this methodology provided a simple access to the first benzosceptrin analogue bearing a bis-2-aminoimidazole moiety. A concomitant addition of two guanidines to the naphtho[1',2':4,5]imidazo[1,2-a]pyrimidine-5,6-dione, which includes the redox neutral debenzylation and guanidine-assisted cleavage of the 2-aminopyrimidine part resulted in the synthesis of the free challenging contiguous bis-2-aminoimidazole moiety of benzosceprins in one step.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/síntesis química , Guanidinas/química , Imidazoles/química , Imidazoles/síntesis química , Naftalenos/química , Pirroles/química , Quinonas/química , Estructura MolecularRESUMEN
A general, straightforward, and atom-economical three-component synthesis of thioamides from alkynes, elemental sulfur, and aliphatic amines has been developed.
Asunto(s)
Alquinos/química , Aminas/química , Azufre/química , Tioamidas/síntesis química , Estructura Molecular , Tioamidas/químicaRESUMEN
A wide variety of functionalized 2-aryl benzimidazoles can be prepared by a solvent-free cobalt- or iron-catalyzed redox condensation of 2-nitroanilines and benzylamines. The cascade including benzylamine oxidation, nitro reduction, condensation, and aromatization occurs without any added reducing or oxidizing agent. The method can be extended to other alkylamines as reducing components or 2-nitrobenzamides as oxidizing components when using an iron/sulfur catalyst to afford various diazaheterocycles.
Asunto(s)
Aminas/química , Compuestos Aza/síntesis química , Cobalto/química , Compuestos Heterocíclicos/síntesis química , Hierro/química , Nitrobencenos/química , Compuestos Aza/química , Catálisis , Compuestos Heterocíclicos/química , Estructura Molecular , Oxidación-ReducciónRESUMEN
A simple, straightforward, and atom economic approach to 2-hetarylbenzothiazoles starting from 2-halonitroarene, methylhetarene, and elemental sulfur under mild conditions is described. The method is highlighted by the direct redox nitro-methyl reaction for carbon-nitrogen bond formation without an added oxidizing or reducing agent.
RESUMEN
The first biomimetic homodimerization of oroidin and clathrodin was effected in the presence HMPA and diphosphonate salts, strong guanidinium and amide chelating agents. The intermolecular associations probably interfere with the entropically and kinetically favored intramolecular cyclizations. Use of oroidin·(1)/2HCl salt or clathrodin·(1)/2HCl was indicative in the presence of the ambident nucleophilic and electrophilic tautomers of the 2-aminoimidazolic oroidin and clathrodin precursors. Surprisingly, the homodimerization of oroidin led to the nagelamide D skeleton, while the homodimerization of clathrodin gave the benzene para-symmetrical structure 19. The common process was rationalized from tautomeric precursors I and III.
Asunto(s)
Hempa/química , Imidazoles/química , Pirroles/química , Ciclización , Biología Marina , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , EstereoisomerismoRESUMEN
Iron sulfide generated in situ from elemental sulfur and iron was found to be highly efficient in catalyzing a redox/condensation cascade reaction between 2-amino/hydroxy nitrobenzenes and activated methyl groups. This method represents a straightforward and highly atom economical approach to 2-hetaryl-benzimidazoles and -benzoxazoles.
Asunto(s)
Bencimidazoles/síntesis química , Benzoxazoles/síntesis química , Compuestos Ferrosos/química , Nitrobencenos/química , Picolinas/química , Bencimidazoles/química , Benzoxazoles/química , Catálisis , Estructura Molecular , Oxidación-ReducciónRESUMEN
A novel remarkably simple solvent-free and catalyst-free synthesis of benzazoles from alkylamines and o-hydroxy/amino/mercaptan anilines using elemental sulfur as traceless oxidizing agent has been developed.
Asunto(s)
Aminas/química , Derivados del Benceno/química , Derivados del Benceno/síntesis química , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Oxidantes/química , Compuestos de Azufre/química , Técnicas Químicas Combinatorias , Compuestos Heterocíclicos con 2 Anillos/química , Estructura MolecularRESUMEN
An efficient and selective multicomponent oxidative coupling of two different aliphatic primary amines into thioamides by elemental sulfur under solvent-free conditions has been developed.
Asunto(s)
Aminas/química , Azufre/química , Tioamidas/síntesis química , Catálisis , Técnicas Químicas Combinatorias , Estructura Molecular , Acoplamiento Oxidativo , Tioamidas/químicaRESUMEN
A novel method of transamidation of carboxamides with amines using catalytic amounts of readily available boric acid under solvent-free conditions has been developed. The scope of the methodology has been demonstrated with (i) primary, secondary, and tertiary amides and phthalimide and (ii) aliphatic, aromatic, cyclic, acyclic, primary, and secondary amines.
Asunto(s)
Amidas/química , Aminas/química , Ácidos Bóricos/química , Aminación , Catálisis , Estructura MolecularRESUMEN
The study of the n-butanol extract of the New Caledonian sponge Agelas dendromorpha led to the isolation and identification of three new pyrrole-2-aminoimidazole (P-2-AI) alkaloids, named agelastatins E (3) and F (4) and benzosceptrin C (5), together with 10 known metabolites, agelastatin A (1), agelastatin D (2), sceptrin (6), manzacidin A, tauroacidin A, taurodispacamide A, nortopsentin D, thymine, longamide, and 4,5-dibromopyrrole-2-carboxamide. Their structures were assigned by spectroscopic data interpretation. All the compounds were tested for cytotoxic activity.
Asunto(s)
Agelas/química , Alcaloides/aislamiento & purificación , Oxazolidinonas/aislamiento & purificación , Alcaloides/química , Alcaloides/farmacología , Animales , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Imidazoles , Células KB , Biología Marina , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Oxazolidinonas/química , Oxazolidinonas/farmacología , PirrolesRESUMEN
Two new modified amino acids, axiphenylalaninium (1) and axityrosinium (2), along with four known metabolites, C2-alpha-D-mannosylpyranosyl-L-tryptophan (3), N3,5'-cycloxanthosine (4), palythine (5), and taurine, were isolated from the marine sponge Axinella polypoides collected in the Mediterranean Sea. The structures were determined by spectroscopic studies and confirmed by X-ray analysis and chemical modifications.