RESUMEN
In present paper, an expeditious total synthesis of naturally occurring 5'-deoxytoyocamycin and 5'-deoxysangivamycin was accomplished. Because of the introduction of a benzoyl group at N-6 of 4-amino-5-cyano-6-bromo-pyrrolo[2,3-d]pyrimidine, a Vorbrüggen glycosylation with 1,2,3-tri-O-acetyl-5-deoxy-ß-D-ribofuranose afforded a completely regioselective N-9 glycosylation product, which is unambiguously confirmed by X-ray diffraction analysis. All of the involved intermediates were well characterized by various spectra.
Asunto(s)
Nucleósidos de Pirimidina/síntesis química , Toyocamicina/análogos & derivados , Glicosilación , Modelos Moleculares , Estructura Molecular , Nucleósidos de Pirimidina/química , Toyocamicina/síntesis química , Toyocamicina/químicaRESUMEN
BACKGROUND/AIM: Organ transplant patients treated with the immunosuppressive drug cyclosporine A often present malignant kidney tumors. Cyclosporine A can promote oncogenesis in a cell-intrinsic manner by increasing the production of vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: We explored the impact of cyclosporine A and the role of the unfolded protein response (UPR) on three human renal cell carcinoma (RCC) cell lines under normoxic and hypoxic (1% O2) conditions. RESULTS: Cyclosporine A regulated the expression of VEGF at the post-transcriptional level. Cyclosporine A induced the inositol requiring enzyme-1α (IRE1α) arm of the UPR and stabilized neosynthesized proteins in RCC cells. Toyocamycin, an inhibitor of IRE1α, abolished the clonogenic growth of RCC cells and reduced induction of VEGF by cyclosporine A under hypoxia. CONCLUSION: Our findings highlight the impact of cyclosporine A on the proteostasis of RCC cells, and suggest the potential therapeutic interest of targeting the UPR against tumors arising in the context of organ transplantation.
Asunto(s)
Carcinoma de Células Renales/metabolismo , Ciclosporina/química , Regulación Neoplásica de la Expresión Génica , Inmunosupresores/química , Neoplasias Renales/metabolismo , Respuesta de Proteína Desplegada , Línea Celular Tumoral/efectos de los fármacos , Endorribonucleasas/metabolismo , Regulación de la Expresión Génica , Humanos , Hipoxia , Oxígeno/metabolismo , Reacción en Cadena de la Polimerasa , Proteínas Serina-Treonina Quinasas/metabolismo , Puromicina/química , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Toyocamicina/química , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Benzimidazole derivatives of 5,6-dichlorobenzimidazole 1-ß-D-ribofuranoside (DRB) comprise the important class of protein kinase CK2 inhibitors. Depending on the structure, benzimidazoles inhibit CK2 with different selectivity and potency. Besides CK2, the compounds can inhibit, with similar activity, other classical eukaryotic protein kinases (e.g. PIM, DYRK, and PKD). The present results show that a majority of the most common CK2 inhibitors can affect the atypical kinase Rio1 in a nanomolar range. Kinetic data confirmed the mode of action of benzimidazoles as typical ATP-competitive inhibitors. In contrast to toyocamycin-the first discovered small-molecule inhibitor of Rio1-the most potent representative of benzimidazoles TIBI (IC50 = 0.09 µM, K i = 0.05 µM) does not influence the oligomeric state of the Rio1 kinase. Docking studies revealed that TIBI can occupy the ATP-binding site of Rio1 in a manner similar to toyocamycin, and enhances the thermostability of the enzyme.
Asunto(s)
Bencimidazoles , Quinasa de la Caseína II/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Bencimidazoles/síntesis química , Bencimidazoles/química , Quinasa de la Caseína II/química , Dominio Catalítico , Estabilidad de Enzimas , Calor , Humanos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/química , Toyocamicina/síntesis química , Toyocamicina/químicaRESUMEN
Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress, which is characteristic of cells with high level of secretory activity and implicated in a variety of disease conditions. In response to ER stress, the cell elicits an adaptive process called the unfolded protein response (UPR) to support cellular homeostasis and survival. However, prolonged and unsolvable ER stress also induces apoptosis. As the most conserved signaling branch of the UPR, the IRE1α-XBP1 pathway plays important roles in both physiological and pathological settings and its activity has profound effects on disease progression and prognosis. Recently, modulating this pathway with small molecule compounds has been demonstrated as a promising approach for disease therapy. In this review, we summarize a list of current investigational compounds targeting this pathway and their therapeutic features for treating human diseases.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Endorribonucleasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Transcripción/metabolismo , Respuesta de Proteína Desplegada , Aldehídos/química , Aldehídos/metabolismo , Animales , Apoptosis , Supervivencia Celular , Cumarinas/química , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Diseño de Fármacos , Descubrimiento de Drogas , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico , Homeostasis , Humanos , Ratones , Neoplasias/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Pronóstico , Pliegue de Proteína , Quercetina/química , Factores de Transcripción del Factor Regulador X , Transducción de Señal , Sulfonamidas , Tiofenos , Toyocamicina/química , Proteína 1 de Unión a la X-BoxRESUMEN
As scientists begin to appreciate the extent to which quaternary structure facilitates protein function, determination of the subunit arrangement within noncovalent protein complexes is increasingly important. While native mass spectrometry shows promise for the study of noncovalent complexes, few developments have been made toward the determination of subunit architecture, and no mass spectrometry activation method yields complete topology information. Here, we illustrate the surface-induced dissociation of a heterohexamer, toyocamycin nitrile hydratase, directly into its constituent trimers. We propose that the single-step nature of this activation in combination with high energy deposition allows for dissociation prior to significant unfolding or other large-scale rearrangement. This method can potentially allow for dissociation of a protein complex into subcomplexes, facilitating the mapping of subunit contacts and thus determination of quaternary structure of protein complexes.
Asunto(s)
Hidroliasas/química , Subunidades de Proteína/química , Toyocamicina/química , Hidroliasas/metabolismo , Modelos Moleculares , Estructura Cuaternaria de Proteína , Subunidades de Proteína/metabolismo , Propiedades de SuperficieRESUMEN
Although 7-deazapurines are well known and feature in the hypermodified RNA base queuosine, and in a range of nucleoside antibiotics such as toyocamycin, a mechanistic understanding of their biosynthesis is a longstanding problem. In particular, the obligatory loss of the N-7 nitrogen atom is puzzling, and in order to address this mechanistic conundrum a novel doubly labeled purine, [2-(13)C, 7-(15)N]-adenine, has been prepared and used as a biosynthetic precursor to toyocamycin in Streptomyces rimosus. NMR spectroscopy and mass spectrometry clearly showed incorporation of (13)C but loss of (15)N in the toyocamycin produced.
Asunto(s)
Adenina/química , Purinas/química , Streptomyces/química , Toyocamicina/química , Adenina/metabolismo , Isótopos de Carbono , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Isótopos de Nitrógeno , Purinas/biosíntesis , Streptomyces/metabolismo , Toyocamicina/biosíntesisRESUMEN
The title compound [systematic name: 4-amino-5-cyano-1-(beta-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine hemihydrate], C(12)H(13)N(5)O(4).0.5H(2)O, is a regioisomer of toyocamycin with the ribofuranosyl residue attached to the pyrimidine moiety of the heterocycle. This analogue exhibits a syn glycosylic bond conformation with a chi torsion angle of 57.51 (17) degrees. The ribofuranose moiety shows an envelope C2'-endo ((2)E) sugar conformation (S-type), with P = 161.6 (2) degrees and tau(m) = 41.3 (1) degrees. The conformation at the exocyclic C4'-C5' bond is +sc (gauche, gauche), with a gamma torsion angle of 54.4 (2) degrees. The crystal packing is stabilized by intermolecular O-H...O, N-H...N and O-H...N hydrogen bonds; water molecules, located on crystallographic twofold axes, participate in interactions. An intramolecular O-H...N hydrogen bond stabilizes the syn conformation of the nucleoside.
Asunto(s)
Carbohidratos/química , Toyocamicina/química , Conformación de Carbohidratos , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , EstereoisomerismoRESUMEN
A ribozyme based gene control element enabled the spatio-temporal regulation of gene function in mammalian cell culture with light.
Asunto(s)
Expresión Génica/efectos de la radiación , ARN Catalítico/metabolismo , Toyocamicina/química , Línea Celular , Humanos , ARN Catalítico/química , ARN Mensajero/metabolismo , Toyocamicina/efectos de la radiación , Rayos UltravioletaRESUMEN
The auxins, plant hormones, play a crucial role in many aspects of plant development by regulating cell division, elongation and differentiation. Toyocamycin, a nucleoside-type antibiotic, was identified as auxin signaling inhibitor in a screen of microbial extracts for inhibition of the auxin-inducible reporter gene assay. Toyocamycin specifically inhibited auxin-responsive gene expression, but did not affect other hormone-inducible gene expression. Toyocamycin also blocked auxin-enhanced degradation of the Aux/IAA repressor modulated by the SCF(TIR1) ubiquitin-proteasome pathway without inhibiting proteolytic activity of proteasome. Furthermore, toyocamycin inhibited auxin-induced lateral root formation and epinastic growth of cotyledon in the Arabidopsis thaliana plant. This evidence suggested that toyocamycin would act on the ubiquitination process regulated by SCF(TIR1) machineries. To address the structural requirements for the specific activity of toyocamycin on auxin signaling, the structure-activity relationships of nine toyocamycin-related compounds, including sangivamycin and tubercidin, were investigated.
Asunto(s)
Proteínas de Arabidopsis/metabolismo , Proteínas F-Box/metabolismo , Ácidos Indolacéticos/antagonistas & inhibidores , Ácidos Indolacéticos/metabolismo , Receptores de Superficie Celular/metabolismo , Transducción de Señal/efectos de los fármacos , Toyocamicina/farmacología , Arabidopsis/efectos de los fármacos , Arabidopsis/genética , Arabidopsis/crecimiento & desarrollo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas F-Box/genética , Genes Reporteros/genética , Estructura Molecular , Complejo de la Endopetidasa Proteasomal/metabolismo , Receptores de Superficie Celular/genética , Relación Estructura-Actividad , Especificidad por Sustrato , Toyocamicina/químicaRESUMEN
The synthesis of model 7 deazapurine derivatives related to tubercidin and toyocamycin has been performed. Tubercidin derivatives were obtained by simple conversion of the amino group of the heterocyclic moiety of the starting 7-deazadenosine compounds, into a hydroxyl group. Preparation of toyocamycin derivatives was accomplished by treatment of the silylated 6-bromo-5-cyanopyrrolo[2,3-d]pyrimidin-4-one with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-d-ribofuranose. The glycosylation reaction afforded a mixture of 8-bromo 7-cyano 2',3',5' tri-O-benzoyl 7-deazainosine and 6-bromo-5-cyano-3-(2',3',5'-tri-O-benzoyl-beta-d-ribofuranosyl)pyrrolo[2,3-d]-pyrimidin-4-one isomers: The structures were assigned on the basis of NMR spectroscopy studies. Next deprotection treatment gave the novel 7-deazainosine ribonucleosides.
Asunto(s)
Inosina/análogos & derivados , Nucleósidos de Pirimidina/síntesis química , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Diseño de Fármacos , Inosina/síntesis química , Inosina/química , Inosina/farmacología , Espectroscopía de Resonancia Magnética , Nucleósidos de Pirimidina/química , Nucleósidos de Pirimidina/farmacología , Virus ARN/efectos de los fármacos , Virus ARN/fisiología , Toyocamicina/análogos & derivados , Toyocamicina/síntesis química , Toyocamicina/química , Tubercidina/análogos & derivados , Tubercidina/síntesis química , Tubercidina/química , Replicación Viral/efectos de los fármacosRESUMEN
We describe an efficient total synthesis of triciribine, a tricyclic nucleoside with antineoplastic and antiviral properties, starting from 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidine.
Asunto(s)
Antineoplásicos/síntesis química , Antivirales/síntesis química , Ribonucleósidos/síntesis química , Virosis/tratamiento farmacológico , Virus/efectos de los fármacos , Humanos , Toyocamicina/químicaRESUMEN
Syntheses of pyrrolo[2,1-f][1,2,4]triazine C-nucleosides are reported. Treatment of pyranulose glycoside with aminoguanidine in acetic acid gave the corresponding semicarbazone in 96% yield. The ring transformation of the semicarbazone in dioxane afforded a 51% yield of 2-amino-7-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)pyrrolo[2,1-f]-[1,2,4]triazine. Vilsmeier formylation of the pyrrolotriazine gave the major product, 5-formylpyrrolo[2,1-f][1,2,4]triazine, in 69% yield. The aldehyde was treated with hydroxylamine hydrochloride in methanol to give aldoximes. Dehydration of aldoxime with trifluoromethanesulfonic anhydride and triethylamine in dichloromethane afforded 5-cyanopyrrolo[2,1-f][1,2,4]triazine in 44% yield. Conversion of the nitrile to the deprotected amide, 2-amino-7-(beta-D-ribofuranosyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide, was accomplished in 96% yield on treatment with 30% H2O2 in ethanol for 1 day at room temperature. Debenzoylation with sodium hydroxide solution produced deprotected C-nucleosides.
Asunto(s)
Antibióticos Antineoplásicos/síntesis química , Nucleósidos de Pirimidina/síntesis química , Ribonucleósidos/síntesis química , Toyocamicina/análogos & derivados , Toyocamicina/síntesis química , Triazinas/síntesis química , Tubercidina/análogos & derivados , Tubercidina/síntesis química , Antibióticos Antineoplásicos/química , Indicadores y Reactivos , Ribonucleósidos/química , Espectrometría de Masa Bombardeada por Átomos Veloces , Estereoisomerismo , Toyocamicina/química , Triazinas/química , Tubercidina/químicaRESUMEN
The structures of five naturally-occurring herbicidal nucleosides have been determined by spectral analysis. Three (5'-deoxyguanosine, coaristeromycin and 5'-deoxytoyocamycin) are novel natural products while the remaining two (coformycin and adenine 9-beta-D-arabinofuranoside) are known natural products which have not previously been reported to be herbicidal.