RESUMEN
Hereditary ATTR amyloidosis is caused by the point mutation in serum protein transthyretin (TTR) that destabilizes its tetrameric structure to dissociate into monomer. The monomers form amyloid fibrils, which are deposited in peripheral nerves and organs, resulting in dysfunction. Therefore, a drug that dissolves amyloid after it has formed, termed amyloid disruptor, is needed as a new therapeutic drug. Here, we first established a high throughput screening system to find TTR interactors from the LOPAC1280 compound library. Among the hit compounds, thioflavin T-based post-treatment assay determined lead compounds for TTR amyloid disruptors, NSC95397 and Gossypol, designated as B and R, respectively. Because these compounds have naphthoquinone-naphthalene structures, we tested 100 naphthoquinone derivatives, and found 10 candidate compounds that disrupted TTR amyloid. Furthermore, to determine whether these 10 compounds are selective for TTR amyloid, we evaluated them against beta-amyloid (Aß1-42). We found two compounds that were selective for TTR and did not disrupt Aß-derived amyloid. Therefore, we succeeded in identifying TTR-selective amyloid disruptors, and demonstrated that naphthoquinone compounds are useful structures as amyloid disruptors. These findings contribute to the on-going efforts to discover new therapeutic tools for TTR amyloidosis.
Asunto(s)
Neuropatías Amiloides Familiares , Amiloidosis , Naftoquinonas , Humanos , Prealbúmina/química , Prealbúmina/genética , Prealbúmina/metabolismo , Amiloide/metabolismo , Amiloide/uso terapéutico , Amiloidosis/metabolismo , Péptidos beta-Amiloides , Naftoquinonas/farmacología , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/metabolismoRESUMEN
BACKGROUND: It is widely known that there is low striatal 123 I-2ß-Carbomethoxy-3ß-(4-iodophenyl)-N-(3- fluoropropyl) nortropane (123 I-FP-CIT) dopamine transporter single photon emission tomography (DaT-SPECT) uptake in patients with dementia with Lewy bodies (DLB). No studies to date have analyzed the association between longitudinal changes of clinical features and DaT uptake in patients with Parkinson syndrome, particularly those with DLB. The aim of this study was to investigate the association between the longitudinal changes in DaT uptake and the severity of parkinsonism and cognitive function in DLB patients. METHODS: A total of 35 outpatients with probable DLB who underwent DaT-SPECT twice (at the initial examination and the follow-up period) in the Memory Disorder Clinic at the Department of Geriatric Medicine, Tokyo Medical University, were enrolled in this study between April 2014 and September 2020. The correlation between annual changes in DaT uptake and clinical features (cognitive function decline and parkinsonism) of the patients was analyzed. RESULTS: A significant correlation was detected between annual changes in parkinsonism symptom severity and DaT uptake in the left posterior putamen (r = -0.39, P = 0.03), and between Mini-Mental State Examination scores and DaT uptake in all regions except the right posterior putamen (P < 0.05) in patients with DLB. CONCLUSIONS: Our results suggested that the pathway from the ventrolateral tier of the substantia nigra to the putamen might be more crucial for motor function than other pathways, not only in Parkinson's disease but also in DLB.
Asunto(s)
Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Anciano , Humanos , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Enfermedad por Cuerpos de Lewy/diagnóstico , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
The ubiquitin-proteasome system (UPS) regulates selective protein degradation to maintain protein homeostasis. Small molecules that inhibit the UPS-dependent protein degradation are promising anti-tumor agents. We report a cell-based luminescent assay using HeLa cells expressing luciferase-fused oxygen-dependent destruction domain (ODD) of hypoxia-inducible factor 1 α (HIF-1 α). ODD is degraded by the UPS and this assay system can aid in the identification of natural products that inhibit either process of the UPS, including ubiquitination/deubiquitination and proteasomal degradation. This reporter assay can exclude the influences of coloring or fluorescent compounds in extracts, thereby leading to effective high-throughput processing. The screening of 15,025 extracts of natural sources identified the culture extract of the fungus Remotididymella sp. (18F02908). Bioassay-guided isolation yielded two new polyketides, mellains A (1) and B (2), together with leptosphaerodione (3) and its acetone adduct 4. Compound 1 was revealed to have an unprecedented benzo[g]isoquinoline-8,10-dione skeleton. Evaluation of the biological activities demonstrated that these polyketides inhibit the proteasomal proteolysis. This is the first report of the identification of proteasome inhibitors from natural sources using a cell-based reporter assay targeting UPS inhibitors.
Asunto(s)
Ascomicetos/química , Productos Biológicos/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/farmacología , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Células HeLa , Humanos , Estructura Molecular , Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
A simple methylenedioxy dibromoindole alkaloid, amakusamine (1), was isolated from a marine sponge of the genus Psammocinia, and its structure was determined from spectroscopic data, time-dependent density-functional theory calculations, and synthesis. Compound 1 inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced formation of multinuclear osteoclasts with an IC50 value of 10.5 µM in RAW264 cells. The structure-activity relationship of 1 was also investigated with synthetic derivatives.
Asunto(s)
Alcaloides/farmacología , Osteoclastos/efectos de los fármacos , Poríferos/química , Ligando RANK/antagonistas & inhibidores , Animales , Japón , Ratones , Estructura Molecular , Células RAW 264.7 , Relación Estructura-ActividadRESUMEN
Fifteen new isopimarane-type diterpenes, taichunins E-S (1-15), and a new 20-nor-isopimarane, taichunin T (16), together with four known compounds were isolated from Aspergillus taichungensis (IBT 19404). The structures of these new compounds were determined by NMR and mass spectroscopy, and their absolute configurations were analyzed by NOESY and TDDFT calculations of ECD spectra. Taichunins G, K, and N (3, 7, and 10) completely inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced formation of multinuclear osteoclasts in RAW264 cells at 5 µM, with 3 showing 92% inhibition at a concentration of 0.2 µM.
Asunto(s)
Abietanos/farmacología , Aspergillus/química , Osteoclastos/efectos de los fármacos , Ligando RANK , Abietanos/aislamiento & purificación , Animales , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Ratones , Estructura Molecular , Células RAW 264.7 , TaiwánRESUMEN
The fungal indole alkaloids are a unique class of complex molecules that have a characteristic bicyclo[2.2.2]diazaoctane ring and frequently contain a spiro-oxindole moiety. While various strains produce these compounds, an intriguing case involves the formation of individual antipodes by two unique species of fungi in the generation of the potent anticancer agents (+)- and (-)-notoamide A. NotI and NotI' have been characterized as flavin-dependent monooxygenases that catalyze epoxidation and semi-pinacol rearrangement to form the spiro-oxindole center within these molecules. This work elucidates a key step in the biosynthesis of the notoamides and provides an evolutionary hypothesis regarding a common ancestor for production of enantiopure notoamides.
Asunto(s)
Flavinas/metabolismo , Alcaloides Indólicos/metabolismo , Oxigenasas de Función Mixta/metabolismo , Oxindoles/metabolismo , Compuestos de Espiro/metabolismo , Flavinas/química , Alcaloides Indólicos/química , Oxigenasas de Función Mixta/química , Conformación Molecular , Oxindoles/química , Compuestos de Espiro/química , EstereoisomerismoRESUMEN
A new isoindolinone alkaloid, irpexine (1), was isolated as a racemate, along with a known green pigment, hypoxyxylerone (2), from the coculture of two endophytic fungi, Irpex lacteus and Phaeosphaeria oryzae. Compound 1 was found to be a newly produced metabolite of I. lacteus in the coculture with P. oryzae. Although 2 was produced in a monoculture of I. lacteus, its production was markedly enhanced by the coculture.
Asunto(s)
Ascomicetos/metabolismo , Endófitos/metabolismo , Polyporales/metabolismo , Bacterias/efectos de los fármacos , Técnicas de Cocultivo , Helechos/microbiología , Células HeLa , Houttuynia/microbiología , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura MolecularRESUMEN
A new halicyclamine derivative, tetradehydrohalicyclamine B (1), was isolated from the marine sponge Acanthostrongylophora ingens, along with halicyclamine B (2) as proteasome inhibitors. Compound 1 is the second example found to have a pyridinium ring in the halicyclamine family. Although the relative configuration of 2 was previously determined by X-ray crystallographic analysis, here we determined the absolute configuration of 2 by ECD experiment. Compounds 1 and 2 inhibited the constitutive proteasome as well as the immunoproteasome. The inhibitory activities of 2 were 4- to 10-fold more potent than those of 1.
Asunto(s)
Depsipéptidos/farmacología , Poríferos/química , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/farmacología , Animales , Cristalografía por Rayos X , Depsipéptidos/química , Depsipéptidos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
Four new norditerpenes, taichunins A-D (1-4), were isolated from the fungus Aspergillus taichungensis (IBT 19404). Compound 1 has a new carbon framework. The absolute configurations were determined by the calculated ECD spectral method. Compound 1 was cytotoxic against HeLa cells with an IC50 value of 4.5 µM, whereas 2-4 were nontoxic at 50 µM.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Aspergillus/química , Diterpenos/farmacología , Antiinfecciosos/farmacología , Antibióticos Antineoplásicos/química , Anticolesterolemiantes/farmacología , Diterpenos/química , Células HeLa , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Osteoclastos/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Ligando RANK/efectos de los fármacos , Ligando RANK/metabolismoRESUMEN
Covering: up to February 2017 Various fungi of the genera Aspergillus, Penicillium, and Malbranchea produce prenylated indole alkaloids possessing a bicyclo[2.2.2]diazaoctane ring system. After the discovery of distinct enantiomers of the natural alkaloids stephacidin A and notoamide B, from A. protuberus MF297-2 and A. amoenus NRRL 35660, another fungi, A. taichungensis, was found to produce their diastereomers, 6-epi-stephacidin A and versicolamide B, as major metabolites. Distinct enantiomers of stephacidin A and 6-epi-stephacidin A may be derived from a common precursor, notoamide S, by enzymes that form a bicyclo[2.2.2]diazaoctane core via a putative intramolecular hetero-Diels-Alder cycloaddition. This review provides our current understanding of the structural and stereochemical homologies and disparities of these alkaloids. Through the deployment of biomimetic syntheses, whole-genome sequencing, and biochemical studies, a unified biogenesis of both the dioxopiperazine and the monooxopiperazine families of prenylated indole alkaloids constituted of bicyclo[2.2.2]diazaoctane ring systems is presented.
Asunto(s)
Hongos/metabolismo , Alcaloides Indólicos/química , Alcaloides Indólicos/metabolismo , Organismos Acuáticos/química , Aspergillus/química , Aspergillus/genética , Aspergillus/metabolismo , Hongos/química , Hongos/genética , Alcaloides Indólicos/aislamiento & purificación , Estructura Molecular , Prenilación , EstereoisomerismoRESUMEN
Himeic acidâ A, which is produced by the marine fungus Aspergillus japonicus MF275, is a specific inhibitor of the ubiquitin-activating enzyme E1 in the ubiquitin-proteasome system. To elucidate the mechanism of himeic acid biosynthesis, feeding experiments with labeled precursors have been performed. The long fatty acyl side chain attached to the pyrone ring is of polyketide origin, whereas the amide substituent is derived from leucine. These results suggest that a polyketide synthase-nonribosomal peptide synthase (PKS-NRPS) is involved in himeic acid biosynthesis. A candidate gene cluster was selected from the results of genome sequencing analysis. Disruption of the PKS-NRPS gene by Agrobacterium-mediated transformation confirms that HimA PKS-NRPS is involved in himeic acid biosynthesis. Thus, the him biosynthetic gene cluster for himeic acid in A.â japonicus MF275 has been identified.
Asunto(s)
Aspergillus/enzimología , Inhibidores Enzimáticos/farmacología , Ácidos Grasos Insaturados/farmacología , Familia de Multigenes/genética , Pironas/farmacología , Enzimas Activadoras de Ubiquitina/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Ácidos Grasos Insaturados/biosíntesis , Ácidos Grasos Insaturados/genética , Estructura Molecular , Relación Estructura-Actividad , Enzimas Activadoras de Ubiquitina/metabolismoRESUMEN
Total syntheses of prenylated pyrrolidinoindoline alkaloids, (-)-mollenines A [(-)-1'] and B (2'), were accomplished via three- and four-step sequences including a bioinspired indole prenylation reaction followed by dioxomorpholine ring formation. Then, the stereochemistry of mollenines A and B was reassigned to 3S,6S,14S,16S by analysis of spectroscopic data and chemical syntheses with different approaches along with the comparison of calculated and experimental ECD spectra. In addition, a thermodynamically controlled epimerization reaction on the dioxomorpholine ring was observed in our synthesis.
Asunto(s)
Morfolinas , Modelos Moleculares , Conformación Molecular , Morfolinas/síntesis química , Morfolinas/química , EstereoisomerismoRESUMEN
The fungus Aspergillus japonicus MF275 produces himeic acid A (1), containing a 4-pyrone ring, along with its congeners, himeic acids B (2) and C (3). During culture, 1 was gradually converted to 3, the corresponding 4-pyridone derivative. A study of the relationship between the culture pH and the fungal metabolites showed that a decrease from pH 6.5 to pH 2 is essential for production of 1, while a subsequent increase to pH 5 is necessary for production of 3. In addition, we revealed that 1 was non-enzymatically converted to 3 by the incorporation of an ammonium nitrogen atom in a pH 5 buffer, and that 1 was converted to 2 at a conversion ratio of 50% during incubation in MeOH for five days.
Asunto(s)
Ácidos Grasos Insaturados/química , Pironas/química , Cloruro de Amonio/química , Aspergillus/química , Aspergillus/metabolismo , Ácidos Grasos Insaturados/metabolismo , Concentración de Iones de Hidrógeno , Metanol/química , Pironas/metabolismoRESUMEN
A new prenylated indoxyl alkaloid, Amoenamide B (1), was isolated from Aspergillus amoenus NRRL 35600 along with Asperochramide A (2). Although many prenylated oxyindole alkaloids, containing bicyclo[2.2.2]diazaoctane cores, have been isolated from the fungus of the genera Aspergillus and Penicillium to date, 1 is the fourth compound with the indoxyl unit containing the cores. During the structure elucidation of 1, we found that the planar structure matched to that of Speramide A (3), isolated from A. ochraceus KM007, but the reported structure of 3 was incorrect and turned out to be that of Taichunamide H (4), recently isolated from A. versicolor HDN11-84.
RESUMEN
The total synthesis of siladenoserinolâ A, an inhibitor of the p53-Hdm2 interaction, has been achieved. AuCl3 -catalyzed hydroalkoxylation of an alkynoate derivative smoothly and regioselectively proceeded to afford a bicycloketal in excellent yield. A glycerophosphocholine moiety was successfully introduced through the Horner-Wadsworth-Emmons reaction using an originally developed phosphonoacetate derivative. Finally, removal of the acid-labile protecting groups, followed by regioselective sulfamate formation of the serinol moiety afforded the desired siladenoserinolâ A, and benzoyl and desulfamated analogues were also successfully synthesized. Biological evaluation showed that the sulfamate is essential for biological activity, and modification of the acyl group on the bicycloketal can improve the inhibitory activity against the p53-Hdm2 interaction.
Asunto(s)
Glicerilfosforilcolina/farmacología , Propanolaminas/farmacología , Glicoles de Propileno/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Catálisis , Relación Dosis-Respuesta a Droga , Glicerilfosforilcolina/síntesis química , Glicerilfosforilcolina/química , Compuestos de Oro/química , Humanos , Estructura Molecular , Propanolaminas/síntesis química , Propanolaminas/química , Glicoles de Propileno/síntesis química , Glicoles de Propileno/química , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The marine-derived Aspergillus protuberus MF297-2 and the terrestrial A. amoenus NRRL 35600 produce enantiomeric prenylated indole alkaloids. Investigation of biological activities of the natural and synthetic derivatives revealed that (-)-enantiomers of notoamides A and B, 6-epi-notoamide T, and stephacidin A inhibited receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclastogenic differentiation of murine RAW264 cells more strongly than their respective (+)-enantiomers. Among them, (-)-6-epi-notoamide T was the most potent inhibitor with an IC50 value of 1.7µM.
Asunto(s)
Alcaloides Indólicos/química , Ligando RANK/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Hongos/efectos de los fármacos , Alcaloides Indólicos/farmacología , Concentración 50 Inhibidora , Ratones , Osteoclastos/citología , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Células RAW 264.7 , EstereoisomerismoRESUMEN
Four new sesquiterpenes, lamellodysidines A and B, O,O-dimethyllingshuiolide A, and 11-epi-O,O-dimethyllingshuiolide A (1-4), were obtained from the marine sponge, Lamellodysidea herbacea, collected in Indonesia. Their planar structures were elucidated by analysis of spectroscopic data. The absolute configurations of the new compounds were determined by the calculated ECD spectra. Compound 1 has a unique carbon framework, and 2 is a new nitrogenous sesquiterpene.
Asunto(s)
Poríferos/química , Sesquiterpenos/aislamiento & purificación , Animales , Indonesia , Estructura Molecular , Sesquiterpenos/químicaRESUMEN
Three new furanosesterterpene tetronic acids, sulawesins A-C (1-3), were isolated from a Psammocinia sp. marine sponge, along with the known compounds ircinins-1 (4) and -2 (5). Although ircinins-1 and -2 were previously isolated as (+)- or (-)-enantiomers from marine sponges, we isolated them as enantiomeric mixtures. Sulawesins A and B possess a new carbon skeleton with a 5-(furan-3-yl)-4-hydroxycyclopent-2-enone moiety and were also found to be diastereomeric mixtures of four isomers by an HPLC analysis with a chiral-phase column. Sulawesin C has a dimeric structure of ircinin-1 and is the first dimer in this family. USP7, a deubiquitinating enzyme, is an emergent target of cancer therapy, and the isolated compounds inhibited USP7 with IC50 values in the range of 2.7-4.6 µM.
Asunto(s)
Furanos/aislamiento & purificación , Furanos/farmacología , Poríferos/química , Sesterterpenos/aislamiento & purificación , Sesterterpenos/farmacología , Terpenos/aislamiento & purificación , Terpenos/farmacología , Animales , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Furanos/química , Humanos , Indonesia , Concentración 50 Inhibidora , Biología Marina , Estructura Molecular , Sesquiterpenos , Sesterterpenos/química , Estereoisomerismo , Relación Estructura-Actividad , Terpenos/química , Ubiquitina Tiolesterasa , Peptidasa Específica de Ubiquitina 7RESUMEN
Six new spongian diterpene derivatives, ceylonins A-F (1-6), were isolated from the Indonesian marine sponge Spongia ceylonensis along with spongia-13(16),14-dien-19-oic acid (7). They contained three additional carbons in ring D to supply an ether-bridged bicyclic ring system. Their structures were elucidated by analyzing NMR spectroscopic data and calculated ECD spectra in comparison to experimental ECD spectra. The bicyclic ring system may be derived from the major metabolite 7 and a C3 unit (an acrylic acid equivalent) through an intermolecular Diels-Alder reaction, which was experimentally supported by the formation of 1-6 from 7 and acrylic acid. The inhibitory effects of the isolated compounds on the RANKL-induced formation of multinuclear osteoclasts in RAW264 macrophages were examined.
Asunto(s)
Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Osteoclastos/efectos de los fármacos , Poríferos/química , Ligando RANK/farmacología , Animales , Diterpenos/química , Indonesia , Espectroscopía de Resonancia Magnética , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Osteoclastos/química , Ligando RANK/químicaRESUMEN
A new prenylated alkaloid, Amoenamide A (6), was isolated from the fungus Aspergillus amoenus NRRL 35600. Previously, 6 was postulated to be a precursor of Notoamide E4 (21) converted from Notoamide E (16), which was a key precursor of the prenylated indole alkaloids in the fungi of the genus Aspergillus. We previously succeeded in the isolation of two pairs of antipodes, Stephacidin A (1) and Notoamide B (2), from A. amoenus and A. protuberus MF297-2 and expected the presence of other antipodes in the culture of A. amoenus. We here report five new antipodes (7-11) along with a new metabolite (12), which was isolated as a natural compound for the first time, from A. amoenus.