RESUMEN
An asymmetric formal synthesis of azadirachtin, a potent insect antifeedant, was accomplished in 30 steps to Ley's synthetic intermediate (longest linear sequence). The synthesis features: 1)â rapid access to the optically active right-hand segment starting from the known 5-hydroxymethyl-2-cyclopentenone scaffold; 2)â construction of the B and E rings by a key intramolecular tandem radical cyclization; 3)â formation of the hemiacetal moiety in the C ring through the α-oxidation of the six-membered lactone followed by methanolysis.
Asunto(s)
Limoninas/síntesis química , Limoninas/química , Conformación MolecularRESUMEN
Cell migration of tumor cells is essential for invasion of the extracellular matrix and for cell dissemination. Inhibition of the cell migration involved in the invasion process represents a potential therapeutic approach to the treatment of tumor metastasis; therefore, a novel series of derivatives of moverastins (moverastins A and B), an inhibitor of tumor cell migration, was designed and chemically synthesized. Among these moverastin derivatives, several compounds showed stronger cell migration inhibitory activity than parental moverastins, and UTKO1 was found to have the most potent inhibitory activity against the migration of human esophageal tumor EC17 cells in a chemotaxis cell chamber assay. Interestingly, although moverastins are considered to inhibit tumor cell migration by inhibiting farnesyltransferase (FTase), UTKO1 did not inhibit FTase, indicating that UTKO1 inhibited tumor cell migration by a mechanism other than the inhibition of FTase.
Asunto(s)
Benzaldehídos/síntesis química , Ciclohexanonas/síntesis química , Benzaldehídos/química , Benzaldehídos/farmacología , Movimiento Celular/efectos de los fármacos , Ciclohexanonas/química , Ciclohexanonas/farmacología , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Células Tumorales CultivadasRESUMEN
Basidifferquinones, isolated from Streptomyces sp., are potent inducers of fruiting-body formation in the basidiomycete, Polyporus arcularius. The first synthesis of (+/-)-basidifferquinone C was accomplished by starting from 3,5-dihydroxy-2-naphthoic acid.
Asunto(s)
Antraquinonas/síntesis química , Antraquinonas/farmacología , Cuerpos Fructíferos de los Hongos/efectos de los fármacos , Cuerpos Fructíferos de los Hongos/crecimiento & desarrollo , Polyporus/efectos de los fármacos , Polyporus/crecimiento & desarrollo , Quinonas/síntesis química , Quinonas/farmacología , Ácidos Carboxílicos/química , Naftalenos/químicaRESUMEN
Cancer cell migration is a required step in cancer metastasis. We screened for inhibitors of cancer cell migration of microbial origin, and obtained moverastin, a member of the cylindrol family, from Aspergillus sp. F7720. However, the results of an NMR spectroscopic analysis raised the possibility that moverastin is a mixture of two diastereomers. Separation of the C-10 epimers of synthetic moverastin and a bioassay revealed that both diastereomers (moverastins A and B) had inhibitory effects on cell migration. Furthermore, we demonstrated that moverastins A and B inhibited FTase in vitro, and they also inhibited both the membrane localization of H-Ras and the activation of the PI3K/Akt pathway in EC17 cells. Thus, moverastins inhibited the migration of tumor cells by inhibiting the farnesylation of H-Ras, and subsequent H-Ras-dependent activation of the PI3K/Akt pathway.
Asunto(s)
Antineoplásicos/farmacología , Aspergillus/química , Benzaldehídos/química , Benzaldehídos/farmacología , Movimiento Celular/efectos de los fármacos , Ciclohexanonas/química , Ciclohexanonas/farmacología , Neoplasias/tratamiento farmacológico , Transferasas Alquil y Aril/antagonistas & inhibidores , Línea Celular Tumoral , Membrana Celular/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Transducción de Señal/efectos de los fármacos , Estereoisomerismo , Proteínas ras/análisis , Proteínas ras/antagonistas & inhibidoresRESUMEN
In the biosynthesis of type B trichothecenes, four oxygenation steps remain to have genes functionally assigned to them. On the basis of the complete genome sequence of Fusarium graminearum, expression patterns of all oxygenase genes were investigated in Fusarium asiaticum (F. graminearum lineage 6). As a result, we identified five cytochrome P450 monooxygenase (CYP) genes that are specifically expressed under trichothecene-producing conditions and are unique to the toxin-producing strains. The entire coding regions of four of these genes were identified in F. asiaticum. When expressed in Saccharomyces cerevisiae, none of the oxygenases were able to transform trichodiene-11-one to expected products. However, one of the oxygenases catalyzed the 2beta-hydroxylation rather than the expected 2alpha-hydroxylation. Targeted disruption of the five CYP genes did not alter the trichothecene profiles of F. asiaticum. The results are discussed in relation to the presence of as-yet-unidentified oxygenation genes that are necessary for the biosynthesis of trichothecenes.
Asunto(s)
Proteínas Fúngicas/genética , Fusarium/enzimología , Genoma Fúngico , Oxigenasas/genética , Tricotecenos/biosíntesis , ADN de Hongos/análisis , ADN de Hongos/genética , Bases de Datos Genéticas , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Fusarium/clasificación , Fusarium/genética , Oxigenasas/metabolismo , Tricotecenos/química , Tricotecenos/metabolismoRESUMEN
Pironetin is a potent inhibitor of tubulin assembly and arrests cell cycle progression in M phase. Analyses of its structure-activity relationships suggested that pironetin covalently binds tubulin. To determine the binding site of pironetin, we synthesized biotinylated pironetin, which inhibited tubulin assembly both in vitro and in situ. The biotinylated pironetin selectively and covalently bound with tubulin. Partial digestion of biotinylated pironetin-treated tubulin by several proteases revealed that the binding site is the C-terminal portion of alpha-tubulin. By systematic alanine scanning, the pironetin binding site was determined to be Lys352 of alpha-tubulin. Lys352 is located at the entrance of a small pocket of alpha-tubulin, and this pocket faces the beta-tubulin of the next dimer. This is the first compound that covalently binds to the alpha subunit of tubulin and Lys352 of alpha-tubulin and inhibits the interaction of tubulin heterodimers.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Lisina/química , Pironas/química , Pironas/farmacología , Moduladores de Tubulina , Secuencia de Aminoácidos , Animales , Antineoplásicos/síntesis química , Sitios de Unión/efectos de los fármacos , Línea Celular , Pollos , Modelos Biológicos , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Estructura Terciaria de Proteína , Pironas/síntesis química , Ratas , Relación Estructura-Actividad , Tubulina (Proteína)/químicaRESUMEN
The aroma of spotted shrimp (Sergia lucence Hansen) was analyzed upon roasting to determine the components that constitute the characteristic roasted shrimp flavor. Our analyses resulted in the identification of ca. 200 volatiles, including high-impact sulfur and nitrogen compounds. In addition, we synthesized all possible stereoisomers of the pyrrolidine derivatives 1 and 4, and of the imine derivatives 16 and 18-20, which are very characteristic for the aroma. The odor evaluation of these chemicals revealed distinct differences, each possessing different aroma characteristics.
Asunto(s)
Decápodos , Calor , Odorantes/análisis , Animales , Culinaria/métodos , Estereoisomerismo , VolatilizaciónRESUMEN
The removal of intervening sequences from transcripts is catalyzed by the spliceosome, a multicomponent complex that assembles on the newly synthesized pre-mRNA. Pre-mRNA translation in the cytoplasm leads to the generation of aberrant proteins that are potentially harmful. Therefore, tight control to prevent undesired pre-mRNA export from the nucleus and its subsequent translation is an essential requirement for reliable gene expression. Here, we show that the natural product FR901464 (1) and its methylated derivative, spliceostatin A (2), inhibit in vitro splicing and promote pre-mRNA accumulation by binding to SF3b, a subcomplex of the U2 small nuclear ribonucleoprotein in the spliceosome. Importantly, treatment of cells with these compounds resulted in leakage of pre-mRNA to the cytoplasm, where it was translated. Knockdown of SF3b by small interfering RNA induced phenotypes similar to those seen with spliceostatin A treatment. Thus, the inhibition of pre-mRNA splicing during early steps involving SF3b allows unspliced mRNA leakage and translation.
Asunto(s)
Transporte Activo de Núcleo Celular/efectos de los fármacos , Antineoplásicos/farmacología , Fosfoproteínas/antagonistas & inhibidores , Precursores del ARN/efectos de los fármacos , Empalme del ARN/efectos de los fármacos , Ribonucleoproteína Nuclear Pequeña U2/antagonistas & inhibidores , Línea Celular Tumoral , Humanos , Fosfoproteínas/genética , Piranos/farmacología , Precursores del ARN/metabolismo , Factores de Empalme de ARN , ARN Interferente Pequeño/farmacología , Proteínas de Unión al ARN , Ribonucleoproteína Nuclear Pequeña U2/genética , Compuestos de Espiro/farmacologíaRESUMEN
Sauriols A and B belong to a class of diarylbutane-lignans and exhibit antifeedant activity. We succeeded in the first synthesis of sauriols A and B by using a simple and efficient asymmetric dimerization of a cinnamic acid derivative as the key step.
Asunto(s)
Cinamatos/química , Lignanos/síntesis química , Dimerización , EstereoisomerismoRESUMEN
Gerfelin, an inhibitor of human geranylgeranyl diphosphate (GGPP) synthase that has been isolated from a culture broth of Beauveria felina QN22047, was synthesized in 4 and 3 steps starting from 2,4-dihydroxy-6-methylbenzoic acid and 3,4,5-trihydroxytoluene, respectively. An effective ligand, 2-(di-tert-butylphosphino)biphenyl, was used in the palladium-catalyzed diaryl ether-forming reaction. Five analogous compounds of gerfelin were also synthesized for a study of the structure-activity relationship.
Asunto(s)
Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Éteres/síntesis química , Éteres/farmacología , Farnesiltransferasa/antagonistas & inhibidores , Compuestos de Bifenilo/química , Catecoles , Éteres/química , Métodos , Ácido Salicílico , Relación Estructura-ActividadRESUMEN
The crystalline structure of N-(S)-2-heptyl (1R,2R)-2-(2,3-anthracenedicarboximido)cyclohexamide (1), which was crystallized from methanol, was determined by an X-ray analysis and had a different conformation from its preferred one in CD3OD by a 1H-NMR analysis. Inter- and intra-molecular CH-pi interaction in a crystal plays a very important role in crystal packing. The preferred conformation of the amide derivative in a solution allows us to exploit (1R,2R)-2-(2,3-anthracenedicarboximido)cyclohexanecarbonyl chloride as a conversion reagent to determine the absolute configuration of chiral amines by 1H-NMR.
Asunto(s)
Amidas/química , Antracenos/química , Cromatografía Líquida de Alta Presión/métodos , Cristalografía por Rayos X , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Soluciones , EstereoisomerismoRESUMEN
We synthesized new chiral fluorescence labeling reagents having a 2,3-anthracenedicarboximide group from D-glucosamine, and it was possible to introduce target alcohols at the anomeric positions of the reagents with beta-selectivity by glycosidations. Especially, it was possible to use methyl glycoside reagent as a glycosyl donor with a Lewis acid and microwave irradiation, and it gave selectively beta-glycoside while the reaction without microwave irradiation gave alpha- and beta-mixed glycosides. Those reagents showed very high chiral discrimination ability, and they made it possible to separate the eight stereoisomers of 4,8,12,16-tetramethylheptadecanol by HPLC after derivatizations.
Asunto(s)
Colorantes Fluorescentes/química , Glucosamina/química , Glicósidos/química , Conformación de Carbohidratos , Colorantes Fluorescentes/síntesis química , Ácidos Heptanoicos/química , Microondas , Modelos Químicos , EstereoisomerismoRESUMEN
The glucosidic precursor of marmelo lactones was synthesized by employing a common intermediate which had been used for the synthesis of the glucosidic precursor of marmelo oxides. The synthesis was performed by modifying the former procedure. Monochloroacetyl was adopted to protect both the glucose and aglycon hydroxyl groups for selective transesterification in the presence of the glycosyl ester. Glycosylation of the aglycon carboxyl group with 1-alpha-bromopermonochloroacetylglucose and final selective alcoholysis yielded the target glucoside.
Asunto(s)
Glicósidos/biosíntesis , Lactonas/química , Lactonas/metabolismo , Rosaceae/metabolismo , Glicosilación , Isomerismo , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura MolecularRESUMEN
Chenodiol is an important bile acid widely used for gallstone dissolution and cholestatic liver diseases. We succeeded in a short-step synthesis of chenodiol, starting from the safer phytosterol, stigmasterol.
Asunto(s)
Ácido Quenodesoxicólico/síntesis química , Indicadores y Reactivos , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Fitosteroles/química , Estigmasterol/químicaRESUMEN
A new method called "Aqua-space" was developed for the isolation of the natural fragrances of plants. Living flowers were enclosed in a space under simulated natural conditions, and humidified air was pumped into the space as a fragrance carrier. In a comparison among three isolation methods, i.e., Aqua-space, headspace, and solvent extraction, the Aqua-space method proved to be the most effective in retaining natural fragrances with abundant oxygenated components key to floral fragrances.
Asunto(s)
Aire/análisis , Gardenia/química , Odorantes/análisis , Cromatografía de Gases , Flores/química , Humedad , Hidrocarburos/análisis , SolventesRESUMEN
Among higher plants graminaceous species have the unique ability to efficiently acquire iron from alkaline soils with low iron solubility by secreting phytosiderophores, which are hexadentate metal chelators with high affinity for Fe(III). Iron(III)-phytosiderophores are subsequently taken up by roots via YS1 transporters, that belong to the OPT oligopeptide transporter family. Despite its physiological importance at alkaline pH, uptake of Fe-phytosiderophores into roots of wild-type maize plants was greater at acidic pH and sensitive to the proton uncoupler CCCP. To access the mechanism of Fe-phytosiderophore acquisition, ZmYS1 was expressed in an iron uptake-defective yeast mutant and in Xenopus oocytes, where ZmYS1-dependent Fe-phytosiderophore transport was stimulated at acidic pH and sensitive to CCCP. Electrophysiological analysis in oocytes demonstrated that Fephytosiderophore transport depends on proton cotransport and on the membrane potential, which allows ZmYS1-mediated transport even at alkaline pH. We further investigated substrate specificity and observed that ZmYS1 complemented the growth defect of the zinc uptake-defective yeast mutant zap1 and transported various phytosiderophore-bound metals into oocytes, including zinc, copper, nickel, and, at a lower rate, also manganese and cadmium. Unexpectedly, ZmYS1 also transported Ni(II), Fe(II), and Fe(III) complexes with nicotianamine, a structural analog of phytosiderophores, which has been shown to act as an intracellular metal chelator in all higher plants. Our results show that ZmYS1 encodes a proton-coupled broad-range metal-phytosiderophore transporter that additionally transports Fe- and Ni-nicotianamine. These biochemical properties indicate a novel role of YS1 transporters for heavy metal homeostasis in plants.
Asunto(s)
Ácido Azetidinocarboxílico/análogos & derivados , Proteínas Portadoras/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Transporte de Membrana , Metales/metabolismo , Proteínas de Plantas/metabolismo , Simportadores/metabolismo , Zea mays/metabolismo , Animales , Ácido Azetidinocarboxílico/metabolismo , Ferritinas/metabolismo , Transporte Iónico , Xenopus laevisRESUMEN
The main biodegradation product of (+/-)-alpha-isomethylionone (2) with standard activated sludge was characterized as (+/-)-1-(2,6,6-trimethyl-2-cyclohexen-1-yl)propan-2-one (1) by its analysis and synthesis. Both enantiomers (1a and 1b) of 1 were synthesized by starting from (R)- and (S)-2,4,4-trimethyl-2-cyclohexen-1-ol (3a and 3b), respectively.