RESUMEN
Two new compounds, cinnamic aldehyde cyclic d-galactitol 3'R,4'S-acetal (1) and cinnamomumolide (2), along with six known compounds, syringaresinol (3), lyoniresinol (4), 5,7,3'-trimethoxyl-( - )-epicatechin (5), 5,7-dimethoxyl-3',4'-di-O-methylene-( +/- )-epicatechin (6), 2-methoxyl-4-hydroxy cinnamyl aldehyde (7), and glucosyringic acid (8), have been isolated from the dried tender stems of Cinnamomum cassia. Their structures were elucidated based on spectroscopic data. Compound 2 was elucidated as 8-methoxyl-9-hydroxy-3',4'-methylenedioxy-3S,4R-diphenyl butyrolactone, named cinnamomumolide, which exhibited activity in protecting against the injury caused by hydrogen peroxide oxidation on human umbilical vein endothelial cells, with an EC(50) value of 10.7 microM. Compounds 3-8 were isolated from the title plant for the first time.
Asunto(s)
4-Butirolactona/análogos & derivados , Cinamatos/aislamiento & purificación , Cinnamomum aromaticum/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Galactitol/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/aislamiento & purificación , 4-Butirolactona/farmacología , Anisoles/aislamiento & purificación , Cinamatos/química , Cinamatos/farmacología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Células Endoteliales/efectos de los fármacos , Furanos/aislamiento & purificación , Galactitol/química , Galactitol/aislamiento & purificación , Galactitol/farmacología , Humanos , Peróxido de Hidrógeno/farmacología , Lignanos/aislamiento & purificación , Estructura Molecular , Naftalenos/aislamiento & purificación , Oxidación-Reducción , Tallos de la Planta/química , Cordón Umbilical/citología , Cordón Umbilical/efectos de los fármacos , Heridas y Lesiones/inducido químicamenteRESUMEN
A new class of galactooligosaccharides has been identified from the terrestrial cyanobacterium Nostoc commune by MS and NMR techniques. These consist of beta-D-galactofuranosyl-(1-->6)-[beta-D-galactofuranosyl-(1-->6)]n-beta-d-1,4-anhydrogalactitols with n ranging from 2 to 8, corresponding to compounds designated 1 through 7. In total these saccharides amounted to approximately 0.35% of the dry thallus of N. commune, while in several other cyanobacteria they were not detected. Possibly they play some role in protection from damage by heat and desiccation as suggested by experiments with heterologous systems. For example, phosphoglucomutase (EC 2.7.5.1) from rabbit muscle was protected against heat inactivation by these oligosaccharides, and alpha-amylase (EC 3.2.1.1) from porcine pancreas by the oligosaccharides 6 and 7. The homologues of lower molecular mass, however, enhanced heat sensitivity of alpha-amylase. The viability of Escherichia coli was completely abolished by desiccation, whereas in the presence of 4 survival rates were approximately 50% of controls not subjected to desiccation. The newly identified saccharides are compared with known galactofuranose-based oligo- and polysaccharides and possible biological functions of them are discussed.
Asunto(s)
Furanos/química , Galactitol/análogos & derivados , Galactosa/análogos & derivados , Nostoc commune/química , Oligosacáridos/análisis , Oligosacáridos/farmacología , Animales , Secuencia de Carbohidratos , Cromatografía por Intercambio Iónico , Cromatografía en Capa Delgada , Desecación , Escherichia coli/citología , Escherichia coli/efectos de los fármacos , Furanos/análisis , Galactitol/análisis , Galactitol/química , Galactosa/análisis , Galactosa/química , Calor , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Oligosacáridos/química , Fosfoglucomutasa/metabolismo , Conejos , Sacarosa/farmacología , Temperatura , Trehalosa/farmacología , alfa-Amilasas/metabolismoRESUMEN
The synthesis of 1-C-substituted 1,4-dideoxy-1,4-imino-D-galactitols involving nitrone umpolung is described. The SmI(2)-induced key coupling proved highly stereoselective in favor of the beta-C-substituted products bearing a three-carbon chain at the pseudoanomeric position. Pyrrolidines 9 and 10, as well as the bicyclic compounds 8 and 11, exhibit weak inhibition of the activity of the UDP-galactopyranose mutase from Escherichia coli.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Galactitol/análogos & derivados , Galactitol/farmacología , Transferasas Intramoleculares/antagonistas & inhibidores , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacología , Inhibidores Enzimáticos/síntesis química , Escherichia coli/enzimología , Galactitol/síntesis química , Pirrolidinas/química , Pirrolidinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
[reaction: see text] Various alpha-C-substituted 1,4-dideoxy-1,4-imino-d-galactitols were prepared efficiently from 1-O-acetyl-2,3,5,6-tetra-O-benzyl-d-glucofuranose by a four-step sequence involving as the key step the highly syn-selective TMSOTf-catalyzed addition of silylated nucleophiles to a glycofuranosylamine. Cross-metathesis of the alpha-C-allylated iminogalactofuranose derivative with an original uridin-5'-yl vinylphosphonate led to novel UDP-galactofuranose mimics. Such compounds are of interest as potential inhibitors of the mycobacterial galactan biosynthesis pathway.
Asunto(s)
Galactitol , Uridina Difosfato Galactosa/química , Ciclización , Galactitol/análogos & derivados , Galactitol/síntesis química , Galactitol/química , Imitación Molecular , Estructura Molecular , EstereoisomerismoRESUMEN
2,3,4,5-Tetra-O-methyl-D-mannaric and galactaric acids and their bis(pentachlorophenyl) esters have been prepared as crystalline compounds, in good yields, from D-mannitol and galactitol, respectively. A new stereoregular polyamide, analogous to Nylon 66, has been prepared by polycondensation of bis(pentachlorophenyl) 2,3,4,5-tetra-O-methyl-D-mannarate with 1,6-diamino-1,6-dideoxy-2,3,4,5-tetra-O-methyl-D-mannitol dihydrochloride. The polymer has a M(w) of 31,100 with a polydispersity of 1.5 (GPC). It was highly hygroscopic and soluble in ethanol, acetone, dimethyl sulfoxide, N,N-dimethylformamide and chloroform, but only slightly soluble in water.
Asunto(s)
Galactitol/síntesis química , Manitol/síntesis química , Nylons/síntesis química , Conformación de Carbohidratos , Carbohidratos/síntesis química , Carbohidratos/química , Galactitol/análogos & derivados , Manitol/análogos & derivados , Modelos Químicos , Nylons/química , EstereoisomerismoRESUMEN
The disialylated poly-(N-acetyllactosamine)-containing O-linked oligosaccharide alditols, released by alkaline borohydride treatment of the enzymically N-deglycosylated beta-subunit of equine chorionic gonadotropin, were purified by fast protein liquid chromatography (FPLC) on Mono Q and analysed by fast ion bombardment mass spectrometry (FAB-MS) and 1H-NMR spectroscopy. The identified oligosaccharide alditols have the following structure: [Formula: see text]
Asunto(s)
Gonadotropina Coriónica/química , Glicoproteínas/química , Oligosacáridos/química , Amino Azúcares/química , Animales , Secuencia de Carbohidratos , Galactitol/análogos & derivados , Caballos , Datos de Secuencia Molecular , Análisis de Secuencia , Ácidos Siálicos/química , Espectrometría de Masa Bombardeada por Átomos VelocesRESUMEN
The synthesis of 2-acetamido-1,4-imino-1,2,4-trideoxy-D-galactitol (1; 2-acetamido-4-amino-1,4-anhydro-2,4-dideoxy-D-galactitol) by two different routes starting from 2-acetamido-2-deoxy-D-glucose is described. Compound 1 is a competitive inhibitor of human lysosomal beta-hexosaminidase A with K(i) values of 18 microM (beta-subunit) and 220 microM (alpha-subunit). Similar properties were found for the already known 2-acetamido-2-deoxy-D-gluco-hydroximo-1,4-lactone.
Asunto(s)
Galactitol/análogos & derivados , Lisosomas/enzimología , beta-N-Acetilhexosaminidasas/antagonistas & inhibidores , Unión Competitiva , Galactitol/síntesis química , Humanos , Iminopiranosas , Modelos Moleculares , Estructura MolecularRESUMEN
Described herein is an efficient method for the synthesis of the eight positional isomers of methylated and acetylated or benzoylated 1,5-anhydro-D-fucitol. The compounds are generated simultaneously by partial methylation of 1,5-anhydro-D-fucitol and subsequent benzoylation, and the individual isomers are obtained in pure form by high-performance liquid chromatography. Debenzoylation of the latter and acetylation yielded the desired acetates. Reported herein are the 1H NMR spectra of the benzoates and the electron-ionization mass spectra of the acetates and the tri-O-methyl derivative. Also reported for the acetates and the tri-O-methyl derivative are their linear temperature programmed gas-liquid chromatography retention indices on three different capillary columns.
Asunto(s)
Química Orgánica/normas , Galactitol/análogos & derivados , Acetatos/química , Acetilación , Benzoatos/química , Ácido Benzoico , Cromatografía Líquida de Alta Presión , Galactitol/química , Isomerismo , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Metilación , Oxidación-ReducciónRESUMEN
The distribution of dianhydrogalactitol-C14 (DAG-C14) which had been administered to rats as an iv bolus injection was studied in plasma and brain tissue. Analysis of samples was carried out by a high-pressure liquid chromatography method which specifically responds to the parent drug. Samples were monitored by both ultraviolet and liquid scintillation spectrometry. Plasma level measurements indicate that intact DAG has a relatively short half-life in plasma (t1/2= 43.7 minutes) and brain (t1/2 = 50.3 minutes). These findings differ significantly from those studies which have measured total radioactivity when monitoring DAG levels; and should be considered in the design of DAG dose regiments. Data from both brain and plasma were consistent with a classic two-compartment open model.
Asunto(s)
Encéfalo/metabolismo , Galactitol/metabolismo , Alcoholes del Azúcar/metabolismo , Animales , Galactitol/análogos & derivados , Galactitol/sangre , Masculino , Ratas , Factores de TiempoAsunto(s)
Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Evaluación de Medicamentos , Compuestos Epoxi/efectos adversos , Compuestos Epoxi/uso terapéutico , Galactitol/efectos adversos , Galactitol/análogos & derivados , Galactitol/uso terapéutico , Humanos , Mitolactol/efectos adversos , Mitolactol/uso terapéutico , Tegafur/efectos adversos , Tegafur/uso terapéutico , Alcaloides de la Vinca/efectos adversos , Alcaloides de la Vinca/uso terapéuticoAsunto(s)
Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Galactitol/análogos & derivados , Neoplasias Pulmonares/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Alcoholes del Azúcar/análogos & derivados , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adulto , Anciano , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/mortalidad , Evaluación de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Galactitol/uso terapéutico , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana EdadRESUMEN
The distribution of iv administered 3H-dianhydrogalactitol (DAG) in the plasma, cerebrospinal fluid (CSF), brain, and tumor tissue was studied in 11 patients. DAG entered the CSF and was slowly eliminated, with a half-life of 20 hours. Unchanged DAG accounted for about 6%-30% of the total radioactivity in the CSF. All the tumors accumulated the drug to a higher extent than the intact white matter, except the one meningioma studied. The highest uptake was observed in the relatively benign astrocytic tumors.
Asunto(s)
Galactitol/metabolismo , Glioma/metabolismo , Tejido Nervioso/metabolismo , Alcoholes del Azúcar/metabolismo , Adulto , Encéfalo/metabolismo , Éteres Cíclicos/líquido cefalorraquídeo , Éteres Cíclicos/metabolismo , Galactitol/análogos & derivados , Galactitol/líquido cefalorraquídeo , Semivida , Humanos , Persona de Mediana Edad , Factores de TiempoRESUMEN
A high-performance liquid chromatographic method is described for measuring submicrogram quantities of dianhydrogalactitol, a promising anti-neoplastic agent, in plasma. The drug is derivatized directly in plasma with sodium diethyldithiocarbamate to form a bis(dithiocarbamoyl) ester which absorbs UV light at 254 nm (am 17,000). The derivatized product is then extracted quantitatively into chloroform and separated by normal phase chromatography (muBondpak CN column). Dianhydrogalactitol concentration below 50 ng/ml of plasma can be detected in the eluent.
Asunto(s)
Galactitol/sangre , Alcoholes del Azúcar/sangre , Fenómenos Químicos , Química , Cromatografía Líquida de Alta Presión/métodos , Ditiocarba , Éteres Cíclicos/sangre , Galactitol/análogos & derivados , Humanos , Espectrofotometría UltravioletaRESUMEN
alpha, omega-Disubstituted derivatives of 2,3-anhydro-DL-threitol (2), 2,3-anhydroerythritol (4), 2,3:4,5-dianhydrogalactitol (8), and 2,3:4,5-dianhydroallitol (12) have been synthesised by epoxidation of the appropriate alkeness and dienes. Benzyloxy carbonyl groups were used for protecting the primary hydroxyl groups during epoxidation.
Asunto(s)
Alquilantes , Eritritol/análogos & derivados , Galactitol/análogos & derivados , Alcoholes del Azúcar , Alcoholes del Azúcar/análogos & derivados , Alquilantes/síntesis química , Eritritol/síntesis química , Éteres Cíclicos/síntesis química , Galactitol/síntesis química , Espectroscopía de Resonancia Magnética , Métodos , Relación Estructura-Actividad , Alcoholes del Azúcar/síntesis químicaRESUMEN
Drug sensitivity of a heteroploid tumour cell line and three clones isolated from it was studied in tissue culture. Cells of the parent line P0, and of clone P1 were fibroblast-like and pseudo- and hypodiploid. Cones P3 and P4 consisted mostly of epithelial and round cells, respectively, and were hypotetraploid. In dose-response experiments, P1 and P4 clones were more sensitive to dianhydrodulcitol than tp0 or P3 clones. Adriamycin was more toxic to P3 than to the other three cell lines. P3 and P4 clones were more sensitive to vincristine than P0 or P1 clones. N-formyl-leurosine, a new derivative of the Vinca alkaloids, was least toxic to P4 cells, and the other three cell lines were equally sensitive. It was concluded that relative sensitivity of the clones depended on the particular drug. Presence of clones of lower sensitivity in heteroploid cell populations may have some bearing on regrowth of tumours after chemotherapy.
Asunto(s)
Cromosomas/efectos de los fármacos , Células Clonales/efectos de los fármacos , Neoplasias Experimentales , Ploidias/efectos de los fármacos , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Doxorrubicina/farmacología , Galactitol/análogos & derivados , Galactitol/farmacología , Ratones , Alcaloides de la Vinca/farmacología , Vincristina/farmacologíaRESUMEN
The pharmacokinetics of dianhydrogalactitol (DAG), NSC-132313, were studied in the beagle dog at doses of 3 mg - kg-1 and 6 mg - kg-1. DAG concentrations in plasma were determined by a gas chromatographic method capable of specifically detecting the parent drug and differentiating between it and products of its degradation or metabolism. Plasma disappearance time curves were generated and shown to follow simple two-compartment model behavior after iv administration of DAG. Distribution and elimination of DAG appeared to be dose-independent in the limited dose range studied. After iv administration, the drug was rapidly distributed throughout extracellular fluids (volume of the central compartment = 462 ml - kg-1) and subsequently was rapidly cleared (total body clearance = 23.4 ml - min-1 - kg-1) and eliminated (t1/2, b = 26.2 min) from the animal. Experiments (in vitro) with the use of radiolabeled DAG indicated that the drug binds reversibly and irreversibly to red blood cells.
Asunto(s)
Antineoplásicos/metabolismo , Galactitol/metabolismo , Alcoholes del Azúcar/metabolismo , Animales , Antineoplásicos/administración & dosificación , Cromatografía de Gases , Perros , Eritrocitos/metabolismo , Éteres Cíclicos/administración & dosificación , Éteres Cíclicos/metabolismo , Femenino , Galactitol/administración & dosificación , Galactitol/análogos & derivados , Masculino , Tasa de Depuración MetabólicaRESUMEN
The survival and cell kinetics effect of 1,2:5,6-dianhydrogalactitol, NSC-132313 (galactitol), were studied on mammalian cells. Nondividing or plateau-phase cells were almost two times more sensitive to galactitol than were cells treated in the dividing state (dose required to reduce survival by 63% on the exponential part of the survival curve (DO)=4.2 mug/ml/hr for dividing cells vs. DO=2.4 mug/ml/hr in nondividing cells). The survival curves were characterized as having shoulder regions, followed by exponential decreases in survival as the drug doses were increased above 12 mug/ml for 1 hour. Synchronized mitotic and G1 phase cells were equally sensitive to galacitol, with approximately 90% of the cells killed by 1-hour exposures to 12.5 mug galactitol/ml. Cells in early S phase were the least sensitive to this drug dose (survival greater than 20%); however, the cells became more sensitive as they progressed through the S phase and into the G2 phase. There were no large differences observed in survival sensitivities anywhere in the cell cycle, suggesting that galactitol was not a cell-cycle phase-specific agent. Cells in mitosis or G1 phases of the cell cycle at the time of treatment with galacitol progressed normally into the next stage of the cell cycle; however, cells exposed to galactitol in S or G2 phases exhibited dose-dependent delays in those phases of the cell cycle. Nondividing cells exposed to high doses of galactitol could not recover from potentially lethal damage (PLD); however, nondividing cells exposed to lower galactitol doses (lethal dose to 10% of the cells) did exhibit slight recovery from PLD. Dividing cells did not recover from PLD at any of the doses tested. Both dividing and nondividing cells were more sensitive (cell kill) to galactitol when it was administered in two dose fractions 4-8 hours apart than when the same total integral dose was given as a single exposure. A 25-50% greater cell kill was achieved in nondividing cell populations given two dose fractions versus a single exposure to galactitol. Up to 60% greater cell kill was obtained with fractionalated doses in dividing cell populations. These responses to fractionated dose treatments were also dose-dependent.