Phosphorylation of 5'-deoxy-5-fluorouridine with inorganic phosphorylating agents.

The phosphorylation of 5'-deoxy-5-fluorouridine (doxifluridine, 5'-DFUR) has been achieved using inorganic cyclo-triphosphate (P(3m), Na(3)P(3)O(9)) and monoimido-cyclo-triphosphate (MCTP, Na(3)P(3)O(8)NH) in aqueous solution. In the reaction of 5'-DFUR with P(3m), 2'-monophospho-5'-DFUR and 3'-monophospho-5'-DFUR were synthesized with a total yield of more than 95%. In the reaction of 5'-DFUR with MCTP, 2'-diphosphoramidophosphono-5'-DFUR and 3'-diphosphoramidophosphono-5'-DFUR were synthesized with a total yield of more than 40%. The phosphorylated products with P(3m) and MCTP were stable in neutral and alkaline solutions.

Encapsulation of nucleotides and DNA into Mg-Al layered double hydroxide.

The encapsulation of mononucleotides and DNA into Mg-Al layered double hydroxide (LDH, also known as hydrotalcite) by intercalation reaction, and release profile of mononucleotides and DNA was examined. Screening of the intercalation conditions (mononucleotide concentration, reaction temperature, reaction time, and pH) was carried out in order to determine precisely the optimal conditions. Intercalation of all examined mononucleotides and DNA into the chloride form of LDH was found to be possible using the ion-exchange method. The amount of mononucleotide taken up was 0.6-1.5 mmol per 1 g LDH. Intercalation compounds were examined using XRD and solid-state NMR. The interlayer distance of 5'-mononucleotide-intercalated LDH was found to be 14.0-15.3A, while that of 3'-mononucleotide-intercalated LDH was 17.4-17.7A. Intercalation of double-helix DNA of less than 500 base pairs was verified, with an uptake of 1.8 mmol per 1 g LDH (based on mononucleotide units). The intercalation mechanism and release profile in aqueous K(2)CO(3) solution were also investigated. Complete release of the nucleotides was found to take place. The encapsulation makes possible to protect mononucleotides and DNA, and promise the carrier of them to gene.

Complete protection of sodium valproate from humidity by using a hydrotalcite composite.

Complete protection of sodium valproate from humidity was successfully accomplished by intercalation into a hydrotalcite-like compound. The obtained hybrid of sodium valproate and the hydrotalcite-like compound was stable and not at all hygroscopic. Even under a relative humidity of 97%, the adsorbed amount of water was less than 0.5%.

Phosphorylation of nucleosides and nucleotides with inorganic monoimido-cyclo-triphosphate.

The phosphorylation of nucleosides (adenosine, guanosine, cytidine, and uridine) and nucleotides (adenosine 5'-monophosphate, guanosine 5'-monophosphate, cytidine 5'-monophosphate and uridine 5'-monophosphate) has been achieved using inorganic monoimido-cyclo-triphosphate (MCTP, Na(3)P(3)O(8)NH) in aqueous solution. In this reaction, the 2'-OH or 3'-OH group of the beta-D-ribofuranose unit was phosphorylated and the total yield was more than 30% and 14%, respectively. The main products were 2'-diphosphoramidophosphononucleoside and 2'-diphosphoramidophosphononucleoside 5'-monophosphate.

Physicochemical characterization of tamoxifen citrate pseudopolymorphs, methanolate and ethanolate.

Two novel pseudopolymorphs, methanolate and ethanolate of tamoxifen [(Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine]citrate, were prepared in addition to forms A and B reported previously. Their crystalline forms were identified and characterized by powder and single crystal X-ray diffractometry, differential scanning calorimetry, thermogravimetric analysis, hot-stage microscopy, scanning electron microscopy and diffuse reflectance infrared Fourier-transform spectroscopy, and their physicochemical stability was also evaluated. The results of single crystal X-ray analysis and thermogravimetric analysis of methanolate and ethanolate suggested that the stoichiometry of tamoxifen citrate : methanol and tamoxifen citrate : ethanol could be composed of a 1 : 1 molecular ratio for both solvates. The results of physicochemical stability evaluations at 75 and 97% RH at 40 and 60 degrees C indicated that the metastable form A was quite stable for at least 2 months even under severe storage conditions, whereas methanolate immediately transformed to a crystalline mixture of forms A and B, and subsequently changed to the stable form B.

Effect of spectroscopic properties on photostability of tamoxifen citrate polymorphs.

The photostability of tamoxifen citrate polymorphs, forms A and B, was investigated by chromatographic and spectroscopic analyses including high-pressure liquid chromatography (HPLC), colorimetry and UV/vis solid-state absorption spectroscopy. On the basis of the results of photostability studies under irradiation by visible light and both UVA (320-400 nm) and a fraction of UVB (290-320 nm) light, form A was chemically unstable, whereas form B was stable against light irradiation. The surface color of pellets prepared with any of these crystal forms turned from white to brown; however, the extent of color change in cross-sections of form A pellet was deeper than that of form B pellet. The maximum peak of UV/vis solid-state absorption spectra of form A was observed at 337 nm within the UVA range and was in longer wavelength regions than form B, which exhibited the strong UV absorption mainly in UVB and UVC region. The results obtained suggested that the photodegradation followed by surface color change of form A crystal was caused by the selective absorption of photoenergy of UVA light irradiated by a xenon lamp.

Phosphorylation of D-glucose derivatives with inorganic monoimido-cyclo-triphosphate.

Phosphorylation of several D-glucose derivatives has been achieved using inorganic monoimido-cyclo-triphosphate (MCTP, Na(3)P(3)O(8)NH) in aqueous solution. In the phosphorylation of D-glucose, D-glucuronic acid, 2-deoxy-D-glucose and D-galactose, 1-O-diphosphoramidophosphono-beta-D-glucose, 1-O-diphosphoramidophosphono-beta-D-glucuronic acid, 1-O-diphosphoramidophosphono-2-deoxy-beta-D-glucose, and 1-O-diphosphoramidophosphono-beta-D-galactose were stereoselectively synthesized with yields of 54, 32, 37 and 46%, respectively. In the case of methyl alpha-D-glucoside, the phosphorylated products were methyl 3-O-diphosphoramidophosphono-alpha-D-glucoside and methyl 4-O-diphosphoramidophosphono-alpha-D-glucoside, and in the case of methyl beta-D-glucoside the products were methyl 2-O-diphosphoramidophosphono-beta-D-glucoside, methyl 3-O-diphosphoramidophosphono-beta-D-glucoside, and methyl 4-O-diphosphoramidophosphono-beta-D-glucoside. For D-mannose and D-allose, several phosphorylated products were obtained and the main products were 1-O-diphosphoramidophosphono-beta-D-aldoses.

Regioselective phosphorylation of branched cyclodextrins with cyclo-mono-mu-imidotriphosphate.

The phosphorylation of the branched cyclodextrins, mono-6-O-(alpha-D-glucopyranosyl)cyclomaltohexaose, mono-6-O-(alpha-D-maltosyl)cyclomaltohexaose, mono-6-O-(alpha-D-glucopyranosyl)cyclomaltoheptaose, and mono-6-O-(alpha-D-maltosyl)cyclomaltoheptaose, in aqueous solution by sodium cyclo-mono-mu-imidotriphosphate (cMITP) was examined. In these reactions, only the 2-OH group of a single alpha-D-glucopyranosyl residue of the cyclodextrin ring was phosphorylated, in a maximum yield of 67%. A possible mechanism for the phosphorylation is discussed.

Intercalation of gaseous thiols and sulfides into Ag+ ion-exchanged aluminum dihydrogen triphosphate.

Ag(+) ion-exchanged layered aluminum dihydrogen triphosphate (AlP) with the interlayer distance of 0.85 nm was synthesized by the ion-exchange of proton in triphosphate with Ag(+) ion. The amount of exchanged Ag(+) ion depended on the concentration of AgNO(3) aqueous solution. Ag(+) ion-exchanged AlP adsorbed gaseous thiols and sulfides into the interlayer region. The adsorption amounts of thiols were more than those of sulfides, thiols with one mercapto group > thiol with two mercapto groups > sulfides, and depended on the amount of exchanged Ag(+) ion in the interlayer region. The thiols with one mercapto group were intercalated to expand the interlayer distance of Ag(+) ion-exchanged AlP, whereas there was no expansion in the adsorption of sulfide. In the case of thiol with two mercapto groups, there was observed contraction of the interlayer distance through the bridging with Ag(+) ions of the upper and lower sides of the interlayer region.

Intercalation of amino acids and peptides into Mg-Al layered double hydroxide by reconstruction method.

The intercalation of amino acids and some peptides into Mg-Al layered double hydroxide known as hydrotalcite was examined. Although the intercalation by ion-exchange method was unsuccessful, all the amino acids except for Lys and Arg, and peptides examined could be intercalated into the layered double hydroxide by reconstruction method using Mg-Al oxide precursor. The uptake amounts of amino acids and peptides were 0.9-2.7 mmol per 1 g of LDH. Intercalation compounds were examined by using XRD and solid-state NMR. For Gly, Ala, Ser, Thr, Pro, Asn, Gln, Asp, Glu, and aspartame the intercalation accompanied the expansion of interlayer distance of the solid products, whereas the other amino acids and oligoglycine showed no expansion. The intercalation mechanism and release profile in K(2)CO(3) aqueous solution were also investigated. And the cointercalation of amino acids and peptides into Mg-Al LDH and easy release of amino acids from the LDH layer were found.

Preparation of 1-hydroxyethylidene-1,1-diphosphonic acid-intercalated layered double hydroxide and its physicochemical properties.

The intercalation of 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP), which is a drug for osteoporosis, in layered double hydroxide (LDH) was examined with the goal of developing a novel drug delivery system (DDS) of HEDP. To prevent side reactions, the intercalation reaction was carried out at 0 degrees C, and at pH 4-6. The uptake of HEDP was determined as 3.5 mmol x g(-1) of LDH, and the interlayer distance increased from 7.8 to 13 A. The HEDP-release profiles into K(2)CO(3) aqueous solution and into various buffer solutions were also examined.

Stereoselective phosphorylation of branched cyclodextrins with inorganic cyclo-triphosphate.

The phosphorylation by inorganic sodium cyclo-triphosphate (P(3m)) having a six-membered ring was examined for cyclomaltohexaose (alpha-cyclodextrin) and branched cyclodextrins (mono-6-O-alpha-D-glucopyranosylcyclomaltohexaose, mono-6-O-alpha-D-maltosylcyclomaltohexaose, mono-6-O-alpha-D-glucopyranosylcyclomaltoheptaose, and mono-6-O-alpha-D-maltosylcyclomaltoheptaose) in aqueous solution. For all cyclomaltooligosaccharides (cyclodextrins) studied, the 2-OH group was stereoselectively phosphorylated. In the reaction of branched cyclodextrins and P(3m), only the 2-OH on the alpha-D-glucopyranosyl group of the cyclodextrin rings was phosphorylated with maximum yields of more than 27%. The phosphorylation mechanism of branched cyclodextrins with P(3m) is also discussed.

Phosphorylation of disaccharides with inorganic cyclo-triphosphate in aqueous solution.

The phosphorylation of disaccharides by inorganic cyclo-triphosphate (P(3m)) with a six-membered ring was examined in aqueous solution. In the phosphorylation of cellobiose, lactose, and alpha,alpha-trehalose with P(3m), beta-D-glucopyranosyl-(1-->4)-beta-D-glucopyranosyl 1-triphosphate, beta-D-galactopyranosyl-(1-->4)-beta-D-glucopyranosyl 1-triphosphate, and 3-O-triphospho-alpha-D-glucopyranosyl-(1-->1)-alpha-D-glucopyranoside were synthesized with maximum yields of 28%, 35%, and 20%, respectively. In the reactions of maltose and sucrose with P(3m), two phosphorylated products were obtained in yields of 42% and 58%, respectively. The main phosphorylated products were assigned to alpha-D-glucopyranosyl-(1-->4)-beta-D-glucopyranosyl 1-triphosphate and beta-D-fructofuranosyl-(2-->1)-2-O-triphospho-alpha-D-glucopyranoside by heteronuclear multiple bond correlation (HMBC) NMR. The phosphorylation mechanism of disaccharides with P(3m) is discussed.