Hiromasa Nagase

Stereocontrolled syntheses of novel styryl lactones, (+)-goniodiol, (+)-goniotriol, (+)-8-acetylgoniotriol, (+)-goniofufurone, (+)-9-deoxygoniopypyrone, (+)-goniopypyrone, and (+)-altholactone from common intermediates and cytotoxicity of their congeners

Abstract Concise syntheses of (+)-goniodiol, (+)-goniotriol, (+)-8-acetylgoniotriol, (+)-goniofufurone, (+)-9-deoxygoniopypyrone, (+)-goniopypyrone, and (+)-altholactone and their congeners from chiral lactonic aldehydes 27 and 36 as common intermediates are described. The key features in the syntheses are based on the in situ generation of unstable aldehydes 27 and 36 followed by their chemoselective reaction with triisopropoxyphenyltitanium to afford both diastereomers 28, 29 and 37, 38 at the C-8 positions. The cytotoxicity of styryl lactone congeners against P388 murine leukemia cells was examined.

Physicochemical properties and inclusion complex formation of δ-cyclodextrin

δ-Cyclodextrin (CD) is a cyclic oligosaccharide composed of nine α-1,4-linked d-glucose units. Its physicochemical properties have been characterized only in terms of its X-ray crystal structure (Fujiwara et al., 1990). A method for the purification of δ-CD was examined, and its physicochemical properties and complexation abilities were elucidated and compared with those of α-, β-, and γ-CD (Kobayashi et al., 1986; Miyazawa et al., 1993). Purification of δ-CD from the commercially available CD powder was mainly carried out with the combined treatment of HPLC and column chromatographies. The molecular weight of δ-CD was determined by FAB-MS, and the cyclic structure of δ-CD was identified by 1H-NMR and 13C-NMR. The aqueous solubility of δ-CD was greater than that of β-CD but less than that of α-CD or γ-CD. No surface activity of δ-CD was observed. δ-CD did not exhibit any hemolytic activity at 4.0 × 10−2 M δ-CD, which was close to its saturated solution. The acid-catalyzed hydrolysis increased in the following order: α-CD < β-CD < γ-CD < δ-CD. δ-CD did not show any significant solubilization effect on most of the slightly soluble or insoluble drugs in water. However, in the case of a large guest molecule such as spironolactone (SP) and digitoxin, which have a steroidal framework, the enhancement of solubility of the guest molecule by δ-CD was greater than that by α-CD. The solubility of SP increased about 30-fold in the presence of δ-CD (4.5 × 10−2 M), showing the features of an Al type phase diagram.

An anhydrous polymorphic form of trehalose.

An anhydrous polymorphic form of alpha,alpha-trehalose was prepared from trehalose dihydrate by two different drying methods: (1) heating under vacuum; and (2) heating in hot air. Preparation of this anhydrous form by vacuum heating showed good reproducibility. This form was characterized by X-ray powder diffraction analysis and differential scanning calorimetry. This anhydrous form was converted to an amorphous phase at 127 degrees C and was found to be hygroscopic. At 43% relative humidity at 25 degrees C, this form rapidly reverted to dihydrate, while the amorphous phase remained unchanged. When an amorphous phase coexisted with this form, the rate of water adsorption to the amorphous phase was slower than that to the amorphous phase alone. These properties of this anhydrous form of alpha,alpha-trehalose may explain the effects of trehalose in dehydration tolerance of plants and insects in the desert.

Stabilization of the lamellar structure of phosphatidylcholine by complex formation with trehalose

Abstract Trehalose (Tre) is found at particularly high concentration in anhydrobiotic organisms, and is effective in stabilizing the bilayer membranes of phospholipids in freeze-drying. We studied the mixture of L -α-dipalmitoylphosphatidylcholine (DPPC) and trehalose at various water contents by differential scanning calorimetry (DSC) and the small angle X-ray diffraction method. The Tre intercalated between lipid bilayers and formed complexes, and the excess Tre crystallized as its dihydrate by the addition of water. The amount of the dihydrate was estimated from the peak area in DSC. The experimental values of the molar ratio (Tre/DPPC) of the complexes thus determined were 1:2 and 1:1, and the corresponding expansions of the lamellar spacing were observed by small angle X-ray diffraction.

Evaluation of a Sulfobutyl Ether β-Cyclodextrin as a Solubilizing/Stabilizing Agent for Several Drugs

To evaluate the potential use of beta-cyclodextrin sulfobutyl ether, 7 sodium salt (SBE7-beta-CD) as a drug solubilizing and stabilizing agent, the solubilizing effects of SBE7-beta-CD on 22 different poorly water-soluble drugs were compared with those of intact beta-CD and heptakis-(2,6-di-O-methyl)-beta-CD (DMCD). SBE7-beta-CD was generally a more effective solubilizer for poorly water-soluble drugs than was intact beta-CD, but SBE7-beta-CD was not as effective as DMCD. The effects of SBE7-beta-CD on the acid hydrolysis rate of prostaglandin I2, the alkaline hydrolysis rate of indomethacin, the dehydration of prostaglandin E1, and the isomerization of prostaglandin A1 were also investigated and compared to those for intact beta-CD, DMCD, and 2,3,6 partially methylated-beta-CD (PMCD). The stabilizing effects of SBE7-beta-CD on chemically unstable drugs were generally higher than those of other CDs.

Interaction of Antimalarial Agent Artemisinin with Cyclodextrins

To obtain an effective solution of the poorly water soluble antimalarial agent artemisinin, the use of several kinds of cyclodextrins (CDs) as solubilizers was examined. The following CDs were used in this study: α-CD, β-CD, γ-CD as parent CDs, 2-hydroxypropyl-β-CD (HP-β-CD), sulfobutyl ether β-CD (SBE7-β-CD), heptakis (2,6-di-O-methyl)-β-CD (DM-β-CD), 2,3,6-partially methylated-β-CD (PM-β-CD) as modified CDs, and glucosyl-β-CD (G1-β-CD), and maltosyl-β-CD (G2-β-CD) as branched CDs. The solubility curves of artemisinin with CDs can all be classified as type AL. The apparent stability constants for artemisinin-parent CD complexes increased in the order of α- < γ- ≤ β-CD. The constants for artemisinin-β-CD derivative (and β-CD) complexes increased in the order of G2-β-CD ≅ G1-β-CD cong; PM-β-CD ≅ β-CD < HP-β-CD < SBE7-β-CD < DM-β-CD. These results suggest that the addition of CDs enables the solubilization of artemisinin.

Stereochemical revision and absolute configuration of codonopsinine

Abstract The stereostructure of codonopsinine has been revised from 1 to 7 based on chemical correlation studies, NOE experiments, and X-ray crystallographic analysis. This establishes the absolute configuration of natural (−)-codonopsinine as 2R,3R,4R,5R.

Effects of Cogrinding with β-Cyclodextrin on the Solid State Fentanyl

Fentanyl base and β-cyclodextrin (β-CD) were coground at 1:1 and 1:2 molar ratios (fentanyl: β-CD) and the physicochemical characteristics of the mixtures were studied using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), solid state (13)C nuclear magnetic resonance (NMR) spectroscopy and powder X-ray diffraction (PXRD) measurement. Additionally, portions of the coground samples were exposed to high relative humidity to investigate fentanyl and β-CD interactions. The results of DSC and PXRD analyses indicate that the ground mixtures are in an amorphous state, and the FTIR measurements show hydrogen bonding interactions between fentanyl and β-CD. Solid state (13)C NMR indicates that a fentanyl/β-CD inclusion compound is formed in the humidified mixture. Furthermore, PXRD data from the humidified mixtures are similar to the PXRD patterns from the inclusion complex.

Isolation, purification, and characterization of cyclomaltodecaose (ε-CD)

e-Cyclodextrin (e-CD) is a cyclic oligosaccharide, composed of ten α-1,4-linked D-glucoses reported by French et al. in 19651), but has not been studied because of the difficulty in the preparation and purification of large-ring CDs composed of more than nine α-1,4-linked D-glucose units. This report describes the purification and characterization of e-CD. Furthermore, the crystal and molecular structure of e-CD hydrate (e-CD 19H2O) was elucidated by X-ray analysis.

A novel intramolecular Diels–Alder approach to securinega alkaloids: formal synthesis of securinine

Abstract A formal total synthesis of securinine (1) was achieved by employing an intramolecular Diels–Alder reaction of the enol ester, derived from 2-acetylpyridine and sorbic anhydride, as a key step.