Masaki Yamasaki

Inclusi on complexations of steroid hormones with cyclodextrins in water and in solid phase

Abstract Inclusion complexation of 18 steroid hormones with 3 cyclodextrins (α, β- and γ-CyDs) in water and in solid phase were studied by the solubility method, spectroscopies (UV, CD, IR and 1H-NMR), X-ray diffractometry and thermal analysis, and their modes of interactions were assessed. A spatial relationship between host and guest molecules was clearly reflected in the magnitude of the stability constant (γ-> β-> α-CyD) and in the stoichiometry of the inclusion complexes. The 1H-NMR studies including spin-lattice relaxation time and chemical shift measurements suggested that the A-ring of the steroid molecule was predominantly included in the cavity of CyDs. The solid complexes of some steroids with β-and γ-CyDs were obtained generally in the molar ratios of 1:2 and 2:3, respectively, and their dissolution behaviors were examined. The results indicated that the CyD complexes may have a great utility as a rapidly dissolving form of steroids in water.

Binding of pirprofen to human serum albumin studied by dialysis and spectroscopy techniques

The interaction of pirprofen with human serum albumin (HSA) was investigated by equilibrium dialysis and spectroscopic (UV absorption, fluorescence, CD, NMR) techniques. It was found that HSA binds pirprofen nonstereospecifically. The binding of pirprofen depends upon the N-B conformational change of albumin. Chloride ions appear to displace the drug from its binding site. The thermodynamic parameters suggest that the interaction may be explained by electrostatic as well as hydrophobic forces. The absorption spectral changes which accompanied the binding of pirprofen to HSA implied that the aromatic portion of drugs was inserted into the hydrophobic crevice in the protein, while the carboxyl group of the drug interacted with a cationic site on the albumin surface. The NMR data indicated that the pyrroline ring and propionic acid parts may be the major binding site for HSA. A specific binding site for pirprofen on the HSA was found to be site II, benzodiazepine site, using fluorescence probes and drug markers. In addition, from the binding data with modified HSA, it seems that Tyr-411 is specifically involved in pirprofen binding.

Comparative study on inclusion complexations of antiinflammatory drug flurbiprofen with β-cyclodextrin and methylated β-cyclodextrins

AbstructSome physicochemical properties of methylated β-cyclodextrins, i.e., heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CyD) and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CyD) were compared with those of natural β-cyclodextrin (β-CyD). Inclusion behaviors of β-CyD and methylated β-CyDs in water and in solid state were studied by solubility analysis, spectroscopies (UV, CD,13C-NMR and IR), X-ray diffractometry and thermal analysis, using an antiinflammatory drug flurbiprofen (FP) as a guest molecule. The spectral data suggest that the inclusion mode of FP-TM-β-CyD is somewhat different from those of FP-β-CyD and FP-DM-β-CyD. The solid complexes of FP with β- and methylated β-CyDs were obtained in molar ratio of 1∶1, and their dissolution behavior and release from suppository base were examined. The data are presented suggesting that DM-β-CyD is particularly useful for improving the pharmaceutical properties of FP in various dosage forms.

Improvement of some pharmaceutical properties of nocloprost by β- and γ-Cyclodextrin Complexation

Inclusion complexation of nocloprost, a potent antiulcer prostaglandin derivative, with α-, β-, and γ-cyclodextrins (CyDs) in aqueous solutions has been studied by the solubility method and13C-NMR spectroscopy. The steric requirement of host-guest interaction was reflected in the magnitude of the stability constants and the thermodynamic parameters of the inclusion complexes. Solid complexes of nocloprost with β- and γ-CyDs in a molar ratio of 1 : 2 were obtained on the basis of aBs-type phase solubility diagram. The X-ray diffraction data suggested that nocloprost is included in the cylindrical channel formed by coaxial alignment of γ-CyD molecules to give a channel type structure. Release and thermal behavior of the solid complexes was examined and compared with nocloprost itself. The results indicated that the β-CyD complex may have great utility among the three CyDs, being a rapid dissolving form of nocloprost with improved thermal stability.

Reduction of photohemolytic activity of benoxaprofen by β-cyclodextrin complexations

Inclusion complexations of benoxaprofen (BXP) withβ-cyclodextrin (β-CyD) and heptakis (2,6-di-O-methyl)-β-CyD (DM-β-CyD) were studied by the solubility method and CD and1H-NMR spectroscopy. Both β-CyDs decelerated the photodecarboxylation of BXP, and suppressed the BXP-photosensitized hemolysis, where the inhibitory effect of DM-β-CyD was larger than that of β-CyD. This order was well correlated with the magnitude of the stability constants of BXP-β-CyD complexes. The peroxidation of lipid components in erythrocyte ghosts induced by BXP was also suppressed particularly by DM-β-CyD. The protective effect of β-CyDs on the BXP-induced photohemolysis seems to be due to the suppression in the photochemical reactions of BXP yielding toxic transient species, together with the inhibition in attacks of the transient species to the membrane, through inclusion complexation.

A furostanol glucuronide from Solanum lyratum

Abstract A new furostanol glucuronide and three known glycosides, SL-O, aspidistrin and methyl proto-aspidistrin, were isolated from the fresh immature berries of Solanum lyratum . The structure of the new compound was characterized as 26- O -β- D -glucopyranosyl-(22ξ,25 R -3β,22,26-trihydroxyfurost-5-ene 3- O -α- L -rhamnopyranosyl-(1 → 2)-[β- D -glucopyranosyl-(1 → 3)]-β- D -glucuronopyranoside.

Catalytic function of a histidyl residue in cytosolic aspartate aminotransferase-catalyzed reactions

Methylene blue-sensitized photooxidation of the cytosolic aspartate aminotransferase from pig heart yielded a preparation which was inactive in the transamination reaction with natural substrates (L-aspartate and a-keto-glutarate) but fully active in the α, β-elimination reaction with β-chloro-Lalanine as well as in the transamination reaction with L-alanine. The inactivation results from photooxidative destruction of a histidyl residue in accord with the result reported by Martinez-Carrion et al. [ J. Biol. Chem. 242, 1426 (1967)]. These results indicates that the histidyl residue does not function as a base abstracting the α-hydrogen atom of these substrates but acts as a catalytic residue involved in the interaction with the distal carboxylate of a natural dicarboxylic substrate as proposed previously [ Morino et al., J. Biol. Chem. 249, 6684 (1974)].

Preparation of heptakis(2,6-di-O-ethyl)-β-cyclodextrin and its nuclear magnetic resonance spectroscopic characterization

Heptakis(2,6-di-O-ethyl)-β-cyclodextrin (DE-β-CyD) was prepared and its 1H and 13C nuclear magnetic resonance (NMR) signals in DMSO-d6 were unequivocally assigned by two-dimensional COSY and ROESY. The results on 1H coupling constants indicated that all ethylated glucose units are in a 4C1 chair conformation. The average spin-lattice relaxation times (T1) of ring carbons of DE-β-CyD were only slightly shorter, and their standard deviations from the mean Tl value were larger, than those of β-cyclodextrin (β-CyD) and heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CyD), suggesting the presence of slightly irregular internal motion in the ethylated glucose units. The temperature dependence of chemical shift of DE-β-CyD in DMSO-d6 suggested that the C3 hydroxyl protons may participate as proton donor in the intramolecular hydrogen bond to the C2 ethoxyl groups of neighboring glucose, and the intramolecular hydrogen bond of DE- and DM-β-CyDs is much stronger than that of β-CyD, suggesting the stable macrocyclic ring structure of DE-β-CyD.

Reduction of protriptyline-photosensitized hemolysis by β-cyclodextrin complexations

Abstract β-Cyclodextrin (β-CyD) and heptakis (2,6-di- O -methyl- β -CyD (DM-β-CyD)) were found to suppress the protriptyline (PTL)-induced hemolysis of human erythrocytes. The inhibitory effect of DM-β-CyD was larger than that of β-CyD in both aerobic and anaerobic conditions. The photodegradation products of PTL in the absence and presence of DM-β-CyD were analyzed by liquid chromatography/mass spectroscopy and their hemolytic activities were surveyed. The results indicate that the protective effects of β-CyDs may be due to the deceleration of the photodegradation of PTL, together with the suppression of the formation of highly toxic products such as 10,11-epoxide and cyclobutyl dimer. The alternative photoreaction pathway of PTL may result from the partial inclusion of PTL molecule within the hydrophobic cavity of β-CyDs, which was assessed by various spectroscopic methods.