Kenya Ishida

Effect of l-menthol on the thermotropic behavior of ceramide 2/cholesterol mixtures as a model for the intercellular lipids in stratum corneum.

The major components of the intercellular lipids in the stratum corneum are ceramides (CERs), cholesterol (CHOL) and free fatty acids. To estimate the effects of l-menthol on the intercellular lipids, we elucidated the thermotropic behavior and lateral structure of a CER2/CHOL mixture. This formed a eutectic mixture at molar fraction of CHOL (Xch) = 0.6, as a lamellar structure with a repeat distance of 3.99 nm, and it showed a hexagonal hydrocarbon chain packing conformation at ambient temperature. In thermograms of the CER2/CHOL mixtures, the addition of l-menthol broadened the transition peaks and reduced the enthalpy of transition. The effect of l-menthol on the change in transition temperature of the eutectic mixture at Xch = 0.6 was weaker than for other molar fractions of CHOL. This suggested that the structure of the eutectic mixture was stable to the effects of l-menthol. Furthermore, l-menthol increased the repeat distance of the lamellar structure and inhibited the formation of hexagonal hydrocarbon chain packing. Therefore, l-menthol induced a disturbance of the lateral structure of the eutectic mixture of CER2/CHOL and the phase transition became unclear. These effects of l-menthol could enhance transdermal drug delivery.

Different effects of l- and d-menthol on the microstructure of ceramide 5/cholesterol/palmitic acid bilayers

The optical activity of transdermal permeation enhancers is one of the crucial factors for the enhancement of drug permeation via the skin. We investigated the effects of optically active menthols on a lipid bilayer model composed of ceramide 5, cholesterol, and palmitic acid. We first examined the fluidizing effects of l- and d-menthols on the lipid bilayers. The fluorescence anisotropy and thermodynamic parameters, such as the transition temperature and transition enthalpy, were significantly reduced by treatment with the optically active menthols. The effects of d-menthol were stronger than those of l-menthol. To discuss further, we also performed a detergent insolubility study and measured wide angle X-ray scattering. The amount of liquid-ordered phase membranes in the bilayers was significantly reduced by treatment with d-menthol. Whereas, l-menthol did not affected to the liquid-ordered phase membranes. The apparent ratio of orthorhombic hydrocarbon chain packing was substantially reduced by treatment with l-menthol. Thus, the distinct effects of optically active menthols on lipid bilayers were clarified: l-menthol acts on orthorhombic hydrocarbon chain packing with high selectivity, whereas d-menthol has no such specific effect. These findings extend our understanding of the mechanisms by which menthols affect the intercellular lipids in the stratum corneum.

Synthesis of l‐Muscone by Asymmetric Methylation via Enol Esters

An effective synthetic route of l‐muscone (1) by asymmetric methylation, followed by enolate‐trapping to generate enol esters as intermediates, was described. Interestingly, the enol esters can be used as substrates for enzymatic optical resolution to improve optical purity. Additionally, several excellent new chiral ligands were discovered for asymmetric methylation of (E)‐cyclopentadec‐2‐enone to produce l‐muscone with high optical purity.

Practical syntheses of D-erythro and L-threo-ceramide [NDS] and difference in contribution of each isomer in microstructure of stratum corneum intercellular lipids

The aims of this study were to develop the efficient synthetic procedure of optically active ceramide and to investigate contribution of stereochemistry of ceramide in stratum corneum of the skin. For the stereoselective asymmetric syntheses of both D-erythro and L-threo-CER [NDS], the practical synthetic routes, utilizing chiral ruthenium catalyzed dynamic kinetic resolution (DKR), were accomplished without any expensive reagents and no chromatographic purification was required for any of intermediates. From the physicochemical investigation of CER [NDS] isomers on the intercellular lipids in the stratum corneum, using simple synthetic lipid model composed of CER [NDS],CHOL and PA, it was clarified that optically active CER [NDS] play a critical role in intercellular lipid model of stratum corneum to form lamellar structure of which essential to barrier function of the mammalian skin.