Bioorganic & Medicinal Chemistry Letters 13 (2003) 813–815
Design, Synthesis, and Evaluation of ꢀ-Galactosylceramide
Mimics Promoting ꢀ-Glucocerebrosidase Activity in Keratinocytes
Kyoko Fukunaga,a,b,* Masahiro Yoshida,b,y Fumio Nakajima,b,c Rie Uematsu,b
Mariko Hara,a Shintaro Inoue,a Hirosato Kondoc,{ and Shin-Ichiro Nishimurad
aBasic Research Laboratory, Kanebo Ltd., 3-28, 5-chome Kotobuki-cho, Odawara-shi, Kanagawa-ken 250-0002, Japan
bSapporo Laboratory for Glycocluster Project, Japan Bioindustry Association, Hokkaido University, Sapporo 060-0810, Japan
cDepartment of Chemistry, Nippon Organon Ltd., 5-90, 1-chome Tomobuchi-cho, Miyakojima-ku, Osaka, Japan
dLaboratory of Bio-Macromolecular Chemistry, Division of Biological Sciences, Graduate School of Science,
Hokkaido University, Sapporo 060-0810, Japan
Received 1 November 2002; accepted 27 December 2002
Abstract—We have established an efficient synthesis of mimics of b-galactosylceramide (b-GalCer) increasing a b-glucocere-
brosidase (b-GlcCer’ase) activity that associates with the skin barrier function. Among the synthetic b-GalCer analogues (6a–6e)
described herein, compound 6e exhibited a potent effect on the activation of b-GlcCer’ase function in vitro and reduced the trans-
epidermal water loss (TEWL) level in a UVB-induced barrier disrupted mice model. These findings indicated that compound 6e
could be useful for cosmetics and medicines to improve skin barrier function.
# 2003 Elsevier Science Ltd. All rights reserved.
b-Galactosylceramide (b-GalCer) is one of the simplest
glycosphingolipids having a lipophilic sphingosine and a
hydrophilic galactose moiety attached via an ether link-
age to sphingosine. b-GalCer is found abundantly in the
myelin sheath of the central and peripheral nervous
system,1,2 and acts as cell surface receptors for bacterial
toxins and viruses.3,4
diseases, such as dry skin, atopic dermatitis and psoriasis,
is only produced by b-GlcCer’ase not but by sphingo-
myelinase.9 Actually, it has been demonstrated that
b-GalCer increased not only the in vitro b-GlcCer’ase
activity but also the in vivo Cer level of stratum cor-
neum to improve the resistance against the above skin
diseases.5,10
Recently, we have reported that b-GalCer promoted the
activity of b-glucocerebrosidase (b-GlcCer’ase) in epi-
dermis and resulted in the increase of the ceramide (Cer)
levels.5 This enzyme plays a critical role for the forma-
tion and maintenance of the epidermal permeability
barrier, by which b-glucosylceramide (b-GlcCer) local-
ized in epidermis is hydrolyzed to Cers that is essential
for the formation of lamellae structure in the stratum
corneum.6,7 Moreover, we found that acylceramide8
(Cer1), an important lipid in preventing various skin
Cer is a natural product and Cer mimics have been
applied for cosmetics. However, it is very difficult to
utilize these compounds widely. Because the general
synthesis of biologically active ceramides involves two
important aspects; one is the establishement of the
chirality and the other the construction of the trans
double bond, so a practical synthesis for active ceramides
has been still studied.11ꢀ15 Therefore, our attention has
been focused on the galactose–attached Cer mimics for
increasing the b-GlcCer’ase activity. In this study, we
designed the structural assembly using the galactose and
the Cer mimic lead from l-serine, in view of the struc-
tural diversity, for example we have applied easily the
various fatty amines or fatty acids in the synthetic
strategy, as shown in Figure 1.
*Corresponding author. Tel.:+81-465-34-6149; fax:+81-465-34-3037;
yCurrent address: Medicinal Chemistry Central Research Laboratory,
Sanwa Kagaku Kenkyusho Co., Ltd., 363 Shiosaki, Hokusei-cho,
Inabe-gun, Mie, 511-0406, Japan.
Here, we describe the synthesis of b-GalCer analogues
6a–6e as the general method. As shown in Scheme 1,
b-d-galactose penta acetate 1 was derived into the
{Current address: Manufacturing Technology R&D Laboratories,
Shionogi & Co., Ltd., 1-3 Kuise Terajima 2-chome, Amagasaki,
Hyogo 660-0813, Japan.
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00006-4