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presumed to destroy homeostasis of cardiovascular or-
gans and progress arteriosclerosis. Since natural S-1P
is considered to have the same action as PDGF, S-1P
is employed as an inflammation-inducing agent to estab-
lish a pseudo-blood vessel in vitro model. By using this
model,26 the actions of the threo-(S,R)-amino-bromide
11f were examined. In the presence of 11f (0.3–
3.0 lM), the number of neutrophils transmigrating
through bovine endothelial cell layer and that adhering
to the cell layer decreased to 74–82% and 36–42% of
the control (without 11f), respectively. Thus the (S,R)-
bromide 11f has shown inhibitory effect on the S-1P-in-
duced inflammation, thereby having possibility for
maintaining the homeostasis of cardiovascular organs.
Receptor subtypes EDG-1/S1P1 and EDG-3/S1P3 are
expressed in vascular endotherial cells and vascular
SMCs,7b whereas the expression of EDG-5/S1P2 is more
abundant in SMCs than in endotherial cells.9b,27 Owing
to the slight difference in receptor subtypes,28 the modes
of actions of the S-1P analogues should be further
elucidated.
7. (a) Ancellin, N.; Hla, T. J. Biol. Chem. 1999, 274, 18997–
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8. For a review: Payne, S. G.; Milstien, S.; Barbour, S. E.;
Spiegel, S. Sem. Cell Dev. Biol. 2004, 15, 467–
476.
In summary, we have synthesized sphingosine-1-phos-
phate derivatives such as threo-(S,S)-analogues starting
from L-serine or (1S,2S)-2-amino-1-aryl-1,3-propanedi-
ols. Bioassays of the S-1P analogues using HL60cells
have indicated that (1) D-threo-(2S,3S)-S-1P homo-
logues (threo-5a,b) inhibit the natural erythro-S-1P-medi-
9. For recent studies, see: (a) Mandala, S.; Hajdu, R.;
Bergstrom, J.; Xie, J.; Milligan, J.; Thornton, R.; Shei, G.-
J.; Card, D.; Keohane, C.; Rosenbach, M.; Hale, J.;
Lynch, C. L.; Rupprecht, K.; Parsons, W.; Rosen, H.
Science 2002, 296, 346–349; (b) Osada, M.; Yatomi, Y.;
Ohmori, T.; Ikeda, H.; Ozaki, Y. Biochem. Biophys. Res.
Commun. 2002, 299, 483–487; (c) Koide, Y.; Hasegawa,
T.; Takahashi, A.; Endo, A.; Mochizuki, N.; Nakagawa,
M.; Nishida, A. J. Med. Chem. 2002, 45, 4629–4638; (d)
Hakogi, T.; Shigenari, T.; Katsumura, S.; Sano, T.;
Kohno, T.; Igarashi, Y. Bioorg. Med. Chem. Lett. 2003,
13, 661–664; (e) Clemens, J.; Davis, M. D.; Lynch, K. R.;
Macdonald, T. L. Bioorg. Med. Chem. Lett. 2003, 13,
3401–3404.
10. Parrill, A. L.; Wang, D.; Bautiska, D. L.; Brocklyn, J. R.
V.; Lorincz, Z.; Fischer, D. J.; Baker, D. L.; Liliom, K.;
Spiegel, S.; Tigyi, G. J. Biol. Chem. 2000, 275, 39379–
39384.
11. (a) Lim, H.-S.; Oh, Y.-S.; Suh, P.-G.; Chung, S.-K.
Bioorg. Med. Chem. Lett. 2003, 13, 237–240; (b) Lim, H.-
S.; Park, J.-J.; Ko, K.; Lee, M.-H.; Chung, S.-K. Bioorg.
Med. Chem. Lett. 2004, 14, 2499–2503.
12. It has been reported in Ref. 5b that, when the EDG/S1P
receptor on HL60cell (prolymphoblastoma) surface is
bound to S-1P, G-protein would be phosphorylated to
activate IP3 kinase, whereafter the intracellular Ca2+
concentration is increased.
13. Murakami, T.; Furusawa, K. Tetrahedron 2002, 58, 9257–
9263.
14. For a review, see: Liang, X.; Andersch, J.; Bols, M. J.
Chem., Soc. Perkin Trans. 1 2001, 2136–2157.
ated Ca2+ ion increase at low concentrations (IC50
=
0.015ꢀ0.031 lM), (2) the long-chain alkenyl group of
threo-S-1P is replaced by aryl (9d–f) or styryl (threo-
5c) group without significant loss of the inhibitory activ-
ity, (3) the C1 phosphate group is replaced by bromide
(11d,f) without loss of the inhibitory activity, (4) Enan-
tiomeric threo-(R,R)-amino alcohol (ent-9d) and deoxy-
amino-bromide (12) do not show the activity. Therefore
the presence and configuration of the amino alcohol
moiety appear to be very important for the antagonist-
like inhibitory effect.
Although we did not use recombinant cells overexpress-
ing exogenous EDG/S1P receptors abundantly and fur-
ther experiments are required to elucidate the
relationship between the S-1P analogues and the recep-
tors, the results described here would substantially con-
tribute to the development of potent and selective
antagonist for EDG/S1P receptors. In addition, some
analogues exhibited inhibitory effects against natural
S-1P-mediated responses: growth of vascular smooth
muscle cells and neutrophils adhesion. Thus they might
contribute therapeutic tools against vascular diseases
such as arteriosclerosis.
15. For a review, see: Wipf, P.; Jahn, H. Tetrahedron 1996, 52,
12853–12909.
16. Szulc, Z. M.; Hannun, Y. A.; Bielawska, A. Tetrahedron
Lett. 2000, 41, 7821–7824.
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