Angewandte
Chemie
Biochim. Biophys. Acta 2002, 1582, 309; results of these studies
support our hypothesis.
receptor subtype-selective recognition by an array of small
molecules by changing the relative three-dimensional
arrangement of pharmacophores attached to a carbohydrate
core. These compounds can be synthesized on a gram scale,
and are stable for at least several months at À208C.
Physiological studies on these subtype-selective agonists, as
well as studies toward the development of potent and
selective LPA antagonists are in progress.
[9] For leading references on the use of carbohydrates as a scaffold
for pharmacophores, see: a) R. Hirschmann, K. C. Nicolaou, S.
Pietranico, J. Salvino, E. M. Leahy, P. A. Sprengeler, G. Furst,
A. B. Smith III, C. D. Strader, M. A. Cascieri, M. R. Candelore,
C. Donaldson, W. Vale, L. Maechler, J. Am. Chem. Soc. 1992,
114, 9217; b) R. Hirschmann, K. C. Nicolaou, S. Pietranico, E. M.
Leahy, J. Salvino, B. Arison, M. A. Cichy, P. G. Spoors, W. C.
Shakespeare, P. A. Sprengeler, P. Hamley, A. B. Smith III, T.
Reisine, K. Raynor, L. Maechler, C. Donaldson, W. Vale, R. M.
Freidinger, M. R. Cascieri, C. D. Strader, J. Am. Chem. Soc.
1993, 115, 12550; for recent examples, see: c) E. Locardi, M.
Stꢀckle, S. Gruner, H. Kessler, J. Am. Chem. Soc. 2001, 123,
8189; d) M. Ghosh, R. G. Dulina, R. Kakarla, M. J. Sofia, J. Org.
Chem. 2000, 65, 8387; e) T. Wunberg, C. Kallus, T. Opatz, S.
Henke, W. Schmidt, H. Kunz, Angew. Chem. 1998, 110, 2620 –
2622; Angew. Chem. Int. Ed. 1998, 37, 2503; for a recent review,
see: f) G. T. Le, G. Abbenante, B. Becker, M. Grathwohl, J.
Halliday, G. Tometzki, J. Zuegg, W. Meutermans, Drug Discov-
ery Today 2003, 8, 701.
Received: February 20, 2004 [Z54065]
Keywords: agonists · biological activity · carbohydrates ·
.
conformation analysis · receptors
[1] For reviews, see: a) T. Hla, M. Lee, N. Ancellin, J. H. Paik, M. J.
Kluk, Science 2001, 294, 1875; b) W. H. Moolenaar, O. Kranen-
burg, F. R. Postma, G. Zondag, Curr. Opin. Cell Biol. 1997, 9,
168.
[2] For a recent review on LPA analogues, see: K. R. Lynch, T. L.
Macdonald, Biochim. Biophys. Acta 2002, 1582, 289.
[3] LPA exists as an equilibrium mixture of 1-acyl and 2-acyl LPA
through intramolecular acyl migration: J. Chevallier, N. Sakai, F.
Robert, T. Kobayashi, J. Gruenberg, S. Matile, Org. Lett. 2000, 2,
1859.
[4] Several approaches were developed to generate stable LPA
analogues by preventing acyl migration; the use of an amide:
a) T. Sugiura, A. Tokumura, L. Gregory, T. Noguchi, S. T.
Weintraub, D. J. Hanahan, Arch. Biochem. Biophys. 1994, 311,
358; the use of fluorinated analogues: b) Y. Xu, G. D. Prestwich,
J. Org. Chem. 2002, 67, 7158; c) Y. Xu, L. Qian, G. D. Prestwich,
J. Org. Chem. 2003, 68, 5320; d) Y. Xu, L. Qian, G. D. Prestwich,
Org. Lett. 2003, 5, 2267; the use of an ether: e) Y. Hasegawa, J. R.
Erickson, G. J. Goddard, S. Yu, S. Liu, K. W. Cheng, A. Eder, K.
Bandoh, J. Aoki, R. Jarosz, A. D. Schrier, K. R. Lynch, G. B.
Mills, X. Fang, J. Biol. Chem. 2003, 278, 11962; f) L. Qian, Y. Xu,
H. Arai, J. Aoki, T. M. McIntyre, G. D. Prestwich, Org. Lett.
2003, 5, 4685.
[10] For synthetic procedures and detailed assay results for these
compounds, see Supporting Information.
[11] K. Bandoh, J. Aoki, H. Hosono, S. Kobayashi, T. Kobayashi, K.
Murakami-Murofushi, M. Tsujimoto, H. Arai, K. Inoue, J. Biol.
Chem. 1999, 274, 27776. In brief, Sf9 insect cells were transfected
with cDNA of cloned human LPA receptors, and the increase in
intracellular Ca2+ concentration upon activation by the agonists
was quantified by using a Ca2+-specific fluorescent probe (Fura-
2). No increase in Ca2+ concentration was observed in wild-type
Sf9 cells in response to 1-oleoyl LPA or these agonists, thus
eliminating the possibility that unknown receptors are affected.
[12] For stereochemical properties of LPA-receptor activation, see:
a) K. Yokoyama, D. L. Baker, T. Virag, K. Liliom, H.-S. Byun, G.
Tigyi, R. Bittman, Biochim. Biophys. Acta 2002, 1582, 295; b) L.
Qian, Y. Xu, Y. Hasegawa, J. Aoki, G. B. Mills, G. D. Prestwich,
J. Med. Chem. 2003, 46, 5575.
[13] The analogue of Prestwich and co-workers is the only example
with this level of activity (see reference [4c]). Compound 13 also
had high potency (100- to 500-fold relative to 1-oleoyl LPA) in
Ca2+-mobilization assays with several cells that express LPA3.
[14] The LPA1-agonist activity was assessed by determining MDA-
cell migratory activity: M. Umezu-Goto, Y. Kishi, A. Taira, K.
Hama, N. Dohmae, K. Takio, T. Yamori, G. B. Mills, K. Inoue, J.
Aoki, H. Arai, J. Cell Biol. 2002, 158, 227. The LPA2-agonist
activity was assessed based on Ca2+-releasing activity from Sf9
cells transfected with LPA2 (reference [11]).
[5] D. W. Hopper, S. P. Ragan, S. B. Hooks, K. R. Lynch, T. L.
Macdonald, J. Med. Chem. 1999, 42, 963.
[6] a) C. E. Heise, W. L. Santos, A. M. Schreihofer, B. H. Heasley,
Y. V. Mukhin, T. L. Macdonald, K. R. Lynch, Mol. Pharmacol.
2001, 60, 1173; b) D. J. Fisher, N. Nusser, T. Virag, K. Yokoyama,
D. Wang, D. L. Baker, D. Baustista, A. L. Parrill, G. Tigyi, Mol.
Pharmacol. 2001, 60, 776; and reference [4a].
[7] Analogue design on the basis of a similar idea was attempted
with aromatic compounds as scaffolds (reference [5]). Those
analogues, however, had only weak (two orders of magnitude
weaker) agonist activity compared to 1-oleoyl LPA. The lack of a
three-dimensional concept in the molecular design might be a
reason for the weak activity.
[8] For computational modeling of the binding structure of LPA to
LPA-receptor subtypes, see: a) D. Wang, Z. Lorincz, D. Bautista,
K. Liliom, G. Tigyi, A. L. Parrill, J. Biol. Chem. 2001, 276, 49213;
b) V. M. Sardar, D. Bautista, D. J. Fischer, K. Yokoyama, N.
Nusser, T. Virag, D. Wang, D. L. Baker, G. Tigyi, A. L. Parrill,
[15] Physiological studies with these analogues are ongoing.
[16] A cell-migration assay with PC3 cells indicated that 15 is 10
times more potent than 1-oleoyl LPA as an LPA1 agonist; see
Supporting Information.
[17] Compound 15 activates the LPA3 receptor with comparable
efficacy to 1-oleoyl LPA; see Supporting Information.
[18] The ring in compound 16 should occupy the same conformation
as that in 15; however, 16 might not fit into the binding pocket of
LPA1 as a result of the bulky substituent.
[19] Only 14 showed inhibitory activity among compounds 2–17.
Angew. Chem. Int. Ed. 2004, 43, 2834 –2837
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