5170
Y. Baba et al. / Bioorg. Med. Chem. 13 (2005) 5164–5170
R.; Wakom, C.; Sakoff, J. A.; McCluskey, A. Bioorg. Med.
Chem. Lett. 2004, 14, 1969–1973; (j) Sheppeck, J. E., II;
Gausss, C.-M.; Chamberlin, A. R. Bioorg. Med. Chem.
1997, 5, 1739–1750, and references cited therein.
4. (a) Baba, Y.; Hirukawa, N.; Tanohira, N.; Sodeoka, M. J.
Am. Chem. Soc 2003, 125, 9740–9749; (b) Preliminary
SAR results, see: Sodeoka, M.; Baba, Y.; Kobayashi, S.;
Hirukawa, N. Bioorg. Med. Chem. Lett. 1997, 7, 1833–
1836; (c) Tatlock, J. H.; Linton, M. A.; Hou, X. J.;
Kissinger, C. R.; Pelletier, L. A.; Showalter, R. E.;
Tempczyk, A.; Villafranca, J. E. Bioorg. Med. Chem.
Lett. 1997, 7, 1007–1012.
5. (a) Tocci, M. J.; Matkovich, D. A.; Collier, K. A.; Kwok,
P.; Dumont, F. J.; Lin, S.; Degudicibus, S.; Siekierka, J. J.;
Chin, J.; Hutchison, N. I. J. Immunol. 1989, 143, 718–726;
(b) Randak, C.; Brabletz, T.; Hergenrother, M.; Sobotta,
I.; Serfling, E. EMBO J 1990, 9, 2529–9536; (c) Flanagan,
W. M.; Corthesy, B.; Bram, R. J.; Crabtree, G. R. Nature
1991, 352, 803–807; (d) McCaffrey, P. G.; Perrino, B. A.;
Soderling, T. R.; Rao, A. J. Biol. Chem. 1993, 268, 3747–
3752.
3 module in conjunction with the force fields supported
by that program. In the first orientation, we defined a
subset for the binding site of the receptor, and formed
an assembly consisting of the receptor and ligand mole-
cules. The subset was defined as the amino acid residues
˚
within 7 A around the phosphate ion, including the cat-
alytic site of PP2B. The initial placements of norcantha-
ridin derivatives within PP2B catalytic site were made
using a Monte Carlo type procedure to search both con-
formational and Cartesian space. Second, a simulated
annealing phase optimized each ligand placement. The
structures were then subjected to energy minimization
based on molecular dynamics.
Acknowledgments
We gratefully acknowledge Professors Nobuyuki Hara-
da and Kenji Monde for measurement of CD spectra
and helpful discussions. We thank Mr. Yasuharu Ijuin
for X-ray analysis. We also thank Dr. Tadashi Shimizu
for assistance. This work was supported in part by
grants from The Naito Foundation, Suzuken Memorial
Foundation, and Hoh-ansha Foundation, a SUNBOR
grant, a Grant-in-Aid for Creative Scientific Research
(No. 13NP0401) and a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of
Science, and a Grant-in-Aid for the COE project, Giant
Molecules and Complex Systems, from The Ministry of
Education, Culture, Sports, Science and Technology
(M.S.), as well as the Chugai Pharmaceutical Award in
Synthetic Organic Chemistry (Y.B.).
6. Tsao, L. N.; Neville, C.; Musaro, A.; McCullagh, K. J. A.;
Rosenthal, N. Nat. Med. 2000, 6, 2–3.
7. (a) Liu, J.; Farmer, J. D., Jr.; Lane, W. S.; Friedman, J.;
Weissman, I.; Schreiber, S. L. Cell 1991, 66, 807–815; (b)
Schreiber, S. L.; Albers, M. W.; Brown, E. J. Acc. Chem.
Res. 1993, 26, 412–420, and references cited therein.
8. For other types of PP2B inhibitors, see: Baumgrass, R.;
Weiwad, M.; Erdmann, F.; Liu, J. O.; Wunderlich, D.;
Grabley, S.; Fisher, G. J. Biol. Chem. 2001, 276, 47914–
47921, and references cited therein.
9. For details of our strategy for developing phosphatase
inhibitors, see: (a) Sodeoka, M.; Sampe, R.; Kojima, S.;
Baba, Y.; Usui, T.; Ueda, K.; Osada, H. J. Med. Chem.
2001, 44, 3216–3222; (b) Usui, T.; Kojima, S.; Kidokoro,
S.; Ueda, K.; Osada, H.; Sodeoka, M. Chem. Biol. 2001, 8,
1209–1220; (c) Sodeoka, M.; Baba, Y. J. Synth. Org.
Chem. Jpn. 2001, 59, 1095–1102.
10. Gausss, C.-M.; Sheppeck, J. E., II; Nairn, A. C.; Cham-
berlin, A. R. Bioorg. Med. Chem. 1997, 5, 1751–1773.
11. Imide derivatives of norcantharidin, which were prepared
by the reaction of norcantharidin with various optically
active amino acids, have been reported, but no chirality
exists in the oxabicyclo[2.2.1]heptane skeleton of these
compounds. See Ref. 3e.
12. Swanson, S. K.-H.; Born, T.; Zydowsky, L. D.; Cho, H.;
Chang, H. Y.; Walsh, C.; Rusnak, F. Proc. Natl. Acad.
Sci. U.S.A. 1992, 89, 3741–3745.
References and notes
1. Wang, G. S. J. Ethnopharmacol. 1989, 26, 147–162.
2. (a) McCluskey, A. H.; Sakoff, J. A. Mini Rev. Med. Chem.
2001, 1, 43–55; (b) Li, Y.-M.; Casida, J. E. Proc. Natl.
Acad. Sci. U.S.A. 1992, 89, 11867–11870; (c) Li, Y.-M.;
MacKintosh, C.; Casida, J. E. Biochem. Pharmacol. 1993,
46, 1435–1443; (d) Honkanen, R. E. FEBS Lett. 1993, 330,
283–286, and references therein.
3. (a) McCluskey, A.; Taylor, C.; Quinn, R. J. Bioorg. Med.
Chem. Lett. 1996, 6, 1025–1028; (b) Enz, A.; Zenke, G.;
Pombo-Villar, E. Bioorg. Med. Chem. Lett. 1997, 7, 2513–
2518; (c) McCluskey, A.; Keane, M. A.; Mudgee, L.-M.;
Sim, A. T. R.; Sakoff, J.; Quinn, R. J. Eur. J. Med. Chem.
2000, 35, 957–964; (d) McCluskey, A.; Bowyer, M. C.;
Collins, E.; Sim, A. T. R.; Sakoff, J. A.; Baldwin, M. L.
Bioorg. Med. Chem. Lett. 2000, 10, 1687–1690; (e)
McCluskey, A.; Walkom, C.; Bowyer, M. C.; Ackland,
S. P.; Gardiner, E.; Sakoff, J. A. Bioorg. Med. Chem. Lett.
2001, 11, 2941–2946; (f) McCluskey, A.; Keane, M. A.;
Walkom, C. C.; Bowyer, M. C.; Sim, A. T. R.; Young, D.
J.; Sakoff, J. A. Bioorg. Med. Chem. Lett. 2002, 12, 391–
393; (g) Sakoff, J. A.; Ackland, S. P.; Baldwin, M. L.;
Keane, M. A.; McCluskey, A. Invest. New Drugs 2002, 20,
1–11; (h) McCluskey, A.; Sim, T. R.; Sakoff, J. A. J. Med.
Chem. 2002, 45, 1151–1175; (i) Hart, M. E.; Chamberlin,
13. (a) Kissinger, C. R.; Perge, H. E.; Knighton, D. R.; Lewis,
C. T.; Pelletier, L. A.; Tempczyk, A.; Kalish, V. J.; Tucker,
K. D.; Showalter, R. E.; Moomaw, E. W.; Gastinel, L. N.;
Habuka, N.; Chen, X.; Maldonado, F.; Barker, J. E.;
Bacquet, R.; Villafranca, J. E. Nature 1995, 378, 641–644;
(b) Griffith, J. P.; Kim, J. L.; Kim, E. E.; Sintchak, M. D.;
Thomson, J. A.; Fitzgibbon, M. J.; Fleming, M. A.;
Caron, P. R.; Hsiao, K.; Navia, M. A. Cell 1995, 82, 507–
522.
14. Goldberg, J.; Huang, H. B.; Kwon, Y. G.; Greengard, P.;
Nairn, A. C.; Kuriyan, J. Nature 1995, 376, 745–753;
Crystal structure of PP1-calyculin complex, see:Kita, A.;
Matsunaga, S.; Takai, A.; Kataiwa, H.; Wakimoto, T.;
Fusetani, N.; Isobe, M.; Miki, K. Structure 2002, 10, 715–
724.
15. Theurillat-Moritz, V.; Vogel, P. Tetrahedron: Asymmetry
1996, 7, 3163–3168.