1938
Y. T. Chen et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1935–1938
compounds function as mimics of phosphotyrosine, and
are designed to form a variety of specific contacts with
residues in the active site of the enzyme. Aryl sub-
stituents that increase the electron density at the ketone
carbonyl group of the inhibitor increase the activity of
the compound. We are currently working to further
improve the potency of these inhibitors by extending
their interactions with the enzyme into regions beyond
the active site. We are also exploring the possibility of
using a-ketocarboxylic acids as the basis for designing
new ligands for SH2 domains.
S.; Norris, K.; Rasmussen, H. B.; Moller, K. B.; Moller,
N. P. H. J. Biol. Chem. 2000, 275, 7101.
1
0. (a) Wrobel, J.; Sredy, J.; Moxham, C.; Dietrich, A.; Li, Z.;
Sawicki, D. R.; Seestaller, L.; Wu, L.; Katz, A.; Sullivan, D.;
Tio, C.; Zhang, Z.-Y. J. Med. Chem. 1999, 42, 3199. (b)
Malamas, M. S.; Sredy, J.; Gunawan, I.; Mihan, B.; Sawicki,
D. R.; Seestaller, L.; Sullivan, D.; Flam, B. R. J. Med. Chem.
2
000, 43, 995. (c) Malamas, M. S.; Sredy, J.; Moxham, C.;
Katz, A.; Xu, W.; McDevitt, R.; Adebayo, F. O.; Sawicki,
D. R.; Seestaller, L.; Sullivan, D.; Taylor, J. R. J. Med. Chem.
2000, 43, 1293. (d) Gao, Y.; Wu, L.; Luo, J. H.; Guo, R.;
Yang, D.; Zhang, Z.-Y.; Burke, T. R., Jr. Bioorg. Med. Chem.
Lett. 2000, 10, 923.
1
1. Beaulieu and co-workers have reported the use of a-keto-
carboxylic acids in the design of ligands for the tyrosine kinase
p56 SH2 domain. Beaulieu, P. L.; Cameron, D. R.; Ferland,
Acknowledgement
lck
J.-M.; Gauthier, J.; Ghiro, E.; Gillard, J.; Gorys, V.; Poirier,
M.; Rancourt, J.; Wernic, D.; Llinas-Brunet, M. J. Med.
Chem. 1999, 42, 1757.
This research was supported by the NIH (Grant
GM57327).
1
6
1
2. Hallmann, G.; Hagele, K. Justus Liebigs Ann. Chem. 1963,
62, 147.
3. All new compounds gave satisfactory 1H NMR, 13
C
NMR, and high-resolution mass spectral data.
1
1
References and Notes
4. Murata, S.; Sugiyama, K.; Tomioka, H. J. Org. Chem.
993, 58, 1976.
1
2
4
3
4
. Burke, T. R.; Zhang, Z.-Y. Biopolymers 1998, 47, 225.
. Al-Obeidi, F. A.; Wu, J. J.; Lam, K. S. Biopolymers 1998,
7, 197.
. Zhang, Z.-Y. CRC Crit. Rev. Biochem. Mol. Biol. 1998, 33, 1.
. Elchebly, M.; Payette, P.; Michaliszyn, E.; Cromlish, W.;
15. Imada, Y.; Mitsue, Y.; Ike, K.; Washizuka, K.-I.; Mura-
hashi, S.-I. Bull. Chem. Soc. Jpn. 1996, 69, 2079.
16. (a) Montserat, J.; Chen, L.; Lawrence, D. S.; Zhang, Z.-Y.
J. Biol. Chem. 1996, 271, 7868. (b) Taylor, S. D.; Kotoris,
C. C.; Dinaut, A. N.; Wang, Q.; Ramachandran, C.; Huang,
Z. Bioorg. Med. Chem. Lett. 1998, 6, 1457.
17. Yao, Z.-J.; Ye, B.; Wu, X.-W.; Wang, S.; Wu, L.; Zhang,
Z.-Y.; Burke, T. R., Jr. Bioorg. Med. Chem. 1998, 6, 1799.
18. Kotoris, C. C.; Chen, M.-J.; Taylor, S. D. Bioorg. Med.
Chem. Lett. 1998, 8, 3275.
Collins, S.; Loy, A. L.; Normandin, D.; Cheng, A.; Himms-
Hagen, J.; Chan, C.-C.; Ramachandran, C.; Gresser, M. J.;
Tremblay, M. L.; Kennedy, B. P. Science 1999, 283, 1544.
5
1
6
. Byon, J. C.; Kusari, A. B.; Kusari, J. Mol. Cell. Biochem.
998, 182, 101.
. Moran, E. J.; Sarshar, S.; Cargill, J. F.; Shahbaz, M. M.;
19. Zhang, Y.-L.; Keng, Y.-F.; Zhao, Y.; Wu, L.; Zhang,
Z.-Y. J. Biol. Chem. 1998, 273, 12281.
20. De Mico, A.; Margarita, R.; Piancatelli, G. Tetrahedron
Lett. 1995, 36, 2679.
Lio, A.; Mjalli, A. M. M.; Armstrong, R. W. J. Am. Chem.
Soc. 1995, 117, 10787.
7
. (a) Groves, M. R.; Yao, Z.-J.; Roller, P. P.; Burke, T. R.,
Jr.; Barford, D. Biochemistry 1998, 37, 17773. (b) Desmarais,
S.; Friesen, R. W.; Zamboni, R.; Ramachandran, C. Biochem.
J. 1999, 337, 219.
21. (a) Hu, L.-Y.; Abeles, R. H. Arch. Biochem. Biophys.
1990, 281, 271. (b) Angelastro, M. R.; Mehdi, S.; Burkhart,
J. P.; Peet, N. P.; Bey, P. J. Med. Chem. 1990, 33, 11.
22. Charifson, P. S.; Shewchuk, L. M.; Rocque, W.; Hummel,
C. W.; Jordan, S. R.; Mohr, C.; Pacofsky, G. J.; Peel, M. R.;
Rodriguez, M.; Sternbach, D. D.; Consler, T. G. Biochemistry
1997, 36, 6283.
8
. Burke, T. R., Jr.; Ye, B.; Akamatsu, M.; Ford, H., Jr.; Yan,
X.; Kole, H. K.; Wolf, G.; Shoelson, S. E.; Roller, P. P. J.
Med. Chem. 1996, 39, 1021.
9
. Andersen, H. S.; Iversen, L. F.; Jeppesen, C. B.; Branner,