Y. S. Shim et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2561–2563
2563
does not correlate with the selectivity data. Three-
dimensional structure at or near the active site is the
more likely determinant of the selectivity. Nevertheless,
LAR is well differentiated from PTP1B in its reaction
with the inhibitors and this observation suggests the
possibility that further excavation of the formyl-
chromone derivatives might lead to a highly potent and
selective PTP1B inhibitordespite the high homology
between PTPases and the effort is in progress.
(e) Cheng, A.; Dube, N.; Gu, F.; Tremblay, M. L. Eur. J.
´
Biochem. 2002, 269, 1050.
5. (a) Goldfine, A. B.; Simonson, D. C.; Folli, F.; Patti, M. E.;
Kahn, C. R. Mol. Cell. Biochem. 1995, 153, 217. (b) Huyer,
G.; Liu, S.; Kelly, J.; Moffat, J.; Payette, P.; Kennedy, B.;
Tsaprailis, G.; Gresser, M. J.; Ramachandran, C. J. Biol.
Chem. 1997, 272, 843. (c) Goldstein, B. J. J. Clin. Endocrinol.
Metab. 2002, 87, 2474.
6. (a) Zinker, B. A.; Rondinone, C. M.; Trevillyan, J. M.;
Gum, R. J.; Clampit, J. E.; Waring, J. F.; Xie, N.; Wilcox, D.;
Jacobson, P.; Frost, L.; Kroeger, P. E.; Reilly, R. M.;
Koterski, S.; Opgenorth, T. J.; Ulrich, R. G.; Crosby, S.;
Butler, M.; Murray, S. F.; McKay, R. A.; Bhanot, S.; Monia,
B. P.; Jirousek, M. R. Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
11357. (b) Kennedy, B. P.; Ramachandran, C. Biochem.
Pharm. 2000, 60, 877. (c) Elchebly, M.; Cheng, A.; Tremblay,
M. L. J. Mol. Med. 2000, 78, 473. (d) Elchebly, M.; Payette,
P.; Michaliszyn, E.; Cromlish, W.; Collins, S.; Loy, A. L.;
Normandin, D.; Cheng, A.; Himms-Hagen, J.; Chan, C. C.;
Ramachandran, C.; Gresser, M. J.; Tremblay, M. L.; Ken-
nedy, B. P. Science 1999, 283, 1544.
In summary, we have shown that formylchromone and
its derivatives are capable of inhibiting PTP1B. Initial
derivatizations of the formylchromone identified com-
pound 14 as a potent inhibitoragainst PTP1B with
strong or medium selectivity against human PTPases,
LAR and TC-PTP. The selectivity togetherwith the
ongoing improvement of the potency suggests that for-
mylchromone could be a novel lead for the design of a
potent and selective PTP1B inhibitor.
7. (a) Zhang, Z.-Y. Annu. Rev. Pharmacol. Toxicol. 2002, 42,
209 and references cited therein. (b) Burke, T. R., Jr.; Zhang,
Z.-Y. Biopolymers 1998, 47, 225 and references cited therein.
(c) Ahn, J. H.; Cho, S. Y.; Ha, J. D.; Chu, S. Y.; Jung, S. H.;
Jung, Y. S.; Baek, J. Y.; Choi, I. K.; Shin, E. Y.; Kang, S. K.;
Kim, S. S.; Cheon, H. G.; Yang, S.-D.; Choi, J.-K. Bioorg.
Med. Chem. Lett. 2002, 12, 1941 and references cited therein.
(d) Burke, Jr., T. R.; Gao, Y.; Yao, Z.-J. In Biomedical
Chemistry, Torrence, P. F., Ed.; John Wiley & Sons, Inc.,
England, 2000, pp 189–210.
8. (a) Liljebris, C.; Martinsson, J.; Tedenborg, L.; Williams,
M.; Barker, E.; Duffy, J. E. S.; Nygren, A.; James, S.
Bioorg. Med. Chem. 2002, 12, 3197. (b) Wipf, P.; Aslan,
D. C.; Southwick, E. C.; Lazo, J. S. Bioorg. Med. Chem.
Lett. 2001, 11, 313. (c) Malamas, M. S.; Sredy, J.; Guna-
wan, I.; Mihan, B.; Sawicki, D. R.; Seestaller, L.; Sullivan,
D.; Flam, B. R. J. Med. Chem. 2000, 43, 995. (d) Watanabe,
T.; Suzuki, T.; Umezawa, Y.; Takeuchi, T.; Otsuka, M.;
Umezawa, K. Tetrahedron 2000, 56, 741. (e) Ham, S. W.;
Park, J.; Lee, S.-J.; Yoo, J. S. Bioorg. Med. Chem. Lett.
1999, 9, 185.
Acknowledgements
This work was supported by the grant (R05-2001-000-
00551-0) from the Basic Research Program of the Korea
Science & Engineering Foundation.
References and Notes
1. (a) Tonks, N. K.; Neel, B. G. Curr. Opin. Cell Biol. 2001,
13, 182. (b) Ostman, A.; Bohmer, F. D. Trends in Cell Biol.
2001, 11, 258. (c) Denu, J. M.; Dixon, J. E. Curr. Biol. 1998, 2,
633.
2. (a) Zhan, X.-L.; Wishart, M. J.; Guan, K.-L. Chem. Rev.
2001, 101, 2477. (b) Zhang, Z.-Y. Curr. Opin. Chem. Biol.
2001, 5, 416. (c) Neel, B. G.; Tonks, N. K. Curr. Opin. Cell
Biol. 1997, 9, 193.
3. (a) Van Huijsduijnen, R. H.; Bombrun, A.; Swinnen, D.
Drug Discov. Today 2002, 7, 1013. (b) Li, L.; Dixon, J. E.
Semin. Immunol. 2000, 12, 75.
9. Park, D.; Shim, Y. S.; Kim, K. C.; Park, J.; Yang, D.; Cho,
H. J. Korean Chem. Soc. 2002, 46, 296.
4. (a) Zick, Y. Trends Cell Biol. 2001, 11, 437. (b) Bailey, C. J.
Biochem. Pharm. 1999, 58, 1511. (c) Taylor, S. I. Cell 1999, 97,
9. (d) Kido, Y.; Burks, D. J.; Withers, D.; Bruning, J. C.;
Kahn, C. R.; White, M. F. J. Clinical Invest. 2000, 105, 199.
10. (a) James, P.; Hall, B. D.; Whelen, S.; Craig, E. A. Gene
1992, 122, 101. (b) Stuckey, J. A.; Schubert, H. L.; Fauman,
E. B.; Zhang, Z. Y.; Dixon, J. E.; Saper, M. A. Nature 1994,
370, 571. (c) van Huijsduijnen, R. H. Gene 1998, 225, 1.