M. Chioua et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4566–4569
4569
12. Marco-Contelles, J.; León, R.; de los Ríos, C.; Guglietta, A.; Terencio, J.; López, M.
G.; García, A. G.; Villarroya, M. J. Med. Chem. 2006, 49, 7607. and references
cited therein.
13. For related studies on dual GSK-3/CDK-1 inhibitors, see: Logé, C.; Testard, A.;
Théry, V.; Lozach, O.; Blairvacq, M.; Robert, J.-M.; Meijer, L.; Besson, T. Eur. J.
Med. Chem. 2008, 43, 1469.
14. (a) Schmidt, H. W.; Junek, H. Monatsch. Chem. 1977, 108, 895; (b) Piper, J. R.;
McCaleb, G. S.; Montgomery, J. A.; Gaumont, Y.; Sirotnak, F. M. J. Med. Chem.
1986, 29, 1080.
15. Murray, T. J.; Zimmerman, S. C.; Kolotuchin, S. V. Tetrahedron 1995, 51, 635.
16. (a) Cottis, S. G.; Clarke, P. B.; Tieckelmann, H. J. Heterocycl. Chem. 1965, 2, 192;
(b) Pochat, F. Tetrahedron 1986, 42, 4461; (c) Abdelrazek, F. M.; Metwally, N. H.;
Sobhy, N. A. Afinidad 2006, 63, 149; (d) El-Mobayed, M.; Essawy, A.-N.; El-
Bahnasawy, A. A.; Amer, A. M. Gazz. Chim. Ital. 1991, 121, 209.
17. All compounds showed NMR and LC/MS data, in full agreement with their
structures, or with the reported data in literature.
Acknowledgements
M.C. thanks Instituto de Salud Carlos III (Ministerio de Salud y
Consumo) for a post-doctoral fellowship. AS thanks CSIC for a I3P
Post-doctoral Contract. J.M.C. thanks also MEC (SAF2006-08764-
C02-01), Comunidad de Madrid (S/SAL-0275-2006), and ISCIII
[Retic RENEVAS (RD06/0026/1002)] for support. J.M.C. thanks Prof.
A. Martínez (IQM, CSIC, Spain) for helpful suggestions and
discussions.
Supplementary data
18. It is well known that in similar heterocyclic systems, alkyl hydrazines displace
Supplementary data associated with this article can be found, in
chloro atoms through the a-nitrogen, and that aryl hydrazides reacts at the b-
nitrogen: (a) Schmidt, P.; Eichenberger, M.; Wilhelm, M.; Druey, J. Helv. Chim.
Acta 1959, 42, 763; (b) Hauser, M.; Peters, E.; Tieckelmann, H. J. Org. Chem.
1960, 25, 1570.
References and Notes
19. The formation of the monocetylated derivative
9 was surprising but
inequivocal as two broad singlets at d 7.40 and 4.82, integrating for two
protons were detected in the 1H MNR spectrum (for a similar reactivity, see:
Pevarello, P. et al. Bioorg. Med. Chem. Lett. 2006, 16, 1084). The location of the
acetyl group at N2 cannot be discarded; in fact, in precursor 4, a clear NOE
effect has been detected between the N–H group and (C3)NH2. Work is in
progress to confirm this hypothesis.
1. Beutner, G. L.; Kuethe, J. T.; Kim, M. M.; Yasuda, N. J. Org. Chem. 2009, 74, 789.
2. 5-Aryl-pyrazolo[3,4-b]pyridines: (a) Witherington, J.; Bordas, V.; Garland, S. L.;
Hickey, D. M. B.; Ife, R. J.; Liddle, J.; Saunders, M.; Smith, D. G.; Ward, R. W.
Bioorg. Med. Chem. Lett. 2003, 13, 1577; 6-aryl-pyrazolo[3,4-b]pyridines: (b)
Witherington, J.; Bordas, V.; Gaiba, A.; Garton, N. S.; Naylor, A.; Rawlings, A. D.;
Slingsby, B. P.; Smith, D. G.; Takle, A. K.; Ward, R. W. Bioorg. Med. Chem. Lett.
2003, 13, 3055; 6-heteroaryl-pyrazolo[3,4-b]pyridines: (c) Witherington, J.;
Bordas, V.; Gaiba, A.; Garton, N. S.; Naylor, A.; Rawlings, A. D.; Slingsby, B. P.;
Smith, D. G.; Takle, A. K.; Ward, R. W. Bioorg. Med. Chem. Lett. 2003, 13, 3059.
3. Manning, G.; Whyte, D. B.; Martínez, R.; Hunter, T.; Sudarsanam, S. Science
2002, 298, 1912.
4. Knockaert, M.; Greengard, P.; Meijer, L. Trends Pharmacol. Sci. 2002, 23, 417.
5. Glycogen Synthase Kinase 3 (GSK-3) and Its Inhibitors; Martínez, A., Castro, A.,
Medina, M., Eds.; John Wiley & Sons, 2006.
6. Woodgett, J. R. Trends Biochem. Sci. 1991, 16, 177.
7. Ghosh, S.; Karin, M. Cell 2002, 109, S91.
20. Doyle, M. P.; Siegfried, B.; Dellaria, J. F. J. Org. Chem. 1977, 42, 2426.
21. (a) Peinador, C.; Veiga, M. C.; Vilar, J.; Quintela, J. M. Heterocycles 1994, 38,
1299; (b) Quintela, J. M.; Soto, J. L. Anal. Quim. C 1983, 368.
22. Álvarez-Insúa, A. S.; Lora-Tamayo, M.; Soto, J. L. Anal. Quim. 1970, 1305.
23. CDK5/p25, GSK-3a/b, DYRK1A were assayed in the presence of 15 lM ATP as
described in references (a), (b) and (c), respectively. (a) Leclerc, S.; Garnier, M.;
Hoessel, R.; Marko, D.; Bibb, J. A.; Snyder, G. L.; Greengard, P.; Biernat, J.;
Mandelkow, E.-M.; Eisenbrand, G.; Meijer, L. J. Biol. Chem. 2001, 276, 251; (b)
Primot, A.; Baratte, B.; Gompel, M.; Borgne, A.; Liabeuf, S.; Romette, J. L.;
Costantini, F.; Meijer, L. Protein Exp. Purif. 2000, 20, 394; (c) Renault, S.; Lozach,
O.; Meijer, L.; Carreaux, F.; Bazureau, J.-P. J. Med. Chem. 2009, in preparation.
24. (a) Aoki, M.; Iwamoto-Sugai, M.; Sugiura, I.; Sasaki, C.; Hasegawa, T.; Okumura,
C.; Sugio, S.; Kohno, T.; Matsuzaki, T. Acta Crystallogr., Sect. D: Biol. Crystallogr.
2000, D56, 1464; (b) Bax, B.; Carter, P. S.; Lewid, C.; Guy, A. R.; Bridges, A.;
Tanner, R.; Pettman, G.; Mannix, C.; Culbert, A. A.; Brown, M. J. B.; Smith, D. G.;
Reith, A. D. Structure (London) 2001, 9, 1143.
8. Peifer, M.; Polakis, P. Science 2000, 287, 1606.
9. Bhatt, R.; Xue, Y.; Berg, S.; Hellberg, S.; Ormö, M.; Nilsson, Y.; Radesáter, A.-C.;
Jerning, E.; Markgren, P.-O.; Borgegàrd, T.; Nylöf, M.; Giménez-Cassina, A.;
Hernández, F.; Lucas, J. L.; Díaz-Nido, J.; Ávila, J. J. Biol. Chem. 2003, 278, 45937.
10. Malumbres, M.; Pevarello, P.; Barbacid, M.; Bischoff, J. R. Trends Pharmacol. Sci.
2008, 29, 16.
11. Oumata, N.; Bettayeb, K.; Ferandin, Y.; Demange, L.; López-Giral, A.; Goddard,
M.-L.; Myrianthopoulos, V.; Mikros, E.; Flajolet, M.; Greengard, P.; Meijer, L.;
Galons, H. J. Med. Chem. 2008, 51, 5229.
25. We thank one the reviewers for this suggestion. The preparation of these new
molecules needs a new synthetic plan, now in progress in our laboratory, based
on the reaction of compound 2 with benzylhydrazine, pyrazole formation,
regioselective N-acylation, and N1 deprotection.