5074
L. Guandalini et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5071–5074
12. Cellai, C.; Laurenzana, A.; Vannucchi, A. M.; Della Malva, N.; Bianchi, L.;
Paoletti, F. FASEB J. 2002, 16, 733.
13. Laurenzana, A.; Cellai, C.; Vannucchi, A. M.; Pancrazzi, A.; Romanelli, M. N.;
Paoletti, F. Leukemia 2005, 19, 390.
14. Cellai, C.; Laurenzana, A.; Vannucchi, A. M.; Caporale, R.; Paglierani, M.; Di
Lollo, S.; Pancrazzi, A.; Paoletti, F. Br. J. Cancer 2006, 94, 1637.
15. Nordenberg, J.; Fenig, E. l.; Landau, M.; Weizman, R.; Weizman, A. Biochem.
Pharmacol. 1999, 58, 1229.
16. Wang, J. K.; Morgan, J. L.; Spector, S. Proc. Nat. Acad. Sci. U.S.A. 1984, 81,
3770.
17. Banker, D. E.; Cooper, J. J.; Fennell, D. A.; Willman, C. L.; Appelbaum, F. R.;
Cotter, F. E. Leuk. Res. 2002, 26, 91.
18. Boitano, A.; Emal, C. D.; Leonetti, F.; Blatt, N. B.; Dineen, T. A.; Ellman, J. A.;
Roush, W. R.; Opipari, A. W.; Glick, G. D. Bioorg. Med. Chem. Lett. 2003, 13,
3327.
19. Dourlat, J.; Liu, W.-Q.; Gresh, N.; Garbay, C. Bioorg. Med. Chem. Lett. 2007, 17,
2517.
20. Minucci, S.; Pelicci, P. G. Nat. Rev. Cancer 2006, 6, 38.
21. Petrella, A.; D’Acunto, C. W.; Rodriquez, M.; Festa, M.; Tosco, A.; Bruno, I.;
Terracciano, S.; Taddei, M.; Paloma, L. G.; Parente, L. Eur. J. Cancer 2008, 44,
740.
These data underlined once more the difference between active
(S)-2 and inactive (R)-2 enantiomers.
In conclusion, newly synthesized hydroxamate-BDZ hybrids
showed to be powerful HDACi regardless of the presence or ab-
sence of a chiral center, as activity of compounds 1 and 2 was com-
parable to that of their non-chiral analogues 3 and 4. Even so, chiral
compounds demonstrated to be stereoselective.
Compounds capable of promoting acetylation of histone H4,
rather than histone H3, were also the most effective inhibitors of
leukemia cell growth and the most active inducers of apoptosis.
As regards growth inhibition activity (S)-2, 4 and SAHA yielded
overlapping IC50 values. The length and structure of the hydroxa-
mic chain can influence HDAC inhibitory properties: alkyne deriv-
atives (short-chain) were approximately two to three times more
active than suberoyl derivatives (long-chain). Work is underway
to optimize the length of the polymethylene chain.
22. Sonoda, H.; Nishida, K.; Yoshioka, T.; Ohtani, M.; Sugita, K. Oncogene 1996, 13,
143.
Acknowledgments
23. The 7-position is easily accessible from a synthetic point of view; in addition,
preliminary evidences on WEB-2086 analogs, synthesized by us, suggested
that introduction on the aryl ring of an hydroxamate-bearing chain could lead
to effective HDAC inhibition. A manuscript is under preparation.
24. Paoletti, F.; Romanelli, M. N.; Cellai, C.; Guandalini, L.; Laurenzana, A. Italian
Patent, FI2007A000288, 2007.
25. Loudni, L.; Roche, J.; Potiron, V.; Clarhat, J.; Bachmann, C.; Gesson, J. P.; Tranoy-
Opalinski, I. Bioorg. Med. Chem. Lett. 2007, 17, 4819.
26. Leit, S.; Wahhab, A.; Allan, M.; Smil, D.; Tessier, P.; Deziel, R.; Chantigny, Y. A.
WO2007022638; Chem. Abstr. 2007, 146, 295962.
This work was supported by grants from MUR (PRIN 2006
to F.P., # 200606139 and # 200606139_001; and to S.S., #
200606139_002) and the University of Florence (ex 60%), Ente Cas-
sa di Risparmio di Firenze (726/2005) and AIL (Associazione Itali-
ana contro le Leucemie Linfomi e Mieloma, Firenze).
27. Hester, J. B.; Ludens, J. H.; Emmert, D. E.; West, B. E. J. Med. Chem. 1989, 32,
1157.
Supplementary data
28. Lanotte, M.; Martin-Thouvenin, V.; Najman, S.; Balerini, P.; Valensi, F.; Berger,
R. Blood 1991, 77, 1080.
29. Singh, E. K.; Ravula, S.; Pan, C.-M.; Pan, P.-S.; Vasko, R. C.; Lapera, S. A.;
Weerasinghe, S. V. W.; Pflum, M. K. H.; McAlpine, S. R. Bioorg. Med. Chem. Lett.
2008, 18, 2549.
Experimental sections are available via the internet. Supple-
mentary data associated with this article can be found, in the on-
30. Hubbs, J. L.; Zhou, H.; Kral, A. M.; Fleming, J. C.; Dahlberg, W. K.; Hughes, B. L.;
Middleton, R. E.; Szewczak, A. A.; Secrist, J. P.; Miller, T. A. Bioorg. Med. Chem.
Lett. 2008, 18, 34.
References and notes
31. Wilson, K. J.; Witter, D. J.; Grimm, J. B.; Siliphaivanh, P.; Otte, K. M.; Kral, A. M.;
Fleming, J. C.; Harsch, A.; Hamill, J. E.; Cruz, J. C.; Chenard, M.; Szewczak, A. A.;
Middleton, R. E.; Hughes, B. L.; Dahlberg, W. K.; Secrist, J. P.; Miller, T. A. Bioorg.
Med. Chem. Lett. 2008, 18, 1859.
32. Yurek-George, A.; Cecil, A. R.; Mo, A. H.; Wen, S.; Rogers, H.; Habens, F.; Maeda,
S.; Yoshida, M.; Packham, G.; Ganesan, A. J. Med. Chem. 2007, 50, 5720.
33. Lu, Q.; Wang, D. S.; Chen, C. S.; Hu, Y. D.; Chen, C. S. J. Med. Chem. 2005, 48,
5530.
1. Zheng, Y. G.; Wu, J.; Chen, Z.; Goodman, M. Med. Res. Rev. 2008. doi:10.1002/
2. Budillon, A.; Di Gennaro, E.; Bruzzese, F.; Rocco, M.; Manzo, G.; Caraglia, M.
Recent Patent Anticancer Drug Discov. 2007, 2, 119.
3. Mai, A.; Massa, S.; Rotili, D.; Cerbara, I.; Valente, S.; Pezzi, R.; Simeoni, S.; Ragno,
R. Med. Res. Rev. 2005, 25, 261.
4. Yoshida, M.; Horinouchi, S.; Beppu, T. Bioessays 1995, 17, 423.
5. Marks, P. A.; Breslow, R. Nat. Biotechnol. 2007, 25, 84.
34. Hanessian, S.; Auzzas, L.; Giannini, G.; Marzi, M.; Cabri, W.; Barbarino, M.;
Vesci, L.; Pisano, C. Bioorg. Med. Chem. Lett. 2007, 17, 6261.
35. Hamblett, C. L.; Methot, J. L.; Mampreian, D. M.; Sloman, D. L.; Stanton, M. G.;
Kral, A. M.; Fleming, J. C.; Cruz, J. C.; Chenard, M.; Ozerova, N.; Hitz, A. M.;
Wang, H.; Deshmukh, S. V.; Nazef, N.; Harsch, A.; Hughes, B. L.; Dahlberg, W. K.;
Szewczak, A. A.; Middleton, R. E.; Mosley, R. T.; Secrist, J. P.; Miller, T. A. Bioorg.
Med. Chem. Lett. 2007, 17, 5300.
36. Shinji, C.; Maeda, S.; Imai, K.; Yoshida, M.; Hashimoto, Y.; Miyachi, H. Bioorg.
Med. Chem. 2006, 14, 7625.
37. Jones, P.; Altamura, S.; Chakravarty, P.; Cecchetti, O.; De Francesco, R.; Gallinari,
P.; Ingenito, R.; Meinke, P. T.; Petrocchi, A.; Rowley, M.; Scarpelli, R.; Serafini, S.;
Steinkuhler, C. Bioorg. Med. Chem. Lett. 2006, 16, 5948.
6. Paris, M.; Porcelloni, M.; Binaschi, M.; Fattori, D. J. Med. Chem. 2008, 51, 1505.
7. Glaser, K. B. Biochem. Pharmacol. 2007, 74, 659.
8. Finnin, M. S.; Donigian, J. R.; Cohen, A.; Richon, V. M.; Rifkind, R. A.; Marks, P. A.;
Breslow, R.; Pavletich, N. P. Nature 1999, 401, 188.
9. Somoza, J. R.; Skene, R. J.; Katz, B. A.; Mol, C.; Ho, J. D.; Jennings, A. J.; Luong, C.;
Arvai, A.; Buggy, J. J.; Chi, E.; Tang, J.; Sang, B. C.; Verner, E.; Wynands, R.; Leahy,
E. M.; Dougan, D. R.; Snell, G.; Navre, M.; Knuth, M. W.; Swanson, R. V.; McRee,
D. E.; Tari, L. W. Structure 2004, 12, 1325.
10. Vannini, A.; Volpari, C.; Filocamo, G.; Casavola, E. C.; Brunetti, M.; Renzoni, D.;
Chakravarty, P.; Paolini, C.; De Francesco, R.; Gallinari, P.; Steinkuhler, C.; Di
Marco, S. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 15064.
11. Wang, D. F.; Helquist, P.; Wiech, N. L.; Wiest, O. J. Med. Chem. 2005, 48, 6936.