3148
R. L. Beard et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3145–3148
Table 2. Compound 4 and ATRA inhibit growth of the human
breast cancer cell lines, T-47D and SK-BR-3,15 compound 4 does not
cause the topical irritation induced by the RARa-selective retinoid,
Am-5803b
Practice; Korean, G., Ed.; Mercel Dekker: New York, 1992; p 47 .
(b) Standeven, A. M.; Johnson, A. T.; Escobar, M.; Chan-
draratna, R. A. S. Toxicol. Appl. Pharmacol. 1996, 138, 169.
4. (a) Petkovich, M.; Brand, N. J.; Krust, A.; Chambon, P.
Nature 1987, 330, 444. (b) Giguere, V.; Ong, E. S.; Segui, P.;
Evans, R. M. Nature 1987, 330, 624. (c) Krust, A.; Kastner, P.;
Petkovich, M.; Zelent, A.; Chambon, P. Proc. Natl. Acad.
U.S.A. 1989, 86, 5310.
Compd
T-47D
IC50 (nM)
(% efficacy)
SK-BR-3
IC50 (nM)
(% efficacy)
Topical irritation
score
(0–21)
ATRA
Am 580
4
200Æ71 (74)
NDa
1.4Æ1.8 (57)
1.7Æ0.5 (99)
NDa
11Æ7(93)
NDa
16Æ1
0 Æ0
5. (a) Heyman, R. A.; Mangelsdorf, D. J.; Dyck, J. A.; Stein,
R. B.; Eichele, G.; Evans, R. M.; Thaller, C. Cell 1992, 68,
397. (b) Levin, A. A.; Sturzenbecker, L. J.; Kazmer, S.; Bosa-
kowski, T.; Huselton, C.; Allenby, G.; Speck, J.; Kratzeisen,
C.; Rosenberger, M.; Lovey, A.; Grippo, J. F. Nature 1992,
355, 359.
6. Elder, J. T.; Fisher, G. J.; Zhang, Q.-Y.; Eisen, D.; Krust,
A.; Kastner, P.; Chambon, P.; Voorhees, J. J. J. Invest. Der-
matol. 1991, 96, 425.
7. Reczek, P. R.; Ostrowski, J.; Yu, K.-L.; Chen, S.; Hammer,
L.; Roalsvig, T.; Starrett, J. E., Jr.; Driscoll, J. P.; Whiting, G.;
Spinazze, P. G.; Tramposch, K. M.; Mansuri, M. M. Skin
Pharmacol. 1995, 8, 292.
8. Beard, R. L.; Chandraratna, R. A. In Handbook of
Experimental Pharmacology, Retinoids The Biochemical and
Molecular Basis of Vitamin A and Retinoid Action; Nau, H.,
Blaner, W. S., Eds.; Springer: Berlin Heidelberg, 1999; Vol.
139, p 185.
aND, not determined. Efficacy (%) is the percent inhibition of BrdU
incorporated in dividing cells at the highest dose tested (1 mM) relative
to vehicle control.
non-selective retinoid agonists. Such compounds will
have improved therapeutic indices relative to the non-
selective retinoids currently available and greater utility
in treating cancers and other serious retinoid responsive
diseases. Compound 4 (AGN 195183) is currently in
Phase I/IIA clinical trials in cancer patients.
Acknowledgements
9. Kagechika, H.; Kawachi, E.; Hashimoto, Y.; Himi, T.;
Shudo, K. J. Med. Chem. 1988, 31, 2182.
We are grateful to Mr. Hai Nguyen for mass spectral
analyses.
10. Renaud, J.-P.; Rochel, N.; Ruff, M.; Vivat, V.; Chambon,
P.; Gronemeyer, H.; Moras, D. Nature 1995, 378, 681.
11. Teng, M.; Duong, T. T.; Klein, E. S.; Pino, M. E.; Chan-
draratna, R. A. S. J. Med. Chem. 1996, 39, 3035.
1
12. All new compounds gave H NMR, 13C NMR, IR, and
References and Notes
HRMS data consistent with their structures.
13. Qing, F.-L.; Fan, J.; Sun, H.-B.; Yue, X.-J. J. Chem. Soc.,
Perkin. Trans. 1 1997, 20, 3053.
14. (a) Transactivation assay: Benbrook, D.; Lernhardt, E.;
Pfahl, M. Nature 1988, 333, 669. (b) Graupner, G.; Malle, G.;
´
Maignan, J.; Lang, G.; Prunieras, M.; Pfahl, M. BBRC 1991,
179, 1554. Binding assay: Allegretto, E. A.; McClurg, M. R.;
Lazarchik, S. B.; Clemm, D. L.; Kerner, S. A.; Elgrot, M. G.;
Boehm, M. F.; White, S. K.; Pike, J. W.; Heyman, R. A.
J. Biol. Chem. 1993, 268, 26625.
15. Fitzgerald, P.; Teng, M.; Chandraratna, R. A. S.; Hey-
man, R. A.; Allegretto, E. A. Cancer Res. 1997, 57, 2642.
1. Review: Sporn, M. B., Roberts, A. B., Goodman, D. S.,
Eds. The Retinoids: Biology, Chemistry, and Medicine; 2nd ed.;
Raven: New York, 1994.
2. (a) Huang, M. E.; Ye, Y. C.; Chen, S. R.; Chai, J. R.; Lu,
J. X.; Zhao, L.; Gu, L. J.; Wang, Z. Y. Blood 1988, 72, 567. (b)
Motzer, R. J.; Schwartz, L.; Law, T. M.; Murphy, B. A.;
Hoffman, A. D.; Albino, A. P.; Vlamis, V.; Nanus, D. M. J.
Clin. Oncol. 1995, 13, 1950. (c) Duvic, M.; Hymes, K; Heald,
P.; Breneman, D.; Martin, A. G.; Myskowski, P.; Crowley, C.;
Yocum, R. C. J. Clin. Oncol. 2001, 19, 2456.
3. (a) Agnish, N. D.; Kochhar, D. M. In Retinoids and Clinical