1908
V. C. O. Njar et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1905±1908
6. (a) White J. A.; Guo, Y-D.; Baetz, K.; Beckett-Jones, B.;
Bonasoro, J.; Hsu, K. E.; Dilworth, F. J.; Jones. G.; Petko-
vich, M. J. Biol. Chem. 1996, 271, 29922. (b) Abu-Abed, S. S.;
Beckett, B. R.; Chiba, H.; Chithalen, J. V.; Jones, G.; Metzger,
D.; Chambon, P.; Petkovich, M. J. Biol. Chem. 1998, 273,
2409. (c) White J. A.; Beckett-Jones, B.; Guo, Y-D.; Dilworth,
F. J.; Bonasoro, J.; Jones. G.; Petkovich, M. J. Biol. Chem.
1997, 272, 18538.
7. (a) Vanden Bossche, H.; Willemsens, G. In Retinoids: 10
Years On; Staurat J. H., Ed.; Karger: Basel, 1990; pp 78±88.
(b) Wouters, W.; Van Dun, J.; Dillen, A.; Coene, M.-C.;
Cools, W.; De Coster, R. Cancer Res. 1992, 52, 2841. (c)
Krekels, M. D. W. G.; Zimmerman, J.; Janssens, B.; Van
Ginckel, R.; Van Hove, C.; Coene, M.-C.; Wouters, W.
Prostate 1995, 29, 35-41.
8. (a) Van Wauwe, J. P.; Coene, M-C.; Goossens, J.; Van
Nijen, G.; Cools, W.; Lauwers, W. J. Pharmacol. Exp. Ther.
1988, 245, 718. (b) De Coster, R.; Wouters, W.; Van Ginckel,
R.; End, D.; Krekels, M.; Coene, M.-C.; Bowden, C. J.
Steroid Biochem. Molec. Biol. 1992, 43, 197.
9. Waxman, J.; Roylance, R. Eur. J. Cancer 1998, 34, 437.
10. Vanden Bossche, H.; Koymans, L.; Mooreels, H. Phar-
mac. Ther. 1995, 57, 79.
11. Njar, V. C. O.; Kato, K.; Nnane, I. P.; Grigoryev, D. N.;
Long, B. J.; Brodie, A. M. H. J. Med. Chem. 1998, 41, 902.
12. A portion of this work was recently presented as an oral
paper: Njar, V. C. O.; Nnane, I. P.; Brodie, A. M. H. Abstract
of Papers, 218th National Meeting of the American Chemical
Society, New Orleans, LA, August 22±26 1999; American
Chemical Society: Washington, DC, 1999; MEDI 166.
13. Freyne, E.; Raeymaekers, A.; Venet, M.; Sanz, G.; Wou-
ters, W.; De Coster, R.; Van Wauwe, J. Bioorg. Med. Chem.
Lett. 1998, 8, 267.
3H, 18-CH3), 1.87 (m, 2H, 2-Hs), 2.02 (s, 3H, 19-CH3), 2.32 (s,
3H, 20-CH3), 4.84 (s, 1H, 4-H), 5.85 (s, 1H, 14-H), 6.21 (s, 3H,
7-, 10- and 12-Hs), 6.33 (d, J=15.0 Hz, 1H, 8-H), 7.00 (t,
J=14.0 Hz, 1H, 11-H), 7.16 (s, 1H, 40-H), 7.26 (s, 1H, 50-H),
7.46, (s, 1H, 20-H), 8.75 (brs, 1H,-COOH). Anal. calcd for
C23H30O2N2: C, 75.38; H, 8.25; N. 7.64. Found: C, 75.72; H,
8.65; N, 7.67. HRMS calcd for C23H30O2N2 366.3061, found
366.305. Data for 7: mp 95±97 ꢁC. 1H NMR (300 MHz) d 1.10
and 1.13 (2s, 6H, 16- and 17-CH3s), 1.50 (brs, 2H, 3-Hs), 1.65
(s, 3H, 18-CH3), 1.97 (m, 2H, 2-Hs), 2.03 (s, 3H, 19-CH3), 2.36
(s, 3H, 20-CH3), 4.86 (s, 1H, 4-H), 5.84 (s, 1H, 14-H), 6.32 (m,
4H, 7-, 8-, 10- and 12-Hs), 7.01 (t, J=14.5 Hz, 1H, 11-H), 8.10
(s, 1H, 30-H), 8.31 (s, 1H, 50-H), 8.46 (brs, 1H,-COOH). Anal.
calcd for C22H29O2N3: C, 71.90; H, 7.95; N, 11.43. Found: C,
71.70; H, 8.11; N, 11.53. HRMS calcd for C22H29O2N3
367.4938, found 367.4935. Data for 8: mp 105±108 ꢁC. 1H
NMR (300 MHz) d 1.11 and 1.14 (2s, 6H, 16- and 17-CH3s),
1.52 (m, 2H, 3-Hs), 1.65 (s, 3H, 18-CH3), 1.96 (m, 2H, 2-Hs),
2.03 (s, 3H, 19-CH3), 2.37 (s, 3H, 20-CH3), 4.78 (s, 1H, 4-H),
5.85 (s, 1H, 14-H), 6.19 (m, 4H, 7-, 8-, 10- and 12-Hs), 7.01 (t,
J=14.2 Hz, 1H, 11-H), 8.46 (s, 2H, 30- and 50-Hs), 8.65 (brs,
1H,-COOH). Anal. calcd for C22H29O2N3: C, 71.90; H, 7.95;
N, 11.43. Found: C, 71.90; H, 7.79; N, 11.30. HRMS calcd for
C22H29O2N3 367.4938, found 367.4939.
17. Van Weuwe, J.; Van Nyen, G.; Coene, M.-C.; Stoppie, P.;
Cols, W.; Goossens, J.; Borghgraef, P.; Janssen, P. A. J. J.
Pharmacol. Expt. Ther. 1992, 261, 773.
18. Hamster liver microsomes (500 mg of protein) were incu-
bated for 30 min at 37 ꢁC with [11,12-3H]ATRA (0.4 mCi,
7.72 pmol) and NADPH. The extracts were analyzed with C18
Bondapak column eluted with a multi-linear gradient solvent
system: I, MeOH:H2O:HCOOH (60:40:0.05) containing
10 mM NH4OAc (100!0%) and ii, MeOH (0!100%) at
2 mL/min. The Rts of ATRA, 4-hydroxy-ATRA and 4-oxo-
ATRA were determined by UV absorbance at 350 nm. Typi-
cally, 80Æ5% of [11,12-3H]ATRA was converted into the
metabolites.
14. Njar, V. C. O. Synthesis, in press.
15. (a) Rosenberger, M. J. Org. Chem. 1982, 47, 1698. (b)
Samokyszyn, V. M.; Gall, W. E.; Zawada, G.; Freyalden-
hoven, M. A.; Chen, G.; Mackenzie, P. I.; Tephly, T. R.;
Radominska-Pandya, A. J. Med. Chem. 2000, 275, 6908.
19. Detailed experiments with these novel RAMBAs involving
enzyme speci®city, retinoid receptor binding, and in vivo anti-
tumor studies are in progress.
16. Data for 4: mp 128±130 ꢁC. H NMR (300 MHz, CDCl3)
1
d 1.13 (s, 6H, 16- and 17-CH3s), 1.56 (m, 2H, 3-Hs), 1.67 (s,