S. Papot et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1835±1837
1837
4. Jacquesy, J.-C.; Gesson, J.-P.; Monneret, C.; Mondon, M.;
Renoux, B.; Florent, J.-C.; Koch, M.; Tillequin, F.; Sedlacek,
H. H.; Gerken, M.; Kolar, C.; Gaudel, G.; Bosslet, K.; Czech,
J.; Homann, D.; Seeman, G. Eur. Pat. Appl. EP 511,917,
1992, Chem. Abstr. 1994, 120, 271070s.
5. Bosslet, K.; Czech, J.; Lorenz, P.; Sedlacek, H. H.; Schuer-
mann, M.; Seeman, G. Br. J. Cancer 1992, 65, 234.
6. (a) Fishman, W. H.; Anlyan, A. J. J. Biol. Chem. 1947, 169,
449. (b) Fishman, W. H.; Baker, J. R.; Borges, P. R. F. Cancer
1959, 12, 240.
7. Sperker, B.; Backman, J. T.; Kroemer, H. K. Clin. Phar-
macol. 1997, 33, 18.
8. Bosslet, K.; Czech, J.; Homann, D. Tumor Targeting
1995, 1, 45.
9. Florent, J.-C.; Gaudel, G.; Mitaku, S.; Monneret, C.; Ges-
son, J.-P.; Jacquesy, J.-C.; Mondon, M.; Renoux, B.; Andria-
nomenjanahary, S.; Michel, S.; Koch, M.; Tillequin, F.;
Gerken, M.; Czech, J.; Straub, R.; Bosslet, K. J. Med. Chem.
1998, 41, 3572.
10. For a study of a similar prodrug of a phenol mustard see:
Lougestay-Madec, R.; Florent, J.-C.; Monneret, C.; Nematti, F.;
Poupon, M.-F. Anti-Cancer Drug Design 1998, 13, 995.
11. (a) Shulman-Roskes, E. M.; Noe, D. A.; Gamcsik, M. P.;
Marlow, A. L.; Hilton, J.; Hausheer, F. H.; Colvin, O. M.;
Ludeman, S. M. J. Med. Chem. 1998, 41, 515. (b) le Roux, C.;
Modro, A. M.; Modro, T. A. J. Org. Chem. 1995, 60, 3832. (c)
Chan, K. K.; Hong, P. S.; Tutsch, K.; Trump, D. L. Cancer Res.
1994, 54, 6421.
Figure 1. (a) HPLC analysis of an assay after incubation of 9 with
GUS for 45 min. Peak noted as X corresponds to 3-nitro-4-hydroxy
benzyl alcohol; (b) HPLC analysis of a mixture of 11 and 4 (for con-
ditions see ref 17).
12. Ghosh, A. K.; Farquhar, D. Tetrahedron Lett. 1997, 38,
8795.
13. Eaton, M. A. W.; Pratt, A. J.; Alexander, R. P. Eur. Pat.
Appl. EP 392,745 1990.
cleavage, oxazolidinone 11 as a result of a side reaction
of the intermediate carbamic acid. Although cyclization
may be very fast in this case, it may thus be worthwhile
to study the rate of decarboxylation of such prodrug
intermediates, depending on amine substrates and con-
ditions, to avoid diusion of the hydrophilic carbamic
acid from the tumor area.
14. Selected data for 9: mp 155 ꢀC, [a]D 570 (c 0.07, H2O);
d1H (CD3OD) 3.50±3.80 (m, 11H), 3.95 (d, 1H, J=9.3 Hz),
5.16 (s, 2H), 5.19 (broad s, 1H), 7.45 (d, 1H, J=8.7 Hz), 7.62
(dd, 1H, J=8.7 and 2.1 Hz), 7.87 (d, 1H, J=2.1 Hz); d13C
(CD3OD) 42.4, 43.0, 50.8, 51.1, 67.3, 73.0, 74.6, 76.9, 77.6,
102.6, 119.1, 126.1, 132.9, 135.0, 142.2, 151.1, 157.6, 170.9; SM
(FAB+): 535 (MN+a), 371, 273, 242, 214; exact mass (FAB HR)
M+Na calcd 535.0498 g mol 1, exp. 535.0509 g mol
.
1
Acknowledgements
15. Cytotoxicity tests were carried out as described in ref 9,
except for the use of LoVo cells.
Financial support from HMR and the `Ligue Nationale
Contre le Cancer, Comite de Charente-Maritime' is
gratefully acknowledged.
16. b-Glucuronidase from E. coli and from bovine liver were
purchased from Sigma (respectively, Cat G-7896, type X-A and
Cat G-0501, type B-10). Assay with b-glucuronidase from E. coli:
90 units of enzyme and 2 mmol of prodrug were incubated in 0.02
M phophate buer pH 7 at 37 ꢀC. Assay with b-glucuronidase
from bovine liver: 100 units of enzyme and 2 mmol of prodrug
were incubated in a 0.02 M phophate buer pH 5 at 37 ꢀC.
17. HPLC conditions: A C18 reverse phase column (Lichro-
sorb, 5 mm, 250Â4.6 mm) was used, the mobile phase was
MeCN±0.02 M phosphate buer, pH 7.0 or 5.0 (70:30) with a
¯ow rate of 0.8 mL min 1. A UV detector WatersTM 486 was
set at 254 nm. An HPLC Refractive Index detector Model
8120 from ICS.N and detection system was driven by PICx
version PIC3 0-4-0 from Normasoft. Retention times for pro-
drug, 3-nitro-4-hydrobenzyl alcohol, oxazolidinone and nor-
nitrogen mustard (and/or chloroethylaziridine), respectively,
are 3.2 , 4 , 4.3 and 5.5 min.
References and Notes
1. Bagshawe, K. D. Br. J. Cancer 1987, 56, 531.
2. (a) Jungheim, L. N.; Sheperd, T. A. Chem. Rev. 1994, 94,
1553. (b) Tillequin, F.; Desbene, S.; Gesson, J.-P.; Monneret,
C. In Studies in Natural Product Chemistry; Atta-ur-Rahman,
Ed.; Amsterdam, 1998; Vol. 21. (c) Syrigos, K. N.; Epenetos,
A. A. Anticancer Res. 1999, 19, 605.
3. Roer, S. R.; Wang, S. M.; Chern, J. W.; Yeh, M. Y.;
Tung, E. Biochem. Pharmacol. 1991, 42, 2062; Wang, S. M.;
Chern, J. W.; Yeh, M. Y.; Ng, J. C.; Tung, E.; Roer, S. R.
Cancer Res. 1992, 52, 4484.