B. Dumont-Hornebeck et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2325±2327
2327
2-aminoaromatic urea, which can be cyclized by diazo-
tation at the last step of the total synthesis. The avail-
ability of this ®rst water soluble tetrazepinone will
stimulate further studies on the interactions of tetra-
zepinones with water soluble biomolecules and thereby
signi®cantly improve our understanding of the mechan-
ism of action of this novel class of cytotoxic agents.
8. Jean-Claude, B. J.; Britten, J. F.; Just, G. Acta Crystallogr.
1993, C49, 1070.
9. Jean-Claude, B. J.; Williams, C. I. Magn. Res. Chem. 1998,
36, 87.
10. Clark, S. A.; Deans, B.; Stevens, M. F. G.; Tisdale, M. J.;
Wheelhouse, R. T.; Denny, B. J.; Hartley, J. A. J. Med. Chem.
1995, 38, 1493.
11. Horspool, K. R.; Stevens, M. F. G.; Newton, C. G.; Lunt,
E.; Walsh, R. J. A.; Pedgrift, B. L.; Baig, G. U.; Lavelle, F. J.
Med. Chem. 1990, 33, 1393.
Acknowledgements
12. Experimental data for 12: Urea 11b (95 mg, 0.2 mmol) was
dissolved in 2.4 N HCl (10 mL) and a solution of 27% NaNO2
(1 mL) [50% enriched with 15N NaNO2] was added dropwise
at 0 ꢀC. After 30 min, the solution was extracted three times
with 25 mL portions of CH2Cl2. The aqueous layer was sepa-
rated and neutralized with saturated sodium bicarbonate, after
which it was further re-extracted three times with 25 mL por-
tions of CH2Cl2. The organic layer was removed and dried
over anhydrous potassium carbonate and evaporated to give
12 (50 mg, 51%) as a pale brown powder: mp 125±130 ꢀC
(eervescence); dH (CDCl3) 7.95 (1H, d, J=2 Hz, Ar), 7.93
(1H, dd, J=8.6 Hz, J=2, Ar), 7.26 (d, 1H, J=8.6, Ar), 7.05
(1H, br s, NHCO), 3.78 (4H, m, (CH2)2), 3.59 (2H, br q,
NCH2CH2NHCO), 3.42 (3H, d, 3J 15NH=2.8 Hz, 15NNCH3),
3.31 (3H, s, N(CO)CH3), 2.64 (2H, t, J=4.5 Hz, NCH2CH2
NHCO), 2.5 (4H, m, morpholine CH2N); dN (CDCl3): 69.16.
dC (CDCl3): 165.25, 159.02, 140.82, 130.42, 130.07, 125.63,
125.57, 119.98, 119.76, 66.58, 57.01, 53.29, 35.90, 35.07. CIMS
(NH3) m/z 319 (MH+ 15NN, 3.3%), 291 (MH+ CH3NCO,
100). Anal. calcd for C16H22N6O3: C, 55.5; H, 6.4; N, 24.3.
Found: C, 55.27; H, 6.33; N, 24.5.
We thank the National Cancer Institute of Canada
(NCIC) and the Fonds pour la formation des Chercheurs
et l'Aide a la Recherche (FCAR) for ®nancial support.
References and Notes
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