B. Hugon et al. / Tetrahedron Letters 44 (2003) 3935–3937
3937
Table 1. Melting points (mp in °C) of compounds 4–9
6. Busby, E. C.; Leistritz, R. T.; Karnitz, L. M.; Sarkaria, J.
N. Cancer Res. 2000, 60, 2108–2112.
7. Wang, Y.; Li, J.; Booher, R. N.; Kraker, A.; Lawrence,
T.; Leopold, W. R.; Sun, Y. Cancer Res. 2001, 61,
8211–8217.
8. Curman, D.; Cinel, B.; Williams, D. E.; Rundle, N.;
Block, W. D.; Goodarzi, A. A.; Hutchins, J. R.; Clarke,
P. R.; Zhou, B.-B. S.; Lees-Miller, S. P.; Andersen, R. J.;
Roberge, M. J. Biol. Chem. 2001, 276, 17914–17919.
9. Berlinck, R. G. S.; Britton, R.; Piers, E.; Lim, L.;
Roberge, M.; Moreira da Rocha, R.; Andersen, R. J. J.
Org. Chem. 1998, 63, 9850–9856.
Compound
Mp (°C)
4
5
6
7
8
9
\300
\300
\300
\300
294 (decomposition)
184 (decomposition)
10. Bergman, J.; Janosik, T.; Koch, E.; Pelcman, B. J. Chem.
obtained only the isomer 3 by refluxing 2 in dioxane for
18 h. Oxidation of compound 3 with DDQ in dioxane
for 24 h led to compound 4 in 60% yield (Scheme 1).13
Soc., Perkin Trans. 1 2000, 2615–2621.
11. Bergman, J.; Desarbre, E.; Koch, E. Tetrahedron 1999,
55, 2363–2370.
12. Typical procedures for the preparation of 4: Method A:
compound 3 (86 mg, 0.277 mmol) was dissolved in diox-
ane (5 mL) and DDQ (138 mg, 0.610 mmol) was added.
The mixture was refluxed for 3 days. After cooling to
room temperature, water and EtOAc were added. The
precipitate was filtered off, washed with water and EtOAc
then dried to give 4 as an orange solid (51 mg, 0.167
mmol, 60% yield).
Analogues 5 and 6 were obtained using identical
sequences of reactions with one or two N-methyl
maleimide moieties.
Compound 7 was synthesized from commercially avail-
able 5-benzyloxy-indole and two N-methyl maleimide
units. Compounds 4–7 being highly insoluble, we inves-
tigated the possibility of obtaining a water-soluble ana-
logue. In previous structure–activity relationship studies
on rebeccamycin analogues, the solubility and the bio-
logical activity could be enhanced by introducing at the
imide nitrogen a diethylaminoethyl chain.14,15 Com-
pound 9 was prepared from anhydride 8 as shown in
Scheme 2.16 Indolylmaleimide was transformed to the
corresponding anhydride using aqueous sodium
hydroxide. A Diels–Alder reaction was then carried out
with N-methyl maleimide, followed by oxidation using
TFA. Finally, the anhydride, which is more reactive
than the imide toward amines, reacted with diethyl-
aminoethylamine to give the N-substituted imide which
was converted to hydrochloride 9. The melting points
of compounds 4–9 are reported in Table 1.
Method B: a mixture of compound 2 (120 mg, 0.388
mmol), dioxane (24 mL) and trifluoroacetic acid (400 mL)
was refluxed for 24 h. After removal of the solvent, the
solid residue was dissolved into EtOAc, washed with
saturated aqueous NaHCO3, and brine. Filtration of the
solid formed at the interface gave 4 (110 mg, 0.360 mmol,
93% yield).
13. Spectral data of 4: IR (KBr): wCꢀO 1690, 1730, 1745, 1780
cm−1; wNH 3280–3380 cm−1. HRMS (FAB+) (M+H)+
calcd for C16H8N3O4, 306.0515, found, 306.0510. 1H
NMR (400 MHz, DMSO-d6) l 7.45 (1H, t, J=7.5 Hz),
7.71 (1H, t, J=7.5 Hz), 7.78 (1H, d, J=8.0 Hz), 9.01
(1H, d, J=8.0 Hz), 11.58 (1H, s, NH), 11.60 (1H, s, NH),
12.72 (1H, s, NH). 13C NMR (100 MHz, DMSO-d6) l
112.9, 121.6, 125.5, 130.0 (C tert arom), 118.0, 119.4,
119.5, 124.3, 125.8, 131.5, 136.8, 144.1 (C quat arom),
166.4 (2C), 168.6, 169.3 (CꢀO).
14. Kaneko, T.; Wong, H.; Utzig, J.; Schurig, J.; Doyle, T.
W. J. Antibiot. 1990, 43, 125–127.
15. Prudhomme, M.; Marminon, C.; Anizon, F.; Moreau, P.;
Hickman, J. A.; Pfeiffer, B.; Renard, P.; Pierre´, A. Proc.
Am. Assoc. Cancer Res. 2001, 42, 257 (Abstr).
In summary, we have described the preparation of
granulatimide analogues in which the aromatic frame-
work is a dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetra-
one. Biological studies are in progress to evaluate the
influence of the replacement of the imidazole heterocy-
cle by a maleimide.
16. Spectral data of 9: IR (KBr): wCꢀO=1710, 1720, 1765,
1775 cm−1, wNH=3300–3600 cm−1. HRMS (FAB+) (M+
1
H+) calcd for C23H23N4O4, 419.1719, found, 419.1713. H
References
NMR (400 MHz, DMSO-d6): 1.27 (6H, t, J=7.0 Hz),
3.18 (3H, s, NCH3), 3.35 (4H, m), 3.50 (2H, m), 4.09 (2H,
t, J=6.5 Hz), 7.51 (1H, t, J=8.0 Hz), 7.75 (1H, t, J=8.0
Hz), 7.84 (1H, d, J=8.5 Hz), 9.04 (1H, d, J=8.5 Hz),
9.43 (1H, br s), 12.95 (1H, s, NH). 13C NMR (100 MHz,
DMSO-d6): 8.2 (2C) (CH3), 24.0 (NCH3), 32.6, 46.1 (2C),
47.9 (CH2), 113.0, 121.8, 125.4, 130.4 (C tert arom),
116.7, 118.2, 119.2, 124.5, 124.7, 130.1, 136.6, 144.3 (C
quat arom), 164.8, 165.0, 167.1, 167.6 (CꢀO).
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