Camptothecin and Minor-Groove Binder Hybrid Molecules
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 223
ester was added to the resulting amine and the mixture was
stirred for 8 h. The solvent was removed in vacuo, and the
residue was purified by column chromatography (silica gel,
THF:CHCl3) to give 39 (21.8 mg, 57% yield): 1H-NMR (DMSO-
d6) δ 10.26 (s, 1H), 10.05 (s, 1H), 8.52 (s, 1H), 8.13 (d, J ) 8
Hz, 1H), 7.62 (dd, J ) 8, 2 Hz, 1H), 7.60 (d, J ) 2 Hz, 1H),
7.56 (d, J ) 2 Hz, 1H), 7.42 (d, J ) 2 Hz, 1H), 7.23 (s, 1H),
7.10 (d, J ) 2 Hz, 1H), 6.99 (d, J ) 2 Hz, 1H), 6.50 (s, 1H,
OH), 5.63 (s, 2H), 5.58 (s, 2H), 5.40 (s, 2H), 5.23 (s, 2H), 4.84
(s, 2H), 4.09 (q, J ) 7 Hz, 2H), 3.18 (s, 3H), 3.16 (s, 3H), 1.82
(m, 2H), 1.23 (t, J ) 7 Hz, 3H), 0.83 (t, J ) 7 Hz, 3H);
HRFABMS calcd for C38H38N6O11H, 755.2677, found 755.2641
(MH+). Anal. (C38H38N6O11‚0.5H2O) C, H, N.
10.16 (s, 1H), 10.08 (s, 1H), 8.55 (s, 1H), 8.21 (t, J ) 6 Hz,
1H), 8.18 (d, J ) 8 Hz, 1H), 7.62 (dd, J ) 8, 2 Hz, 1H), 7.54 (d,
J ) 2 Hz, 1H), 7.43 (s, 2H), 7.36 (d, J ) 2 Hz, 1H), 7.26 (s,
1H), 7.06 (s, 2H), 6.90 (d, J ) 2 Hz, 1H), 6.50 (bs, 1H, OH),
5.64 (s, 4H), 5.40 (s, 2H), 5.23 (s, 2H), 4.85 (s, 2H), 3.20 (m,
2H), 3.16 (s, 6H), 3.13 (s, 3H), 2.60 (t, J ) 6 Hz, 2H), 2.40 (s,
6H), 1.85 (m, 2H), 1.72 (m, 2H), 0.96 (t, J ) 7 Hz, 3H); FABMS
calcd for C48H54N10O12H 963.40, found 963.40 (MH+). Anal.
(C48H54N10O12‚H2O) C, H, N.
10-[2-[1-(Meth oxym eth yl)-4-bu tyr a m id op yr r ole-2-ca r -
b oxa m id o]et h oxy]-20(R,S)-ca m p t ot h ecin (44). Acid 21
(13.2 mg, 0.055 mmol), DCC (11.3 mg, 0.055 mmol), and HOBt
(7.4 mg, 0.055 mmol) were stirred in DMF (30 mL) for 8 h.
Amine 9 (22.2 mg, 0.05 mmol) and triethylamine (10 mg, 0.1
mmol) were added, and stirring was continued for 8 h.
Workup was similar to that used for 38, and purification was
achieved by flash chromatography (silica gel, CHCl3:THF) to
give 44 (22.4 mg, 71% yield): 1H-NMR (DMSO-d6) δ 9.80 (s,
1H), 8.52 (s, 1H), 8.39 (t, J ) 6 Hz, 1H), 8.07 (d, J ) 8 Hz,
1H), 7.58 (d, J ) 2 Hz, 1H), 7.50 (dd, J ) 8, 2 Hz, 1H), 7.31 (d,
J ) 2 Hz, 1H), 7.28 (s, 1H), 6.80 (d, J ) 2 Hz, 1H), 6.50 (bs,
1H, OH), 5.60 (s, 2H), 5.40 (s, 2H), 5.24 (t, 2H, J ) 6 Hz), 5.23
(s, 2H), 3.64 (m, 2H), 3.15 (s, 3H), 2.20 (t, 2H, J ) 7 Hz), 1.86
(m, 2H), 1.58 (m, 2H), 0.90 (t, J ) 7 Hz, 3H); FABMS calcd for
10-[[[1-(Meth oxym eth yl)-2-[[1-(m eth oxym eth yl)-2-[[1-
(m et h oxym et h yl)-2-ca r b et h oxyp yr r ol-4-yl]ca r b a m oyl]-
p yr r ol-4-yl]ca r ba m oyl]p yr r ol-4-yl]ca r ba m oyl]m eth oxy]-
2(R,S)-ca m p toth ecin (40). Compound 11 (42.56 mg, 0.08
mmol) and 10% Pd/C (10 mg) in 20 mL of THF-MeOH (1:1)
was hydrogenated at atmospheric pressure for 4 h and then
filtered. The filtrate was concentrated in vacuo, and then DMF
(10 mL), CH2Cl2 (10 mL), 8 (21.2 mg, 0.05 mmol), and EDCI
(0.055 mmol) were added successively. The solution was
stirred under argon overnight and then evaporated to dryness.
The residue was purified on a silica gel column eluting with
THF:CHCl3 (1:1) to yield 40 (23.6 mg, 52% yield): 1H-NMR
(DMSO-d6) δ 10.30 (s, 1H), 10.18 (s, 1H), 10.12 (s, 1H), 8.55
(s, 1H), 8.14 (d, J ) 8 Hz, 1H), 7.63 (dd, J ) 8, 2 Hz, 1H), 7.62
(d, J ) 2 Hz, 1H), 7.55 (d, J ) 2 Hz, 1H), 7.42 (s, 2H), 7.28 (s,
1H), 7.13 (d, J ) 2 Hz, 1H), 7.10 (d, J ) 2 Hz, 1H), 7.01 (d, J
) 2 Hz, 1H), 6.50 (s, 1H, OH), 5.68 (s, 4H), 5.58 (s, 2H), 5.40
(s, 2H), 5.24 (s, 2H), 4.88 (s, 2H), 4.20 (q, J ) 7 Hz, 2H), 3.16
(s, 9H), 1.83 (m, 2H), 1.26 (t, J ) 7 Hz, 3H), 0.85 (t, J ) 7 Hz,
C33H35N5O8H 630.25, found 630.36 (MH+). Anal. (C33H35
-
N5O8‚H2O) C, H, N.
10-[2-[1-(Me t h oxym e t h yl)-4-[1-(m e t h oxym e t h yl)-4-
b u t yr a m id op yr r ole-2-ca r b oxa m id o)p yr r ole-2-ca r b oxy-
a m id o]eth oxy]-20(R,S)-ca m p toth ecin (45). Acid 23 (19.14
mg, 0.055 mmol), DCC (11.3 mg, 0.055 mmol), and HOBt (7.4
mg, 0.055 mmol) were stirred in DMF (30 mL) for 8 h. Amine
9 (22.2 mg, 0.05 mmol) and triethylamine (10 mg, 0.1 mmol)
were added, and stirring was continued for 8 h. Workup was
similar to that used for 38, and purification was achieved by
flash chromatography (silica gel, CHCl3:THF) to give 45 (26.6
mg, 68% yield): 1H-NMR (DMSO-d6) δ 10.04 (s, 1H), 9.82 (s,
1H), 8.52 (s, 1H), 8.42 (t, J ) 6 Hz, 1H), 8.05 (d, J ) 8 Hz,
1H), 7.58 (d, J ) 2 Hz, 1H), 7.51 (dd, J ) 8, 2 Hz, 1H), 7.39 (d,
J ) 2 Hz, 1H), 7.36 (d, J ) 2 Hz, 1H), 7.26 (s, 1H), 6.98 (d, J
) 2 Hz, 1H), 6.90 (d, J ) 2 Hz, 1H), 6.50 (bs, 1H, OH), 5.62 (s,
2H), 5.60 (s, 2H), 5.40 (s, 2H), 5.22 (s, 2H), 4.28 (t, J ) 6 Hz,
2H), 3.63 (m, 2H), 3.18 (s, 3H), 3.16 (s, 3H), 2.18 (t, J ) 7 Hz,
2H), 1.84 (m, 2H), 1.58 (m, 2H), 0.90 (t, J ) 7 Hz, 3H);
HRFABMS calcd for C40H43N7O10H 782.3149, found 782.3149
(MH+). Anal. (C40H43N7O10) C, H, N.
3H); HRFABMS calcd for C45H46N8O13
H 907.3262, found
907.3204 (MH+). Anal. (C45H46N8O13‚H2O) C, H, N.
10-[[[1-(Meth oxym eth yl)-2-[[3-(dim eth ylam in o)pr opyl]-
car bam oyl]pyr r ol-4-yl]car bam oyl]m eth oxy]-20(R,S)-cam p-
toth ecin (41). Acid 8 (21.2 mg, 0.05 mmol), DCC (11.3 mg,
0.055 mmol), and HOBt (7.4 mg, 0.055 mmol) were stirred in
DMF (20 mL) for 6 h. Separately, a solution of 26 (22.7 mg,
0.08 mmol) and 10% Pd/C in 20 mL of MeOH was stirred under
a hydrogen atmosphere (4 h) and then filtered. The filtrate
was concentrated and dried under vacuum. The residue was
added to the above solution, and stirring was continued for 8
h. The solvent was removed in vacuo, and the residue was
purified by column chromatography (silica gel, CHCl3:MeOH)
to give 41 (19 mg, 55% yield): 1H-NMR (DMSO-d6) δ 10.22 (s,
1H), 8.56 (s, 1H), 8.19 (t, J ) 6 Hz, 1H), 8.12 (d, J ) 8 Hz,
1H), 7.63 (dd, J ) 8, 2 Hz, 1H), 7.53 (d, J ) 2 Hz, 1H), 7.35 (d,
J ) 2 Hz, 1H), 7.25 (s, 1H), 6.82 (d, J ) 2 Hz, 1H), 6.50 (bs,
1H), 5.60 (s, 2H), 5.42 (s, 2H), 5.24 (s, 2H), 4.83 (s, 2H), 3.19
(m, 2H), 3.14 (s, 3H), 2.22 (t, 2H, J ) 6 Hz), 2.05 (s, 6H), 1.82
(m, 2H), 1.58 (m, 2H), 0.86 (t, J ) 7 Hz, 3H); HRFABMS calcd
for C34H38N6O8H 659.2829, found 659.2822 (MH+). Anal.
(C34H38N6O8) C, H, N.
10-[[[1-(Meth oxym eth yl)-2-[[1-(m eth oxym eth yl)-2-[[3-
(dim eth ylam in o)pr opyl]car bam oyl]pyr r olyl-4-yl]car bam -
oyl]p yr r ol-4-yl]ca r b a m oyl]m e t h oxy]-20(R ,S )-ca m p t o-
th ecin (42). Compound 42 was prepared in 65% yield from
acid 8 (21.2 mg, 0.05 mmol) and 27 (26.16 mg, 0.06 mmol) in
a manner similar to that described for 41: 1H-NMR (DMSO-
d6) δ 10.32 (s, 1H), 10.08 (s, 1H), 8.53 (s, 1H), 8.21 (t, J ) 6
Hz, 1H), 8.12 (d, J ) 8 Hz, 1H), 7.63 (dd, J ) 8, 2 Hz, 1H),
7.53 (d, J ) 2 Hz, 1H), 7.42 (d, J ) 2 Hz, 1H), 7.35 (d, J ) 2
Hz, 1H), 7.26 (s, 1H), 7.08 (d, J ) 2 Hz, 1H), 6.88 (d, J ) 2 Hz,
1H), 5.63 (s, 2H), 5.60 (s, 2H), 5.29 (s, 2H), 4.85 (s, 2H), 3.20
(m, 2H), 3.12 (s, 6H), 2.58 (t, 2H, J ) 6 Hz), 2.35 (s, 6H), 1.85
(m, 2H), 1.66 (m, 2H), 0.85 (t, J ) 7 Hz, 3H); HRFABMS calcd
for C41H46N8O10H 811.3415, found 811.3377 (MH+). Anal.
(C41H46N8O10) C, H, N.
10-[2-[1-(Met h oxym et h yl)-4-[1-(m et h oxym et h yl)-4-[1-
(m eth oxym eth yl)-4-bu tyr a m id op yr r ole-2-ca r boxa m id o]-
p yr r ole-2-ca r boxa m id o]p yr r ole-2-ca r boxa m id o]eth oxy]-
20(R,S)-ca m p toth ecin (46). Acid 25 (30 mg, 0.05 mmol),
DCC (11.3 mg, 0.055 mmol), and HOBt (7.4 mg, 0.055 mmol)
were stirred in DMF (30 mL) for 8 h. Amine 9 (22.2 mg, 0.05
mmol) and triethylamine (10 mg, 0.1 mmol) were added, and
stirring was continued for 8 h. Workup was similar to that
used for 38, and purification was achieved by flash chroma-
tography (silica gel, CHCl3:THF) to give 46 (27.1 mg, 58%
yield): 1H-NMR (DMSO-d6) δ 10.10 (s, 2H), 9.83 (s, 1H), 8.52
(s, 1H), 8.42 (t, J ) 6 Hz, 1H), 8.05 (d, J ) 8 Hz, 1H), 7.58 (d,
J ) 2 Hz, 1H), 7.50 (dd, J ) 8, 2 Hz, 1H), 7.43 (d, J ) 2 Hz,
1H), 7.40 (d, J ) 2 Hz, 1H), 7.38 (d, J ) 2 Hz, 1H), 7.25 (s,
1H), 7.10 (d, J ) 2 Hz, 1H), 7.00 (d, J ) 2 Hz, 1H), 6.92 (d, J
) 2 Hz, 1H), 6.50 (bs, 1H, OH), 5.62 (s, 6H), 5.40 (s, 2H), 5.23
(s, 2H), 4.25 (t, J ) 6 Hz, 2H), 3.64 (m, 2H), 3.18 (s, 3H), 3.17
(s, 3H), 3.16 (s, 3H), 2.22 (t, 2H, J ) 7 Hz), 1.83 (m, 2H), 1.58
(m, 2H), 0.90 (m, 6H); FABMS calcd for C47H51N9O12H 934.37,
found 934.42 (MH+). Anal. (C47H51N9O12) C, H, N.
10-[2-[1-(Meth oxym eth yl)-4-[4-(d im eth yla m in o)bu tyr a -
m id o]p yr r ole-2-ca r b oxa m id o]et h oxy]-20(R,S)-ca m p t o-
th ecin (47). Acid 14 (15.6 mg, 0.055 mmol), DCC (11.3 mg,
0.055 mmol), and HOBt (7.4 mg, 0.055 mmol) were stirred in
DMF (30 mL) for 8 h. Amine 9 (22.2 mg, 0.05 mmol) and
triethylamine (10 mg, 0.1 mmol) were added, and stirring was
continued for 8 h. Workup was similar to that used for 41,
and purification was achieved by flash chromatography (silica
gel, CHCl3:THF) to give 47 (17.17 mg, 51% yield): 1H-NMR
(DMSO-d6) δ 9.93 (s, 1H), 8.50 (s, 1H), 8.42 (t, J ) 6 Hz, 1H),
8.02 (d, J ) 8 Hz, 1H), 7.50 (m, 2H), 7.30 (d, J ) 2 Hz, 1H),
10-[[[1-(Meth oxym eth yl)-2-[[1-(m eth oxym eth yl)-2-[[1-
(m eth oxym eth yl)-2-[[3-(d im eth yla m in o)p r op yl]ca r ba m -
oyl]p yr r ol-4-yl]ca r ba m oyl]p yr r ol-4-yl]ca r ba m oyl]p yr r ol-
4-yl]car bam oyl]m eth oxy]-20(R,S)-cam ptoth ecin (43). Com-
pound 43 was prepared in 58% yield from acid 8 (21.2 mg,
0.05 mmol) and 28 (47 mg, 0.08 mmol) in a manner similar to
that described for 41: 1H-NMR (DMSO-d6) δ 10.38 (s, 1H),