R-Halogenoacrylic Derivatives of Distamycin A
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 10 2621
chromatography (8:2 DCM/MeOH), compound 20 was obtained
as a pale yellow solid (194 mg, 50% yield): 1H NMR (DMSO-
d6): δ 1.68 (m, 2H), 3.18 (m, 2H), 3.21 (m, 2H), 3.78 (s, 3H),
3.81 (s, 3H), 3.83 (s, 3H), 3.84 (s, 3H), 6.21 (d, J ) 2.9 Hz,
1H), 6.64 (d, J ) 2.9 Hz, 1H), 6.70-7.40 (m, 4H), 6.92 (d, J )
1.8 Hz, 1H), 7.03 (m, 3H), 7.18 (d, J ) 1.8 Hz, 1H), 7.21 (m,
3H), 7.46 (m, 1H), 8.02 (t, J ) 5.9 Hz, 1H), 9.84 (s, 1H), 9.90
(s, 1H), 9.92 (s, 1H), 10.28 (s, 1H); MS (ESI) m/z 738 [(M +
H)+]; Anal. (C31H37BrN12O5‚HCl) C, H, N.
N-(5-{[(5-{[(5-{[(4-{[Am in o(im in o)m eth yl]am in o}bu tyl)-
a m in o]ca r bon yl}-1-m eth yl-1H-p yr r ol-3-yl)a m in o]ca r bon -
yl}-1-m eth yl-1H-p yr r ol-3-yl)a m in o]ca r bon yl}-1-m eth yl-
1H-p yr r ol-3-yl)-4-[(2-br om oa cr yloyl)a m in o]-1-m eth yl-1H-
p yr r ole-2-ca r boxa m id e Hyd r och lor id e (21). Following the
general procedure of method A, starting from 4-[(2-bromoacry-
loyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid 31 (273 mg,
1 mmol) and 4-amino-N-(5-{[(5-{[(4-{[amino(imino)methyl]-
amino}butyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]-
carbonyl}-1-methyl-1H-pyrrol-3-yl)-1-methyl-1H-pyrrole-2-car-
boxamide dihydrochloride 47 (285 mg, 0.5 mmol), after flash
chromatography (8:2 DCM/MeOH), compound 21 was obtained
as a white solid (213 mg, 54% yield): 1H NMR (DMSO-d6): δ
1.48 (m, 4H), 3.12 (m, 2H), 3.18 (m, 2H), 3.78 (s, 3H), 3.81 (s,
3H), 3.83 (s, 3H), 3.84 (s, 3H), 6.20 (d, J ) 2.9 Hz, 1H), 6.66
(d, J ) 2.9 Hz, 1H), 6.88 (d, J ) 1.8 Hz, 1H), 7.04 (m, 3H),
7.14 (d, J ) 1.8 Hz, 1H), 7.22 (m, 3H), 6.60-7.40 (bs, 4H),
7.51 (t, J ) 5.9 Hz, 1H), 8.02 (t, J ) 5.9 Hz, 1H), 9.85 (s, 1H),
9.91 (s, 1H), 9.94 (s, 1H), 10.28 (s, 1H); MS (ESI) m/z 752 [(M
+ H)+]; Anal. (C32H39BrN12O5‚HCl) C, H, N.
4-[(2-Br om oa cr yloyl)a m in o]-N-[5-({[5-({[5-({[2-(4,5-d i-
h yd r o-1H-im id a zol-2-yla m in o)eth yl]a m in o}ca r bon yl)-1-
m eth yl-1H-pyr r ol-3-yl]am in o}car bon yl)-1-m eth yl-1H-pyr -
r ol-3-yl]a m in o}ca r b on yl)-1-m e t h yl-1H -p yr r ol-3-yl]-1-
m eth yl-1H-p yr r ole-2-ca r boxa m id e Hyd r och lor id e (22).
Following the general procedure of method A, starting from
4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxylic
acid 31 (273 mg, 1 mmol) and 4-amino-N-[5-({[5-({[2-(4,5-
dihydro-1H-imidazol-2-ylamino)ethyl]amino}carbonyl)-1-meth-
yl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H-pyrrol-3-yl]-1-
methyl-1H-pyrrole-2-carboxamide dihydrochloride 49 (276 mg,
0.5 mmol), after flash chromatography (8:2 DCM/MeOH; 8/2),
compound 22 was obtained as a white solid (177 mg, 45%
yield): 1H NMR (DMSO-d6): δ 3.26 (m, 4H), 3.59 (m, 4H), 3.79
(s, 3H), 3.81 (s, 3H), 3.82 (s, 3H), 3.83 (s, 3H), 6.21 (d, J ) 2.9
Hz, 1H), 6.68 (d, J ) 2.9 Hz, 1H), 6.92 (d, J ) 1.8 Hz, 1H),
7.02 (m, 3H), 7.19 (d, J ) 1.8 Hz, 1H), 7.22 (m, 3H), 7.40-
8.60 (bs, 2H), 8.08 (m, 1H), 8.22 (m, 1H), 9.90 (s, 1H), 9.92 (s,
1H), 9.96 (s, 1H) 10.28 (s, 1H); MS (ESI) m/z 750 [(M + H)+];
Anal. (C32H37BrN12O5‚HCl) C, H, N.
N -{5-[({5-[({5-[({2-[(Am in oc a r b on yl)a m in o]e t h yl}-
a m i n o )c a r b o n y l]-1-m e t h y l-1H -p y r r o l-3-y l}a m i n o )-
ca r b on yl]-1-m et h yl-1H -p yr r ol-3-yl}a m in o)ca r b on yl]-1-
m et h yl-1H -p yr r ol-3-yl}-4-[(2-b r om oa cr yloyl)a m in o]-1-
m et h yl-1H -p yr r ole-2-ca r b oxa m id e (23). Following the
general procedure of method A, starting from 4-[(2-bromoacry-
loyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid 31 (273 mg,
1 mmol) and 4-amino-N-{5-[({5-[({2-[(aminocarbonyl)amino]-
ethyl}amino)carbonyl]-1-methyl-1H-yrrol-3-yl}amino)carbonyl]-
1-methyl-1H-pyrrol-3-yl}-1-methyl-1H-pyrrole-2-carboxam-
idehydrochloride50(252mg,0.5mmol),after flash chromatography
(8:2 DCM/MeOH), compound 23 was obtained as a pale yellow
solid (190 mg, 50% yield): 1H NMR (DMSO-d6): δ 3.10 (m,
2H), 3.18 (m, 2H), 3.79 (s, 3H), 3.83 (s, 3H), 3.84 (s, 6H), 5.48
(s, 2H), 6.06 (m, 1H), 6.21 (d, J ) 2.9 Hz, 1H), 6.68 (d, J ) 2.9
Hz, 1H), 6.83 (d, J ) 1.8 Hz, 1H), 7.04 (m, 3H), 7.18 (d, J )
1.8 Hz, 1H), 7.21 (m, 3H), 8.02 (t, J ) 5.9 Hz, 1H), 9.87 (s,
1H), 9.91 (s, 1H), 9.94 (s, 1H), 10.29 (s, 1H); MS (ESI) m/z 725
[(M + H)+]; Anal. (C30H34BrN11O6) C, H, N.
4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxylic
acid 31 (546 mg, 2.0 mmol) and 4-amino-N-[5-({[5-({[3-amino-
3-(hydroxyimino)propyl]amino}carbonyl)-1-methyl-1H-pyrrol-
3-yl]amino}carbonyl)-1-methyl-1H-pyrrol-3-yl]-1-methyl-1H-
pyrrole-2-carboxamide hydrochloride 39 (506 mg, 1.0 mmol),
after flash chromatography (8.5:1.5 DCM/MeOH), compound
24 was obtained as a pale hazel solid (470 mg, 65% yield): 1H
NMR (DMSO-d6): δ 2.31 (m, 2H), 3.38 (m, 2H), 3.79 (s, 3H),
3.83 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 6.21 (d, J ) 2.9 Hz,
1H), 6.69 (d, J ) 2.9 Hz, 1H), 6.90 (d, J ) 1.8 Hz, 1H), 7.02
(m, 3H), 7.18 (d, J ) 1.8 Hz, 1H), 7.21 (m, 3H), 7.80-8.20 (bs,
2H), 8.12 (t, J ) 5.9 Hz, 1H), 9.88 (s, 1H), 9.91 (s, 1H), 9.94 (s,
1H), 10.27 (s, 1H), 12.22 (bs, 1H); MS (ESI) m/z 725 (M + H)+];
Anal. (C30 H34 Br N11 O6) C, H, N.
N-[5-({[5-({[5-({[3-Am in o-3-(cyan oim in o)pr opyl]am in o}-
ca r b on yl)-1-m et h yl-1H -p yr r ol-3-yl]a m in o}ca r b on yl)-1-
m eth yl-1H-pyr r ol-3-yl]am in o}car bon yl)-1-m eth yl-1H-pyr -
r ol-3-yl]-4-[(2-br om oacr yloyl)am in o]-1-m eth yl-1H-pyr r ole-
2-ca r boxa m id e (25). Following the general procedure of
method A, starting from 4-[(2-bromoacryloyl)amino]-1-methyl-
1H-pyrrole-2-carboxylic acid 31 (164 mg, 0.60 mmol) and
4-amino-N-[5-({[5-({[3-amino-3-(cyanoimino)propyl]amino}-
carbonyl)-1-methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-
1H-pyrrol-3-yl]-1-methyl-1H-pyrrole-2-carboxamide hydrochlo-
ride 40 (175 mg, 0.34 mmol), after flash chromatography (9:1
DCM/MeOH), compound 25 was obtained as an hazel solid
(150 mg, 60% yield): 1H NMR (DMSO-d6): δ 2.60 (bs, 2H),
3.45 (bs, 2H), 3.79 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 3.86 (s,
3H), 6.22 (d, J ) 2.9 Hz, 1H), 6.67 (d, J ) 2.9 Hz, 1H), 6.90 (d,
J ) 1.8 Hz, 1H), 7.04 (m, 3H), 7.19 (d, J ) 1.8 Hz, 1H), 7.22
(m, 2H), 8.08 (bs, 1H), 8.30 (bs, 2H), 9.88 (s, 1H), 9.92 (s, 1H),
9.95 (s, 1H), 10.27 (s, 1H); MS (FAB) m/z 732 [(M - H)-]; Anal.
(C31H33BrN12O5) C, H, N.
N-{5-[({5-[({5-[({2-(Car boxam ide)eth yl}am in o)car bon yl]-
1-m eth yl-1H-p yr r ol-3-yl}a m in o)ca r bon yl]-1-m eth yl-1H-
p yr r ol-3-yl}a m in o)ca r bon yl]-1-m eth yl-1H-p yr r ol-3-yl}-4-
[(2-b r o m o a c r y lo y l)a m i n o ]-1-m e t h y l-1H -p y r r o le -2-
ca r boxa m id e (26). Following the general procedure of method
A, starting from 4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyr-
role-2-carboxylic acid 31 (163 mg, 0.60 mmol) and 4-amino-
N-[5-({[5-({[3-amino-3-(cyanoimino)propyl]amino}carbonyl)-1-
methyl-1H-pyrrol-3-yl]amino}carbonyl)-1-methyl-1H-pyrrol-3-
yl]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride 44 (175
mg, 0.34 mmol), after flash chromatography (9:1 DCM/MeOH),
compound 26 was obtained as a yellow solid (145 mg, 60%
yield): 1H NMR (DMSO-d6): δ 2.28 (t, J ) 6.5 Hz, 2H), 3.34
(m, 2H), 3.79 (s, 3H), 3.81 (s, 3H), 3.83 (s, 3H), 3.84 (s, 3H),
6.21 (d, J ) 2.9 Hz, 1H), 6.66 (d, J ) 2.9 Hz, 1H), 6.79 (bs,
1H), 6.82 (d, J ) 1.8 Hz, 1H), 7.02 (m, 3H), 7.18 (d, J ) 1.8
Hz, 1H), 7.21 (m, 3H), 7.31 (bs, 1H), 7.98 (t, J ) 5.8 Hz, 1H),
9.86 (s, 1H), 9.91 (s, 1H), 9.96 (s, 1H), 10.28 (s, 1H); MS (FAB)
m/z 710 [(M + H)+]; Anal. (C30H33BrN10O6) C, H, N.
4-[(2-Br om oa cr yloyl)a m in o]-N-(5-{[(5-{[(5-{[(2-cya n o-
eth yl)a m in o]ca r bon yl}-1-m eth yl-1H-p yr r ol-3-yl)a m in o]-
ca r b on yl}-1-m et h yl-1H -p yr r ol-3-yl)a m in o]ca r b on yl}-1-
m e t h y l-1H -p y r r o l-3-y l)-1-m e t h y l-1H -p y r r o le -2-c a r -
boxa m id e (27). Following the general procedure of method
A, starting from 4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyr-
role-2-carboxylic acid 31 (163 mg, 0.60 mmol), and 4-amino-
N-(5-{[(5-{[(2-cyanoethyl)amino]carbonyl}-1-methyl-1H-pyrrol-
3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-1-methyl-1H-
pyrrole-2-carboxamide hydrochloride 43 (142 mg, 0.30 mmol),
after flash chromatography (9.5:0.5 DCM/MeOH), compound
27 was obtained as an ivory solid (125 mg, 60% yield): 1H
NMR (DMSO-d6): δ 2.75 (t, J ) 6.5 Hz, 2H), 3.42 (m, 2H),
3.60 (s, 3H), 3.87 (s, 3H), 3.88 (s, 6H), 6.25 (d, J ) 2.9 Hz,
1H), 6.70 (d, J ) 2.9 Hz, 1H), 6.92 (d, J ) 1.8 Hz, 1H), 7.03
(m, 3H), 7.15 (m, 4H), 8.36 (t, J ) 5.9 Hz, 1H), 9.95 (s, 1H),
9.97 (s, 1H), 10.00 (s, 1H), 10.32 (s, 1H); MS (FAB) m/z 692
[(M + H)+]; Anal. (C30H31BrN10O5) C, H, N.
N -[5-({[5-({[5-({[3-Am in o-3-(h yd r oxyim in o)p r op yl]-
a m in o }c a r b o n y l)-1-m e t h y l-1H -p y r r o l-3-y l]a m in o }-
ca r b on yl)-1-m et h yl-1H -p yr r ol-3-yl]a m in o}ca r b on yl)-1-
m et h yl-1H -p yr r ol-3-yl]-4-[(2-b r om oa cr yloyl)a m in o]-1-
m eth yl-1H-p yr r ole-2-ca r boxa m id e Hyd r och lor id e (24).
Following the general procedure of method A, starting from
Tu m or Mod els. L1210 murine lymphocytic leukemia was
from NCI (Frederick, MD). Human lung (N592 and A549),
colon (HCT-116 and HT-29), and prostatic (DU 145) carcino-
mas were from American Type Culture Collection (Rockville,