4178
K. Wang, Z.-Z. Liu / European Journal of Medicinal Chemistry 45 (2010) 4175e4179
561.2137. 1H NMR (300 MHz, CDCl3):
d
¼ 8.81 (s, 1H), 7.60 (d, 1H,
121.49, 120.80, 120.21, 111.32, 109.23, 107.66, 106.83, 56.39, 52.11,
50.04, 37.54, 24.89, 24.13, 15.25, 11.27.
J ¼ 2.7 Hz), 7.57 (s, 1H), 7.29 (m, 1H), 7.02 (m, 8H), 6.78 (m, 3H), 6.62
(t, 1H, J ¼ 7.8 Hz), 5.92 (d, 1H, J ¼ 7.8 Hz), 4.83 (q, J ¼ 6.0 Hz), 4.74 (s,
2H), 3.74 (m, 1H), 3.65 (s, 3H), 3.20 (s, 3H), 3.02 (dd, 2H, J1 ¼ 5.1 Hz,
4.1.11. Metyl(2S)-2-[(2-{3-[4-(1H-3-indolyl)-1-methyl-2,5-dioxo-
2,5-dihydro-1H-3-pyrrolyl]-1H-1-indoyl}acetyl)amino]-3-
methylbutanoate (8k)
J2 ¼ 13.8 Hz). 13C NMR (100 MHz, CDCl3):
d
¼ 172.25, 171.09, 167.11,
136.11, 135.80, 135.08, 131.47, 129.08, 128.95, 128.56, 128.31, 127.08,
126.58, 126.34, 125.40, 123.15, 122.59, 122.43, 121.67, 120.93, 120.39,
111.28, 109.26, 107.76, 106.89, 52.95, 52.43, 49.89, 37.48, 24.19.
Yield 65%, red solid, mp: 123e125 ꢀC; [
a
]
20: ꢁ5.0 (0.002,
D
CH2Cl2); HRMS (ES) calcd for C29H29N4O5 [M þ H]þ: 513.2132,
found 513.2143. 1HNMR (300 MHz, CDCl3):
d
¼ 8.90 (s, 1H), 7.76 (s,
4.1.7. Methyl 3-[(2-{3-[4-(1H-3-indolyl)-1-methyl-2,5-dioxo-2.5-
dihydro-1H-3-pyrrolyl]-1H-1-indolyl} acetyl) amino] propanoate
(8g)
1H), 7.68 (d, 1H, J ¼ 2.7 Hz), 7.24 (m, 2H), 7.06 (m, 3H), 6.86 (d, 1H,
J ¼ 7.8 Hz), 6.72 (m, 2H), 5.97 (d, 1H, J ¼ 8.7 Hz), 4.85 (s, 2H), 4.52
(dd, 1H, J1 ¼ 4.8 Hz, J2 ¼ 8.4 Hz), 3.64 (s, 3H), 3.19 (s, 3H), 2.08 (m,
1H), 0.83 (d, 3H, J ¼ 7.2 Hz), 0.68 (d, 3H, J ¼ 6.6 Hz). 13C NMR
Yield 62%, red solid, mp: 103e104 ꢀC; HRMS (ES) calcd for
C27H25N4O5 [M
(300 MHz, CDCl3):
þ
H]þ: 485.1819, found 485.1804. 1H NMR
¼ 8.70 (s, 1H), 7.77 (d, 1H, J ¼ 2.7 Hz), 7.53 (s,
(100 MHz, CDCl3):
d
¼ 172.30, 172.23, 171.50, 167.40, 136.10, 135.81,
d
131.64,128.53,128.34,126.45,126.39,125.61,123.06,122.46,122.38,
121.51, 120.84, 120.25, 111.30, 109.23, 107.73, 106.90, 57.08, 52.19,
50.07, 30.85, 24.16, 18.81, 17.43.
1H), 7.33 (d, 1H, J ¼ 8.1 Hz), 7.12 (m, 4H), 6.99 (d, 1H, J ¼ 7.8 Hz), 6.85
(m, 2H), 5.91 (t, 1H, J ¼ 6.0 Hz), 4.76 (s, 2H), 3.42 (m, 5H), 3.20 (s,
3H), 2.44 (t, 2H, J ¼ 6.3 Hz). 13C NMR (300 MHz, CDCl3):
¼ 172.15,
d
172.04, 136.20, 135.95, 131.40, 128.66, 126.41, 125.16, 123.29, 122.73,
122.54, 121.73, 121.07, 120.36, 111.44, 109.22, 107.82, 106.96, 51.74,
50.29, 34.93, 33.59, 24.22.
4.1.12. Methyl (2S)-3-(4-hydroxyphenyl)-2-[(2-{3-[4-(1H-3-
indolyl)-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl]-1H-1-
indolyl} acetyl) amino] propanoate (8l)
Yield 63%, red solid, mp: 153e155 ꢀC; [
a
]
D
20: ꢁ25.0 (0.002,
4.1.8. Methyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(2-{3-[4-(1H-3-
indolyl)-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl]-1H-1-
indolyl} acetyl) amino] propanoate (8h)
CH2Cl2); HRMS (ES) calcd for C33H29N4O6 [M þ H]þ: 577.2082,
found 577.2063. 1H NMR (300 MHz, CDCl3):
d
¼ 9.09 (d, 1H,
J ¼ 1.5 Hz), 7.45 (s, 1H), 7.24 (m, 2H), 7.12 (m, 3H), 7.02 (t, 1H,
J ¼ 7.2 Hz), 6.90 (d, 1H, J ¼ 1H), 6.79 (m, 2 H), 6.65 (s, 1H), 6.47 (d,
2H, J ¼ 8.4 Hz), 6.38 (d, 2H, J ¼ 8.4 Hz), 6.00 (d, 1H, J ¼ 8.1 Hz), 4.83
(dd, J1 ¼5.4 Hz, J2 ¼ 13.5 Hz), 4.63 (dd, J1 ¼17.1 Hz, J2 ¼ 13.1 Hz), 3.64
(s, 3H), 3.15 (s, 3H), 2.89 (d, 2H, J ¼ 5.4 Hz). 13C NMR (100 MHz,
Yield 73%, red solid, mp: 154e155 ꢀC; [
a]
20: ꢁ133.0 (0.002,
D
CH2Cl2); HRMS (ES) calcd for C33H29N4O7 [M þ H]þ: 593.2036,
found 593.2033. 1H NMR (300 MHz, CDCl3):
d
¼ 8.74 (s, 1H), 7.69 (d,
1H, J ¼ 2.7 Hz), 7.49 (s, 1H), 7.30 (d, 1H, J ¼ 8.1 Hz), 7.13 (m, 2H), 7.07
(t, 2H, J ¼ 7.5 Hz), 6.89 (m, 2H), 6.70 (t, 2H, J ¼ 7.5 Hz), 6.59 (d, 1H,
J ¼ 7.8 Hz), 6.19 (d, 1H, J ¼ 1.8 Hz), 5.75 (d, 1H, J ¼ 7.8 Hz), 5.67 (s,
1H), 4.71 (m, 3H), 3.64 (s, 3H), 3.22 (s, 3H), 2.87 (dd, 1H, J1 ¼ 4.5 Hz,
J2 ¼ 13.5 Hz), 2.69 (dd, 1H, J1 ¼ 7.2 Hz, J2 ¼ 14.1 Hz). 13C NMR
CDCl3):
d
¼ 172.41, 172.17, 171.13, 167.13, 154.94, 136.29, 136.00,
131.68, 130.04, 128.96, 128.82, 126.60, 126.29, 125.94, 125.23,
123.23, 122.79, 122.64, 121.94, 121.05, 120.46, 115.66, 111.37, 109.39,
107.61, 106.72, 60.38, 52.43, 49.96, 36.57, 24.18.
(75 MHz, CDCl3):
d
¼ 173.25, 172.04, 171.06, 167.25, 143.51, 136.13,
135.95, 131.31, 129.04, 127.05, 126.18, 125.17, 123.33, 122.76, 122.40,
121.81, 121.28, 121.06, 120.52, 115.68, 115.43, 111.38, 109.44, 107.59,
106.83, 52.98, 52.38, 49.93, 36.74, 24.29.
4.1.13. Dimethyl (2S)-2-[(2-{3-[4-(1H-3-indolyl)-1-methyl-2,5-
dioxo-2,5-dihydro-1H-3-pyrrolyl]-1H-1-indolyl} acetyl) amino]
pentanedioate (8m)
Yield 83%, red solid, mp: 108e110 ꢀC; [
a
]
D
20: ꢁ2.5 (0.002,
4.1.9. Dimethyl (2S)-2-[(2-{3-[4-(1H-3-indolyl)-1-methyl-2,5-
dioxo-2,5-dihydro-1H-3-pyrrolyl]-1H-1-indolyl} acetyl) amino]
butanedioate (8i)
CH2Cl2); HRMS (ES) calcd for C30H29N4O7 [M þ H]þ: 557.2031,
found 557.2037. 1H NMR (300 MHz, CDCl3):
d
¼ 8.65 (s, 1H), 7.23 (m,
3H), 7.53 (m, 1H), 7.33 (d, 1H, J ¼ 8.1 Hz), 7.22 (s, 1H), 7.11 (m, 2H),
6.95 (d, 1H, J ¼ 8.1 Hz), 6.79 (t, 2H, J ¼ 7.2 Hz), 6.19 (d, 1H, J ¼ 8.1 Hz),
4.85 (s, 2H), 4.59 (m, 1H), 3.66 (s, 3H), 3.58 (s, 3H), 3.20 (s, 3H), 2.27
(m, 2H), 1.74 (m, 2H).
Yield 70%, red solid, mp: 97e99 ꢀC; [
a]
20: þ19.2 (0.002, CH2Cl2);
D
HRMS (ES) calcd for C29H27N4O7 [M þ H]þ: 543.1874, found
543.1852. 1H NMR (300 MHz, CDCl3):
d
¼ 8.75 (s, 1H), 7.70 (s, 1H),
7.66 (d, 1H, J ¼ 2.7 Hz), 7.28 (d, 1H, J ¼ 8.4 Hz), 7.18 (m, 2H), 7.07 (m,
2H), 6.89 (d, 1H, J ¼ 8.1 Hz), 6.83 (t, 1H, J ¼ 7.8 Hz), 6.74 (t, 1H,
6.6 Hz), 6.50 (d, 1H, J ¼ 8.1 Hz), 4.82 (m, 3H), 3.64 (s, 3H), 3.43 (s,
3H), 3.19 (s, 3H), 2.94 (dd, 1H, J1 ¼ 4.5 Hz, J2 ¼ 17.1 Hz), 2.81 (dd, 1H,
4.1.14. Methyl (2S,3S)-3-hydroxy-2-[(2-{3-[4-(1H-3-indolyl)-1-
methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl]-1H-1-indolyl} acetyl)
amino] butanoate (8n)
J1 ¼ 4.5 Hz, J2 ¼ 17.1 Hz). 13C NMR (100 MHz, CDCl3):
d
¼ 172.20,
Yield 67%, red solid, mp: 158e160 ꢀC; [
a]
20: ꢁ12.0 (0.002,
D
170.81, 170.32, 167.28, 136.22, 135.84, 131.59, 128.66, 128.57, 126.62,
126.29, 125.57, 122.96, 122.53, 122.43, 121.81, 120.80, 120.47, 111.24,
109.26, 107.68, 106.94, 52.83, 52.00, 50.07, 48.45, 35.68, 24.15.
CH2Cl2); HRMS (ES) calcd for C28H27N4O6 [M þ H]þ: 516.1956, found
516.1961. 1H NMR (300 MHz, CDCl3):
d
¼ 9.03 (d, 1H, 2.1 Hz), 7.64 (s,
1H), 7.57 (d, 1H, J ¼ 2.7 Hz), 7.24 (m, 2H), 7.03 (m, 3H), 6.82 (d, 1H,
J ¼ 7.8 Hz), 6.71 (m, 2H), 6.37 (d,1H, J ¼ 9.0 Hz), 4.81 (s, 2H), 4.53 (dd,
J1 ¼ 2.4 Hz, J2 ¼ 9.0 Hz), 4.30 (d, 1H, J ¼ 5.1 Hz), 3.63 (s, 3H), 3.12 (s,
3H), 2.70 (s, 1H), 1.08 (d, 3H, J ¼ 6.6 Hz). 13C NMR (100 MHz, CDCl3):
4.1.10. Methyl (2S,3R)-2-[(2-{3-[4-(1H-3-indolyl)-1-methyl-2,5-
dioxo-2,5-dihydro-1H-3-pyrrolyl]-1H-1-indoyl} acetyl) amino]-3-
methylpentanoate (8j)
d
¼ 172.44, 172.23, 170.63, 168.21, 136.30, 136.78, 131.44, 128.62,
Yield 76%, red solid, mp: 118e120 ꢀC; [
a
]
20: ꢁ3.0 (0.002,
126.41, 125.59, 123.16, 122.66, 122.35, 121.76, 120.95, 120.53, 111.24,
109.33, 107.84, 107.05, 67.59, 57.23, 52.64, 50.04, 30.90, 20.01.
D
CH2Cl2); HRMS (ES) calcd for C30H31N4O5 [M þ H]þ: 527.2289,
found 527.2288. 1H NMR (300 MHz, CDCl3):
d
¼ 8.94 (s, 1H), 7.75 (s,
1H), 7.67 (d, 1H, J ¼ 2.7 Hz), 7.23 (m, 2H), 7.04 (m, 3H), 6.86 (d, 1H,
J ¼ 8.1 Hz), 6.72 (m, 2H), 6.00 (d, 1H, J ¼ 8.7 Hz), 4.83 (s, 2H), 4.57
(dd, 1H, J1 ¼ 4.8 Hz, J2 ¼ 8.4 Hz), 3.64 (s, 3H), 3.19 (s, 3H), 1.79 (m,
1H), 1.19 (m, 2H), 0.90 (m, 3H), 0.77 (m, 3H). 13C NMR (100 MHz,
5. Pharmacology
The tumor cell lines panel consisted of BCT-8, BEL-7402, A2780,
MCF-7, A549, BGC-823. Human cancer cells were cultured in
PRMI1640 or DMEM/F12 supplemented with 10% fetal bovine
serum, containing penicillin streptomycin at 37 ꢀC and humidified at
CDCl3):
d
¼ 172.30, 172.22, 171.47, 167.25, 136.11, 135.83, 131.66,
128.58, 128.34, 126.40, 126.36, 125.58, 122.99, 122.40, 122.36,