1776
L. Matesic et al. / Bioorg. Med. Chem. 19 (2011) 1771–1778
[MꢂH]ꢂ; 79Br79Br; 79Br81Br; 81Br81Br; HRMS (ESI-) m/z: calcd for
(s, 1H), 6.82 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 7.03 (d,
J = 8.5 Hz, 2H), 7.06 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H),
7.22 (d, J = 8.0 Hz, 2H), 7.61 (s, 1H), 7.72 (s, 1H), 7.81 (d,
J = 7.5 Hz, 2H), 7.84 (s, 1H), 7.96 (d, J = 8.5 Hz, 2H). dC (126 MHz;
C
24H19N2O279Br81Br: 526.9799 [MꢂCO2H]ꢂ; found 526.9722
[MꢂCO2H]ꢂ.
.
4.1.1.4. (E and Z)-3-[5,7-Dibromo-1-(4-methoxybenzyl)-2-oxo-
CDCl3): 22.5, 22.6, 23.4, 28.7, 29.1, 32.2, 32.5, 39.5, 39.7, 44.0,
.
.
.
.
.
indolin-3-ylideneamino]benzoic acid (3d).
Orange powder
44.6, 51.9, 52.1, 52.7, 55.5, 104.0, 104.8, 111.4, 114.4, 114.4,
.
.
.
(144 mg, 56%); mixture of E and Z isomers (E/Z 49:51); mp 229–
231 °C; Rf 0.37 (silica, DCM/MeOH 9:1); IR mmax 2950 (COOH),
115.9, 116.8, 117.4, 119.4, 119.6, 120.6, 125.8, 127.9, 128.2,
.
.
128.3, 128.4, 129.1, 132.1, 133.2, 141.5, 142.1, 142.5, 144.2,
1719 (CO), 1698, 1515, 1449, 1297, 1250, 1141, 812, 768 cmꢂ1
.
146.6, 150.4, 151.4, 151.9, 152.1, 157.6, 159.3, 163.6, 167.0,
.
.
dH (500 MHz; DMSO-d6): 3.71 (s, 3H), 3.73 (s, 3H), 5.13 (s, 2H),
5.30 (s, 2H), 6.41 (s, 1H), 6.86 (d, J = 8.5 Hz, 2H), 6.90 (d,
J = 9.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H),
7.29 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz,
1H), 7.59 (s, 1H), 7.65 (t, J = 8.0 Hz, 2H), 7.74 (d, J = 7.5 Hz, 1H),
7.82 (s, 1H), 7.85 (s, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.91 (s, 1H),
167.4, 170.0, 170.5, 173.3. MS (ESI+) m/z: 727; 729; 731 [MH]+;
749; 751; 753 [M+Na]+; 79Br79Br; 79Br81Br; 81Br81Br; HRMS (ESI+)
m/z: calcd for C32H32N4NaO679Br81Br: 751.0566 [M+Na]+; found
751.0531 [M+Na]+.
4.1.2.2. Methyl (S,E and S,Z)-2-acetamido-6-(2-{4-[5,7-dibromo-
1-(4-methoxybenzyl)-2-oxoindolin-3-ylideneami-
.
13.13 (br s, 2H). dC (126 MHz; DMSO-d6): d 44.0, 44.5, 55.7,
.
.
104.1, 104.7, 114.6, 114.6, 114.8, 116.0, 118.3, 120.7, 120.9,
no]phenyl}acetamido)hexanoate
(4b).
Red
crystals
.
.
122.0, 124.5, 125.2, 126.6, 126.8, 126.9, 127.5, 128.1, 128.2,
(33.3 mg, 41%); mixture of E and Z isomers (E/Z 49:51); mp 99–
101 °C; Rf 0.33 (silica, CHCl3/MeOH 95:5). dH (500 MHz; CDCl3):
1.21–1.82 (m, 12H), 1.98 (s, 3H), 2.02 (s, 3H), 3.17–3.27 (m, 4H),
3.57 (s, 2H), 3.62 (s, 2H), 3.71 (s, 3H), 3.73 (s, 3H), 3.76 (s, 3H),
3.78 (s, 3H), 4.51–4.58 (m, 2H), 5.27 (s, 2H), 5.43 (s, 2H), 5.65 (br
s, 1H), 5.72 (br s, 1H), 6.23 (d, J = 8.0 Hz, 1H), 6.27 (d, J = 8.0 Hz,
1H), 6.80 (d, J = 1.5 Hz, 1H), 6.82 (d, J = 8.5 Hz, 2H), 6.85 (d,
J = 8.0 Hz, 2H), 6.97 (d, J = 8.5 Hz, 2H), 7.11–7.15 (m, 4H), 7.22 (d,
J = 9.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.40–7.46 (m, 2H), 7.59 (d,
J = 1.5 Hz, 1H), 7.69 (s, 1H), 7.83 (d, J = 1.5 Hz, 1H). dC (126 MHz;
.
129.3, 129.4, 130.8, 132.1, 140.8, 141.0, 143.1, 144.5, 149.1,
.
.
150.4, 151.2, 153.0, 158.1, 159.0, 163.6, 167.5, 167.8. MS (ESI-)
m/z: 541; 543; 545 [MꢂH]ꢂ; 79Br79Br; 79Br81Br; 81Br81Br; HRMS
(ESI-) m/z: calcd for C23H15N2O479Br79Br: 540.9399 [MꢂH]ꢂ; found
540.9424 [MꢂH]ꢂ.
4.1.1.5. (E and Z)-2-{3-[5,7-Dibromo-1-(4-methoxybenzyl)-2-
oxoindolin-3-ylideneamino]phenyl}acetic acid (3e).
Red
powder (187 mg, 71%); mixture of E and Z isomers (E/Z 67:33);
mp 182–184 °C; Rf 0.33 (silica, DCM/MeOH 9:1); IR mmax 2944
(COOH), 1719 (CO), 1698, 1515, 1449, 1297, 1250, 1141, 812,
768 cmꢂ1. dH (500 MHz; DMSO-d6): d 3.56 (s, 2H), 3.63 (s, 2H),
3.71 (s, 3H), 3.73 (s, 3H), 5.14 (s, 2H), 5.30 (s, 2H), 6.61 (s, 1H),
6.86 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.5 Hz,
1H), 7.04 (s, 1H), 7.08 (d, J = 7.5 Hz, 1H), 7.17 (d, J = 8.5 Hz, 2H),
7.20 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 7.5 Hz,
1H), 7.46 (t, J = 7.5 Hz, 1H), 7.78–7.80 (m, 2H), 7.90 (s, 1H), 8.00
.
CDCl3): d 22.5, 23.3, 23.4, 29.1, 30.0, 31.9, 32.2, 39.2, 39.3, 43.5,
.
.
.
43.7, 44.0, 44.6, 52.1, 52.6, 52.7, 55.5, 104.0, 104.7, 114.3,
.
.
.
114.4, 115.6, 116.7, 117.4, 118.2, 120.1, 121.1, 125.5, 126.2,
127.7, 128.2, 128.2, 128.5, 128.9, 129.9, 130.9, 132.3, 133.3,
141.0, 141.7, 142.1, 144.0, 148.6, 149.7, 151.9, 157.9, 159.3,
.
.
.
.
.
.
.
163.8, 170.4, 171.2, 171.4, 173.2. HRMS (ESI+) m/z: calcd for
C
33H35N4O679Br81Br: 743.0903 [MH]+; found 743.0888 [MH]+.
.
(s, 1H).à dC (126 MHz; DMSO-d6): 41.2, 41.6, 43.9, 44.5, 55.7,
4.1.2.3. Methyl (S,E and S,Z)-2-acetamido-6-(3-{4-[5,7-dibromo-
1-(4-methoxybenzyl)-2-oxoindolin-3-ylideneami-
.
.
104.1, 104.6, 114.5, 114.6, 115.1, 115.4, 115.9, 116.0, 117.4,
118.6, 118.7, 120.6, 121.8, 125.0, 126.8, 126.9, 127.3, 127.5,
127.8, 128.1, 128.2, 128.8, 129.3, 129.4, 130.3, 140.6, 141.0,
no]phenyl}propanamido)hexanoate
(4c).
Red
powder
.
.
(111 mg, 70%); mixture of E and Z isomers (E/Z 55:45); mp 161–
163 °C; Rf 0.42 (silica, DCM/MeOH 9:1); IR mmax 3288 (NH), 1734
.
142.8, 144.3, 148.6, 150.3, 152.3, 158.0, 159.0, 163.7, 173.0,
173.1. MS (ESI-) m/z: 555; 557; 559 [MꢂH]ꢂ; 79Br79Br; 79Br81Br;
81Br81Br; HRMS (ESI-) m/z: calcd for C24H17N2O479Br81Br:
556.9535 [MꢂH]ꢂ; found 556.9568 [MꢂH]ꢂ.
(CO), 1638, 1558, 1446, 1296, 1251, 1180, 1137, 804, 721 cmꢂ1
.
dH (500 MHz; CDCl3): 1.29–1.82 (m, 12H), 1.99 (s, 3H), 2.03 (s,
3H), 2.43–2.52 (m, 4H), 2.94–3.04 (m, 4H), 3.12–3.27 (m, 4H),
3.72 (s, 3H), 3.73 (s, 3H), 3.76 (s, 3H), 3.78 (s, 3H), 4.55 (t,
J = 4.0 Hz, 2H), 5.27 (s, 2H), 5.43 (s, 2H), 5.62 (br s, 1H), 5.66 (br
s, 1H), 6.32 (d, J = 6.0 Hz, 2H), 6.81 (d, J = 4.0 Hz, 2H), 6.83 (s, 1H),
6.85 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 7.5 Hz, 2H), 7.10 (d, J = 8.0 Hz,
2H), 7.15 (d, J = 8.5 Hz, 2H), 7.21 (t, J = 7.5 Hz, 4H), 7.29 (d,
J = 8.0 Hz, 2H), 7.58 (s, 1H), 7.68 (s, 1H), 7.85 (s, 1H). dC
(126 MHz; CDCl3): 22.5, 22.6, 23.3, 23.4, 28.9, 29.1, 31.6, 31.7,
4.1.2. General procedure for the synthesis of the imine–lysine
conjugates (4a–e)
The isatin imine (3a–e, 1 equiv) was dissolved in dry DCM (1 mL
per 30 mg of imine) with the aid of sonication. On ice, 1-hydroxy-
benzotriazole hydrate (HOBt) (1 equiv) was added, followed by
N,N0-dicyclohexylcarbodiimide (DCC) (1 equiv), N,N-diisopropyl-
.
ethylamine (DIPEA) (1.1 equiv) and (S)-N -acetyl-lysine methyl es-
32.1, 32.3, 38.6, 38.9, 39.0, 39.1, 43.9, 44.6, 52.0, 52.1, 52.6,
a
.
.
.
.
ter hydrochloride (Ac-Lys-OMeꢀHCl) (1 equiv). The reaction
mixture was warmed to rt and stirred for 24 h. The precipitate
was removed by filtration and the filtrate evaporated. The resulting
solid was purified by column chromatography on silica gel using a
CHCl3/MeOH gradient of 100:0 to 95:5 to yield the imine-lysine
conjugate 4a–e.
55.5, 103.8, 104.6, 114.3, 114.4, 115.6, 116.6, 117.9, 119.8,
121.2, 125.4, 126.5, 128.1, 128.2, 128.2, 128.6, 128.6, 128.8,
129.9, 139.4, 140.1, 140.7, 141.5, 141.9, 144.0, 146.2, 147.7,
.
.
.
.
.
.
149.2, 151.8, 157.9, 159.2, 159.3, 163.9, 170.5, 172.4, 172.6,
173.2. MS (ESI+) m/z: 755; 757; 759 [MH]+; 79Br79Br; 79Br81Br;
.
81Br81Br; HRMS (ESI+) m/z: calcd for C34H36N4NaO679Br81Br:
779.0879 [M+Na]+; found 779.0896 [M+Na]+.
4.1.2.1. Methyl (S,E and S,Z)-2-acetamido-6-{4-[5,7-dibromo-1-
(4-methoxybenzyl)-2-oxoindolin-3-ylideneamino]benzamido}
4.1.2.4. Methyl (S,E and S,Z)-2-acetamido-6-{3-[5,7-dibromo-1-
hexanoate (4a).
Orange crystals (18.7 mg, 50%); mixture of E
(4-methoxybenzyl)-2-oxoindolin-3-ylideneamino]benzamido}
and Z isomers (E/Z 53:47); mp 165–167 °C; Rf 0.41 (silica, CHCl3/
MeOH 95:5). dH (500 MHz; CDCl3): 1.39–1.89 (m, 12H), 2.00 (s,
6H), 3.42–3.53 (m, 4H), 3.73 (s, 3H), 3.75 (s, 3H), 3.77 (s, 3H),
3.79 (s, 3H), 4.59–4.64 (m, 2H), 5.24 (s, 2H), 5.44 (s, 2H), 6.23
(dd, J = 7.0, 15 Hz, 2H), 6.33 (br s, 1H), 6.51 (br s, 1H), 6.77
hexanoate (4d).
Orange crystals (83.4 mg, 78%); mixture of E
and Z isomers (E/Z 47:53); mp 74–76 °C; Rf 0.56 (silica, CHCl3/
MeOH 95:5). IR mmax 3293 (NH), 1734 (CO), 1645, 1547, 1446,
1318, 1249, 1142, 801, 721 cmꢂ1. dH (500 MHz; CDCl3): 1.36–
1.91 (m, 12H), 1.97 (t, J = 7.0 Hz, 6H), 3.41–3.48 (m, 4H), 3.72