Y. Zhou et al. / Bioorg. Med. Chem. 18 (2010) 2165–2172
2171
5.14–5.16 (d, J = 8.7 Hz, 1H), 3.97–3.99 (m, 1H), 3.76 (s, 6H), 2.05–
2.12 (m, 2H), 1.37–1.56 (m, 4H), 0.88–0.99 (m, 12H); 13C NMR
(125 MHz, CDCl3) dC = 170.6, 170.1, 169.5, 165.8, 164.5, 163.3,
161.9, 92.7, 88.2, 66.7, 65.8, 62.1, 61.5, 56.4, 58.1, 53.5, 52.6,
38.2, 37.8, 25.3, 24.9, 18.4, 15.5. Elemental Anal. Calcd for
C17H30N2O4: C, 62.55; H, 9.26; N, 8.58. Found: C, 62.76; H, 9.41;
N, 8.82.
dH = 9.10–9.16 (m, 1H), 8.02–8.04 (m, 1H), 7.55–7.57 (d,
J = 11.6 Hz, 1H), 7.26–7.37 (m, 10H), 6.00–6.04 (t, J = 8.2 Hz, 1H),
5.06–5.08 (d, J = 8.2 Hz, 1H), 4.56–4.61 (m, 1H), 4.39–4.45 (m,
3H), 4.19–4.21 (t, J = 5.35 Hz, 2H), 3.65–3.70 (m, 7H), 1.23–1.25
(d, J = 6.2 Hz, 6H); 13C NMR (125 MHz, CDCl3) dC = 173.8, 166.1,
141.1, 137.6, 128.4 (4C), 128.1 (2C), 96.6, 93.9, 74.2, 73.9, 71.2,
66.0, 65.0, 61.2, 54.5, 52.7 (2C), 16.2 (2C). Elemental Anal. Calcd
for C27H34N2O6: C, 67.20; H, 7.10; N, 5.81. Found: C, 67.42; H,
7.25; N, 6.06.
4.3.10. N,N0-(Z-Allylidene-1,3-diyl)bisleucine methyl ester (2j)
Yellow powder. Yield: 76%. ½a D25
¼ ꢀ115:2 (c = 1.6, MeOH); ESI/
ꢂ
MS: 327 [M+H]+; IR (KBr disk): 3388, 3186, 2955, 1736,1605, 1505,
1435, 1342, 1211, 1173, 1080, 733 cmꢀ1. 1H NMR (500 MHz, CDCl3)
dH = 10.44–10.48 (t, J = 7.7 Hz, 1H), 9.86–9.90 (t, J = 7.8 Hz, 1H),
8.07–8.12 (dd, J = 8.3 Hz, J = 8.3 Hz, 1H), 6.33–6.37 (t, J = 8.3 Hz,
1H), 5.04–5.06 (d, J = 8.3 Hz, 1H), 4.12–4.26 (m, 1H), 3.77 (s, 6H),
1.85–1.99 (m, 2H), 1.73–1.82 (m, 4H), 0.91–0.99 (m, 12H); 13C
NMR (125 MHz, CDCl3) dC = 170.7 (2C), 163.3 (2C), 92.7, 66.6,
62.1, 52.6 (2C), 37.0, 25.3, 15.5 (4C), 11.1 (2C). Elemental Anal.
Calcd for C17H30N2O4: C, 62.55; H, 9.26; N, 8.58; O, 19.61. Found:
C, 62.78; H, 9.41; N, 8.33.
4.3.15. N,N0-(Z-Allylidene-1,3-diyl)bisvaline methyl ester (2o)
Yellow powder. Yield: 60%. Mp 91–93 °C. ½a D25
¼ ꢀ86:0 (c = 0.9,
ꢂ
MeOH); ESI/MS: 299 [M+H]+; IR (KBr disk): 3148, 2963, 2878,
1744, 1211, 1142, 856, 779, 664 cmꢀ1 1H NMR (500 MHz, CDCl3)
.
dH = 9.24–9.26 (m, 1H), 8.02–8.06 (m, 1H), 7.78–7.82 (m, 1H), 6.12–
6.16 (t, J = 9.1 Hz, 1H), 5.01–5.13 (d, J = 9.1 Hz, 1H), 4.17–4.27 (m,
1H), 3.76 (s, 6H), 2.16–2.26 (m, 2H), 0.86–1.00 (m, 12H); 13C NMR
(125 MHz, CDCl3) dC = 190.1, 171.8 (2C), 92.3, 67.5, 67.3, 53.0, 52.9,
31.2, 19.0 (2C), 17.8 (2C). Elemental Anal. Calcd for C15H26N2O4: C,
60.38; H, 8.78; N, 9.39. Found: C, 60.60; H, 8.92; N, 9.14.
4.3.11. N,N0-(Z-Allylidene-1,3-diyl)bismethionine methyl ester
4.3.16. N,N0-(Z-Allylidene-1,3-diyl)bistryptophane methyl ester
(2k)
(2p)
Yellow powder. Yield: 44%. ½a D25
ꢂ
¼ ꢀ18:3 (c = 0.77, MeOH); ESI/
Yellow powder. Yield: 72%. Mp 126–128 °C. ½a D25
¼ 26:4 (c = 1.0,
ꢂ
MS: 363 [M+H]+; IR (KBr disk): 3171, 2963, 1744, 1605, 1435, 1335,
MeOH); ESI/MS: 473 [M+H]+; IR (KBr disk): 3210, 3032, 2955,
1211, 734 cmꢀ1
.
1H NMR (500 MHz, CDCl3) dH = 10.40–10.45 (m,
1736, 1605, 1435, 1342, 1273, 1211, 1096, 748 cmꢀ1 1H NMR
.
1H), 9.96–9.98 (m, 1H), 8.04–8.08 (t, J = 10.1 Hz, 1H), 6.16–6.20
(t, J = 9.1 Hz, 1H), 5.05–5.07 (d, J = 9.1 Hz, 1H), 4.45–4.47 (m, 1H),
3.77 (s, 6H), 2.65–3.69 (m, 2H), 2.59 (m, 2H), 2.27 (m, 4H), 2.08
(m, 6H); 13C NMR (125 MHz, CDCl3) dC = 173.4, 170.8, 166.2,
163.3, 161.7, 95.9, 92.8, 89.3, 60.2, 60.0, 55.5, 30.5, 21.1, 18.4,
15.3. Elemental Anal. Calcd for C15H26N2O4S2: C, 49.70; H, 7.23;
N, 7.73. Found: C, 49.50; H, 7.09; N, 7.98.
(500 MHz, CDCl3) dH = 11.08 (s, 2H), 9.90–10.42 (q, J = 8.8 Hz, 1H),
9.81–9.85 (t, J = 8.0 Hz, 1H), 7.46–7.50 (m, 2H), 7.32–7.38 (m,
2H), 7.15–7.19 (m, 2H), 7.01–7.09 (m, 3H), 6.13–6.15 (t,
J = 7.3 Hz, 1H), 5.00–5.02 (d, J = 7.3 Hz, 1H), 4.54–4.57 (m, 1H),
3.70–3.72 (d, J = 5.55 Hz, 6H), 3.12–3.32 (m, 6H); 13C NMR
(125 MHz, CDCl3) dC = 171.2, 169.7, 166.1, 137.6, 128.4 (4C),
128.1 (2C), 96.6, 74.2, 71.2 (4C), 66.0, 65.0, 61.2, 54.5 (2C), 52.7
(2C), 16.2 (2C). Elemental Anal. Calcd for C27H28N4O4: C, 68.63;
H, 5.97; N, 11.86. Found: C, 68.41; H, 5.81; N, 11.60.
4.3.12. N,N0-(Z-Allylidene-1,3-diyl)bisphenylalanine methyl
ester (2l)
Yellow powder. Yield: 51%. Mp 52–54 °C. ½a D25
ꢂ
¼ ꢀ5:3 (c = 1.0,
4.3.17. N,N0-(Z-Allylidene-1,3-diyl)bistyrosine methyl ester (2q)
MeOH); ESI/MS: 395 [M+H]+; IR (KBr disk): 3148, 2955, 1736,
Yellow powder. Yield: 74%. ½a D25
¼ 0:8 (c = 1.7, MeOH); ESI/MS:
ꢂ
1605, 1435, 1342, 1219, 1080, 1034, 756, 703 cmꢀ1
.
1H NMR
427 [M+H]+; IR (KBr disk): 3186, 3009, 1744, 1065, 1443, 1373,
(500 MHz, CDCl3) dH = 10.35 (s, 1H), 10.08 (s, 1H), 7.82–7.84 (d,
J = 11.9 Hz, 1H), 7.52–7.58 (m, 1H), 7.20–7.32 (m, 8H), 6.20–6.24
(t, J = 9.0 Hz, 1H), 5.09–5.11 (d, J = 9.0 Hz, 1H), 4.84–4.90 (m, 1H),
4.59 (s, 1H), 3.71 (s, 6H), 3.18–3.27 (m, 2H), 2.98–3.06 (m, 2H);
13C NMR (125 MHz, CDCl3) dC = 170.2 (2C), 163.2, 136.5, 136.2
(2C), 129.8 (4C), 128.9 (4C), 1127.4 (2C), 91.0, 57.7 (2C), 53.1
(2C), 37.7, 37.0. Elemental Anal. Calcd for C23H26N2O4: C, 70.03;
H, 6.64; N, 7.10. Found: C, 69.80; H, 6.50; N, 6.87.
1250, 1173, 10472, 833, 687 cmꢀ1 1H NMR (500 MHz, CDCl3)
.
dH = 9.51 (s, 2H), 7.63–7.80 (m, 1H), 7.20–7.30 (m, 1H), 6.95–6.97
(d, J = 7.4 Hz, 4H), 6.67–6.69 (d, J = 8.3 Hz, 3H), 6.10–6.14 (t,
J = 8.4 Hz, 1H), 5.76 (s, 1H), 5.04–5.08 (t, J = 8.4 Hz, 1H), 4.13 (s,
2H), 3.63 (s, 6H), 2.98–3.00 (m, 2H), 2.79–2.83 (t, J = 8.1 Hz, 2H);
13C NMR (125 MHz, CDCl3) dC = 172.3 (2C), 172.1 (2C), 156.7 (2C),
1130.6 (4C), 115.6 (4C), 65.4, 55.4 (2C), 52.4 (2C), 22.7 (2C), 15.6
(2C). Elemental Anal. Calcd for C23H26N2O6: C, 64.78; H, 6.15; N,
6.57. Found: C, 64.55; H, 6.00; N, 6.32.
4.3.13. N,N0-(Z-Allylidene-1,3-diyl)bis-O-benzylserine methyl
ester (2m)
4.4. Pain threshold assay
Yellow powder. Yield: 38%. ½a D25
¼ ꢀ24:3 (c = 0.9, MeOH); ESI/
ꢂ
MS: 455 [M+H]+; IR (KBr disk): 3171,1736, 1620, 1435, 1327,
Male ICR mice (weighting 20 2 g) were purchased from the
Experimental Animal Center of Peking University. The study de-
scribed herein was performed according to a protocol reviewed
and approved by the Ethics Committee of Capital Medical Univer-
sity. The committee assures the welfare of the animals was main-
tained in accordance with the requirements of the animal welfare
act and according to the guide for care and use of laboratory
animals.
1281, 1204, 1080, 1011, 748, 702 cmꢀ1 1H NMR (500 MHz, CDCl3)
.
dH = 9.38 (s, 1H), 7.78–7.82 (d, J = 11.9 Hz, 2H), 7.28–7.30 (m, 10H),
6.08–6.12 (t, J = 9.5 Hz, 1H), 5.00–5.02 (d, J = 9.5 Hz, 1H), 4.51–4.53
(m, 5H), 3.92–3.97 (m, 2H), 3.81–3.84 (m, 2H), 3.69 (s, 6H); 13C
NMR (125 MHz, CDCl3) dC = 173.4 (2C), 167.4 (2C), 161.6, 137.2
(2C), 128.5 (6C), 127.9 (4C), 96.7, 73.4 (2C), 69.6, 62.4, 54.4, 53.0
(2C). Elemental Anal. Calcd for C25H30N2O6: C, 66.06; H, 6.65; N,
6.16. Found: C, 65.83; H, 6.50; N, 5.93.
The mice were housed in a 12/12 light/dark cycle at 21 2 °C for
one day before used. Each of the mice in drug receiving groups was
orally given a single dose of 20 lmol/kg of one of 2a–q in 0.2 ml of
4.3.14. N,N0-(Z-Allylidene-1,3-diyl)bis-O-benzylthreonine
methyl ester (2n)
normal saline (NS). The mouse in control group was orally given
0.2 ml of NS alone or intraperitoneally given a single dose of
Yellow powder. Yield: 85%. ½a D25
¼ 5:7 (c = 1.3, MeOH); ESI/MS:
ꢂ
483 [M+H]+; IR (KBr disk): 3186, 3032, 2978, 2955, 1751, 1605,
20
lmol/kg of morphine in NS. Analgesic effects of 2a–q were eval-
1450, 1211, 1088, 1011, 748 cmꢀ1 1H NMR (500 MHz, CDCl3)
.
uated by tail-flick test. The value of basic pain threshold of each