Z. Xiao et al. / Bioorg. Med. Chem. 12 (2004) 3339–3344
3343
1
benzoic acid, p-nitroaniline, sodium azide, and tri-
methylsilyl cyanide to provide intermediates 15, 16, 17,
and 18, respectively. Compound 15 was condensed with
the appropriate amines in the presence of N,N0-di-
cyclohexylcarbodiimide (DCC) and 4-(dimethyl-
amino)pyridine (DMAP) to provide compounds 6–8.
Intermediates 16 and 17 underwent Pd–C catalyzed
hydrogenation to afford 19 and 20, respectively, which
were subsequently condensed with the corresponding
acids to give compounds 9 and 10. Deprotection of
compound 10 through catalytic hydrogenation provided
compound 11. Intermediate 18 was easily hydrolyzed to
the carboxylic acid 21 in the presence of acetic acid and
hydrochloric acid.20 Condensation of 21 with the
appropriate amines provided compounds 12 and 13,
respectively. The structures of compounds 6–13 were
confirmed by spectroscopic and analytical data.
MS m=e: 787 [M]þ; H NMR (acetone) d 9.01 (s, 1H,
–OH), 7.40 (d, J ¼ 8:7 Hz, 2H, 300,500-H), 7.32 (m, 5H,
20000-60000-H), 7.12 (d, J ¼ 8:4 Hz, 2H, 20,60-H), 6.82 (s, 1H,
5-H), 6.75 (d, J ¼ 8:4 Hz, 2H, 30,50-H), 6.69 (d,
J ¼ 8:7 Hz, 2H, 200,600-H), 6.52 (s, 1H, 8-H), 6.39 (s, 2H,
20,60-H), 5.96 (s, 2H, –OCH2O–), 5.03 (d, J ¼ 6:9 Hz,
2H, –OCH2–Ph), 4.88 (m, 1H, 1-H), 4.55 (d, J ¼ 4:5 Hz,
1H, 4-H), 4.41 (m, 1H, –CO–CH–N–), 4.39 (t,
J ¼ 8:1 Hz, 1H, 11-H), 3.91 (t, J ¼ 8:1 Hz, 1H, 11-H),
3.70 (s, 6H, 30,50-OCH3), 3.31–3.10 (m, 4H, 2, 3-H,
–CO–CH–CH2–), 2.92 (m, 1H, 3-H).
25
D
Compound 10: yield 80%; mp 155–157 °C; ½aꢀ )24.0 (c
0.05, acetone); IR (film) 1745 (lactone), 1735 (amides)
1475, 1450, 1420 (aromatic C@C) cmꢁ1; MS m=e: 697
[M+1]þ; 1H NMR (DMSO) d 9.15 (s, 1H, –OH), 8.37 (d,
J ¼ 8:1 Hz, 1H, –NH), 8.23 (s, 1H, –OH), 7.46 (d,
J ¼ 7:5 Hz, 1H, –NH), 7.30 (m, 5H, 20-60-H), 7.05 (d,
J ¼ 8:4 Hz, 2H, 200,600-H), 6.65 (d, J ¼ 8:4 Hz, 2H, 30,500-
H), 6.57 (s, 1H, 5-H), 6.52 (s, 1H, 8-H), 6.24 (s, 2H, 20,60-
H), 5.99 (d, J ¼ 15:3 Hz, 2H, –OCH2O–), 5.13 (m, 1H,
1-H), 4.96 (d, J ¼ 5:1 Hz, 2H, –OCH2–Ph), 4.50 (d,
J ¼ 5:1 Hz, 1H, 4-H), 4.19 (t, J ¼ 8:1 Hz, 1H, 11-H),
4.11 (m, 1H, –CO–CH–N–), 3.85 (t, J ¼ 8:1 Hz, 1H, 11-
H), 3.63 (s, 6H, 30,50-OCH3), 3.32 (m, 1H, 2-H), 3.05 (d,
J ¼ 5:4 Hz, 2H, –CO–CH–CH2–), 2.82 (m, 1H, 3-H).
25
D
Compound 6: yield 45%; mp 152–154 °C (dec); ½aꢀ
)36.0 (c 0.05, acetone); IR (film) 1727 (lactone and
amide) 1475, 1455, 1273 (aromatic C@C) cmꢁ1; MS m=e:
709 [M)1]þ; H NMR (CDCl3) d 7.52 (d, J ¼ 8:7 Hz,
1
2H, 200,600-H), 7.43 (d, J ¼ 8:7 Hz, 2H, 20,60-H), 7.41 (m,
2H, 40000,70000-H), 6.72 (s, 1H, 5-H), 6.63 (d, J ¼ 8:7 Hz,
2H, 30,50-H), 6.62 (m, 50000,60000-H), 6.54 (s, 1H, 8-H), 6.53
(d, J ¼ 8:7 Hz, 2H, 300,500-H), 6.33 (s, 2H, 20,60-H), 5.90
(dd, 2H, –OCH2O–), 4.74 (m, 1H, 4-H), 4.60 (d,
J ¼ 4:8 Hz, 1H, 1-H), 4.37 (t, J ¼ 7:8 Hz, 1H, 11-H),
3.78 (m, 1H, 11-H), 3.80 (s, 6H, 30,50-OCH3), 3.50 (m,
1H, 2-H), 3.06 (m, 1H, 3-H).
25
Compound 11: yield 30%; mp 172–175 °C; ½aꢀ )66.0 (c
D
0.05, acetone); IR (film) 1770 (lactone), 1701 (amide),
1465, 1458, 1365 (aromatic C@C), 1122 (phenol) cmꢁ1
;
MS m=e: 563[M+1]þ; 1H NMR (CD3OD) d 7.04 (d,
J ¼ 8:4 Hz, 2H, 200,600-H), 6.68 (d, J ¼ 8:4 Hz, 2H, 300,500-
H), 6.32 (s, 1H, 5-H), 6.20 (s, 2H, 20,60-H), 6.19 (s, 1H, 8-
H), 5.93 (dd, J ¼ 2:4, 0.9 Hz, 2H, –OCH2O–), 4.98 (d,
J ¼ 2:1 Hz, 1H, 1-H), 4.42 (d, J ¼ 5:1 Hz, 1H, 4-H),
4.23 (t, J ¼ 8:1 Hz, 1H, 11-H), 3.96 (t, J ¼ 8:1 Hz, 1H,
11-H), 3.70 (s, 1H, –CO–CH–N–), 3.60 (s, 6H, 30,50-
OCH3), 3.18 (m, 1H, 2-H), 2.88 (m, 1H, 3-H).
25
D
Compound 7: yield 31%; mp 203 °C (dec); ½aꢀ )183.3 (c
0.03, acetone); IR (film) 1737 (lactone) 1727 (amide and
ester) 1462, 1445, 1427 (aromatic C@C) 1217 (phe-
nol) cmꢁ1; MS m=e: 696 [M]þ; 1H NMR (acetone) d 8.38
(s, 1H, –OH), 7.71 (d, J ¼ 8:7 Hz, 2H, 300,500-H), 7.51 (d,
J ¼ 8:1 Hz, 1H, –NH), 7.21 (s, 1H, –OH), 7.12 (d,
J ¼ 8:7 Hz, 2H, 20,60-H), 6.82 (s, 1H, 5-H), 6.75 (d,
J ¼ 8:7 Hz, 2H, 30,50-H), 6.74 (d, J ¼ 8:7 Hz, 2H, 200,600-
H), 6.52 (s, 1H, 8-H), 6.40 (s, 2H, 20,60-H), 5.96 (dd, 2H,
–OCH2O–), 5.03 (m, 1H, 1-H), 4.80 (m, 1H, –CO–CH–
N–), 4.55 (d, J ¼ 4:5 Hz, 1H, 4-H), 4.39 (t, J ¼ 8:1 Hz,
1H, 11-H), 3.85 (t, J ¼ 8:1 Hz, 1H, 11-H), 3.70 (s, 6H,
30,50-OCH3), 3.25–3.02 (m, 4H, 2, 3-H, –CO–CH–CH2–).
25
Compound 12: yield 35%; mp 131–133 °C; ½aꢀ )100.0
D
(c 0.2, acetone); IR (film) 1740, 1735 (lactone and amide)
1455, 1365 (aromatic C@C) 1217 (phenol) cmꢁ1; MS
m=e: 574 [M)1]þ; H NMR (CDCl3) d 7.37 (m, 5H, 200-
1
600 H), 7.08 (s, 1H, 5-H), 6.39 (s, 1H, 8-H), 6.07 (s, 2H,
20,60-H), 5.91 (d, J ¼ 1:8 Hz, 2H, –OCH2O–), 5.17 (d,
J ¼ 2:7 Hz, 1H, 1-H), 4.11 (m, 5H, 4, 11-H, –NH–CH2–),
3.72 (s, 6H, 30,50-OCH3), 3.13 (m, 1H, 3-H), 2.80 (m, 1H,
2-H).
25
D
Compound 8: yield 91%; mp 177–179 °C (dec); ½aꢀ
)48.0 (c 0.05, acetone); IR (film) 1736 (lactone) 1727
(amide and ester) 1478, 1461, 1433 (aromatic C@C)
1217 (phenol) cmꢁ1; MS m=e: 720 [M+1]þ; 1H NMR
(acetone, D2O exchange) d 7.67 (d, J ¼ 8:7 Hz, 2H, 300,
500-H), 7.58 (d, J ¼ 8:1 Hz, 1H, 10-H), 7.35 (d,
J ¼ 8:1 Hz, 1H, 20-H), 7.22 (s, 1H, –CO–NH–), 7.02 (m,
4H, 40-70-H), 6.77 (s, 1H, 5-H), 6.73 (d, J ¼ 8:7 Hz, 2H,
200,600-H), 6.49 (s, 1H, 8-H), 6.35 (s, 2H, 20,60-H), 5.94 (d,
J ¼ 2:1 Hz, 2H, –OCH2O–), 5.00 (m, 1H, 1-H), 4.90 (m,
1H, –CO–CH–N–), 4.54 (d, J ¼ 4:8 Hz, 1H, 4-H), 4.37
(t, J ¼ 7:8 Hz, 1H, 11-H), 3.78 (t, J ¼ 7:8 Hz, 1H, 11-H),
3.71 (s, 6H, 30,50-OCH3), 3.64 (s, 3H, COOCH3), 3.43–
3.16 (m, 4H, 2, 3-H, –NH–CH–CH2–).
Compound 13: yield 41%; MS m=e: 627 [M)1]þ; 1H
NMR (CDCl3) d 7.46 (d, J ¼ 7:5 Hz, 1H, 10-H), 7.27 (d,
J ¼ 7:8 Hz, 1H, 20-H), 7.18 (s, 1H, 5-H), 7.07 (m, 5H, 8-
H, 40-70-H), 6.88 (s, 2H, 20, 60-H), 5.99 (d, J ¼ 9:9 Hz,
2H, –OCH2O–), 4.88 (m, 2H, 1-H, –NH–CH–CO–),
4.12–3.70 (m, 3H, 4, 11-H), 3.61 (s, 6H, 30,50-OCH3),
3.60 (s, 3H, COOCH3), 3.30–3.17 (m, 4H, 2,3-H, –NH–
CH–CH2–).
4.2. Biology
25
Compound 9: yield 48%; mp 192–195 °C; ½aꢀ )76.0 (c
D
0.05, acetone); IR (film) 1738 (lactone, with shoulder)
Cell growth inhibition assay. Cell growth inhibition was
assayed using the sulforhodamine B (SRB) protocol
1475, 1450, 1420 (aromatic C@C) 1216 (phenol) cmꢁ1
;