Y. L. Choi et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3036–3040
3039
Table 4
Cytotoxic activities of aristolactam analogues
O
MeO
N
R1
MeO
R6
R8
R7
Compound
R1
R6
H
R7
H
R8
H
Yield (%)
77
Cytotoxicity, GI50 (lM)
A549
0.95
SK-OV-3
1.29
A431
0.94
MES-SA
MES-SA/DX5
HCT-15
1.73
HCT-15/CLO2
1.58
28
1.46
1.51
N
N
29
30
31
32
OMe
OMe
H
OMe
H
–OCH2O–
Cl
H
H
67
40
42
47
1.54
4.10
<0.1
0.26
1.71
6.72
<0.1
0.91
1.19
2.95
<0.1
0.18
nda
nda
4.22
5.91
0.10
0.92
nda
nda
nda
nda
<0.1
0.59
<0.1
0.61
0.14
0.83
H
H
H
33
OMe
H
OMe
42
0.19
0.33
0.15
0.39
0.51
0.72
0.57
34
–OCH2O–
70
<0.1
0.003
nda
<0.1
0.021
nda
<0.0001
0.0012
<0.00001
<0.0001
0.0051
<0.0001
0.93
<0.0001
0.19
0.0095
7.92
Doxorubicin
Paclitaxel
<0.00001
0.16
0.011
0.83
a
nd = not determined.
Chem. 2001, 66, 8064; (d) Rys, V.; Couture, A.; Deniau, E.; Grandclaudon, P. Eur.
J. Org. Chem. 2003, 1231.
Acknowledgments
11. Couture, A.; Deniau, E.; Grandclaudon, P.; Rybalko-Rosen, H.; Léonce, S.;
Pfeiffer, B.; Renard, P. Bioorg. Med. Chem. Lett. 2002, 12, 3557.
12. (a) Kim, J. K.; Kim, Y. H.; Nam, H. T.; Kim, B. T.; Heo, J.-N. Org. Lett. 2008, 10,
3543; (b) Kim, Y. H.; Lee, H.; Kim, Y. J.; Kim, B. T.; Heo, J.-N. J. Org. Chem. 2008,
73, 495.
We thank the Korea Research Institute of Chemical Technology
for the financial support (SI-0905).
13. Typical procedure for synthesis of isoindolin-1-ones. To
a solution of 2-
References and notes
(bromomethyl)benzoate (1.0 mmol) in 5 mL of THF was added amine
1
(5.0 mmol). The mixture was stirred at room temperature for 2 h–2 d while
monitoring the reaction progress. After removing THF under reduced pressure,
the residue was diluted with H2O (10 mL) and extracted with EtOAc
(3 Â 10 mL). The combined organic layers were washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was purified by
recrystallization (EtOAc/hexanes) to provide isoindolin-1-one 2. 1H NMR
(300 MHz, CDCl3) data for 2e (80%): d 7.33 (s, 1H), 4.23 (s, 2H), 3.93 (s, 3H),
3.91 (s, 3H), 3.67 (q, 2H, J = 7.2 Hz), 1.28 (t, 3H, J = 7.2 Hz). Compound 2f (88%):
d 7.25 (s, 1H), 4.56 (heptet, 1H, J = 6.9 Hz), 4.11 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H),
1.23 (d, 6H, J = 6.9 Hz). Compound 2g (98%): d 7.34 (s, 1H), 4.44 (d, 2H,
J = 2.5 Hz), 4.36 (s, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 2.31 (t, 1H, J = 2.5 Hz).
Compound 2h (88%): d 7.34 (s, 1H), 4.37 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.80
(t, 2H, J = 4.9 Hz), 3.63 (t, 2H, J = 4.9 Hz), 3.37 (s, 3H). Compound 2i (98%): d
7.34 (s, 1H), 4.35 (s, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.48 (d, 2H, J = 7.1 Hz), 1.11–
1.00 (m, 1H), 0.63–0.56 (m, 2H), 0.37–0.32 (m, 2H). Compound 2j (66%): d
7.30–7.17 (m, 6H), 4.07 (s, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.84 (t, 2H, J = 7.2 Hz),
2.97 (t, 2H, J = 7.2 Hz). Compound 2k (98%): d 7.37 (s, 1H), 7.25 (d, 1H,
J = 4.9 Hz), 7.05 (d, 1H, J = 3.3 Hz), 6.99–6.96 (dd, 1H, J = 4.9, 3.6 Hz), 4.96 (s,
2H), 4.20 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H). Compound 2l (89%): d 7.74 (d, 2H,
J = 8.7 Hz), 7.46 (d, 2H, J = 8.6 Hz), 7.40 (s, 1H), 4.68 (s, 2H), 3.96 (s, 3H), 3.94 (s,
3H), 1.34 (s, 9H). Compound 2m (90%): d 7.73 (d, 2H, J = 9.0 Hz), 7.41 (s, 1H),
6.99 (d, 2H, J = 9.0 Hz), 4.67 (s, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 3.85 (s, 3H).
Compound 2n (82%): d 8.59 (d, 2H, J = 6.6 Hz), 7.39 (s, 1H), 7.20 (d, 2H,
J = 7.8 Hz), 4.80 (s, 2H), 4.16 (s, 2H), 3.954 (s, 3H), 3.951 (s, 3H). Compound 2o
(98%): d 7.33 (s, 1H), 4.32 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.72 (t, 2H,
J = 6.5 Hz), 2.58 (t, 2H, J = 6.4 Hz), 2.28 (s, 6H). Compound 2p (89%): d 7.33 (s,
1H), 4.35 (s, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.70 (t, 2H, J = 6.6 Hz), 2.73 (t, 2H,
J = 6.6 Hz), 2.60 (q, 4H, J = 7.1 Hz), 1.03 (t, 6H, J = 7.1 Hz). Compound 2q (98%): d
7.33 (s, 1H), 4.33 (s, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.74 (t, 2H, J = 6.3 Hz), 3.69 (t,
4H, J = 3.6 Hz), 2.64 (t, 2H, J = 6.3 Hz), 2.52 (bs, 4H). Compound 2r (99%): d 7.33
(s, 1H), 4.35 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.72 (t, 2H, J = 6.6 Hz), 2.58 (t, 2H,
J = 6.6 Hz), 2.44 (s, 4H), 1.61–1.47 (m, 4H), 1.45–1.41 (m, 2H).
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14. Typical procedure for synthesis of phenanthrene lactams. To
a
thick-well
borosilicate glass vial (3 mL) was added isoindolin-1-one
2
(0.5 mmol),
boronic acid (0.6 mmol), Pd(PPh3)4 (4 mol %), and Cs2CO3 (1.5 mmol)