S.L. Zhang et al. / Chinese Chemical Letters 21 (2010) 1071–1074
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Table 1
The substituents, melting points, 1H NMR and MS data of compounds 7a–7h and 12a–12d.
Compd.
X
N
Ar
mp (8C)
1H NMR (300 MHz, DMSO-d6) d
MS m/z
7a
191–192
9.72 (s, 1H), 8.45 (d, 2H, J = 5.2 Hz), 8.17 (m, 1H), 8.13 (m, 1H),
8.02 (m, 1H), 7.98–7.88 (m, 2H), 7.34–7.25 (m, 3H), 7.24–7.13
(m, 2H), 4.63 (s, 2H), 3.47 (s, 4H), 3.33 (s, 2H), 2.87 (s, 4H)
10.21 (s, 1H), 8.45 (d, 2H, J = 5.5 Hz), 8.20–8.14 (m, 1H),
8.11 (m, 2H), 7.99–7.86 (m, 2H), 7.67 (dd, 1H, J = 8.8, 2.4 Hz),
7.58 (d, 1H, J = 8.8 Hz), 7.31 (d, 2H, J = 5.8 Hz), 4.62 (s, 2H),
3.47 (s, 4H), 3.31 (s, 2H), 2.83 (s, 4H)
457.3
7b
7c
7d
7e
N
N
N
N
192–193
78–79
507.3
509.3
9.67 (s, 1H), 8.45 (d, 2H, J = 5.5 Hz), 8.16 (m, 1H), 8.11 (m, 1H),
7.93 (m, 2H), 7.47–7.35 (m, 2H), 7.31 (d, 2H, J = 5.5 Hz),
7.05 (d, 1H, J = 8.1 Hz), 4.62 (s, 2H), 3.46 (s, 4H), 3.24 (s, 2H),
2.82 (s, 4H), 2.19 (s, 3H), 2.16 (s, 3H)
467.4
207–208
177–178
10.00 (s, 1H), 8.45 (d, J = 5.9 Hz, 2H), 8.16 (m, 1H), 8.12 (m, 1H),
7.93 (m, 2H), 7.72 (d, 2H, J = 8.8 Hz), 7.37 (d, 2H, J = 8.9 Hz),
7.31 (d, 2H, J = 5.8 Hz), 4.62 (s, 2H), 3.47 (s, 4H), 3.29 (s, 2H),
2.83 (s, 4H)
473.1
475.1
9.41 (s, 1H), 8.45(d, 2H, J = 5.5 Hz), 8.15 (m, 2H), 7.93 (m, 2H),
7.66 (s, 1H), 7.31 (s, 2H), 7.10 (d, 1H, J = 8.1 Hz),
467.4
471.3
501.2
6.87 (d, 1H, J = 7.6 Hz), 4.62 (s, 2H), 3.48 (s, 4H), 3.27 (s, 2H),
2.88 (s, 4H), 2.25 (s, 3H), 2.21 (s, 3H)
7f
N
N
192–193
109–110
9.66 (s, 1H), 8.45 (d, 2H, J = 5.0 Hz), 8.21–8.15 (m, 1H),
8.14–8.08 (m, 1H), 7.92 (m, 2H), 7.85 (d, 1H, J = 6.9 Hz),
7.32 (d, 2H, J = 5.2 Hz), 7.15 (dd, 1H, J = 10.8, 8.5 Hz), 6.95 (s, 1H),
4.63 (s, 2H), 3.46 (s, 4H), 3.32 (s, 2H), 2.86 (s, 4H), 2.28 (s, 3H)
7g
10.14 (s, 1H), 8.45 (d, 2H, J = 5.9 Hz), 8.22–8.14 (m, 1H),
8.14–8.08 (m, 1H), 8.00–7.84 (m, 2H), 7.31 (d, 2H, J = 5.9 Hz),
5.94 (s, 1H), 4.62 (s, 2H), 3.88 (s, 6H), 3.47 (s, 2H), 3.42 (s, 4H),
2.86 (s, 4H)
7h
N
C
175–176
76–77
10.17 (s, 1H), 8.93 (dd, 1H, J = 4.2, 1.5 Hz), 8.50–8.43 (m, 2H),
8.39 (d, 1H, J = 8.1 Hz), 8.22–8.09 (m, 2H), 7.94 (m, 2H), 7.88 (m, 2H),
7.81–7.72 (m, 1H), 7.61 (m, 1H), 7.32 (d, 2H, J = 6.0 Hz), 4.63 (s, 2H),
3.54 (s, 4H), 3.44 (s, 2H), 2.94 (s, 4H)
490.2
500.4
12a
10.14 (s, 1H), 8.17 (m, 1H), 8.08 (m, 1H), 7.97–7.81 (m, 2H),
7.40–7.21 (m, 4H), 7.18 (t, 1H, J = 7.0 Hz), 5.94 (s, 1H), 4.58 (s, 2H),
3.88 (s, 6H), 3.47 (s, 2H), 3.42 (s, 4H), 2.86 (s, 4H)
12b
12c
12d
C
C
C
124–125
92–93
10.18 (s, 1H), 8.93 (dd, 1H, J = 4.2, 1.6 Hz), 8.40 (d, 1H, J = 8.3 Hz),
8.20 (m, 1H), 8.16–8.10 (m, 1H), 7.90 (m, 4H), 7.83–7.72 (m, 1H),
7.61 (m, 1H), 7.37–7.23 (m, 4H), 7.17 (t, 1H, J = 7.1 Hz), 4.59 (s, 2H),
3.53 (s, 4H), 3.44 (s, 2H), 2.94 (s, 4H)
489.3
10.24 (s, 1H), 8.18 (d, 1H, J = 6.9 Hz), 8.09 (d, 1H, J = 6.6 Hz),
7.91 (m, 2H), 7.83 (m, 2H), 7.34–7.24 (m, 5H), 7.18 (d, 1H, J = 6.8 Hz),
4.58 (s, 2H), 3.48 (s, 4H), 3.34 (s, 2H), 2.86 (s, 4H)
506.1
508.1
94–95
10.37 (s, 1H), 8.18 (d, 1H, J = 9.0 Hz), 8.09 (d, 1H, J = 6.6 Hz),
7.96–7.84 (m, 2H), 7.50 (d, 2H, J = 7.8 Hz), 7.37–7.21 (m, 4H),
7.16 (t, 1H, J = 7.0 Hz), 6.92 (t, 1H, J = 9.4 Hz), 4.58 (s, 2H),
3.45 (s, 4H), 3.32 (s, 2H), 2.89–2.70 (m, 4H)
474.4
Besides, the antitumor activities of 7a–7h were much more potent than those of compounds 12a–12d against the
three human cancer cell lines in most cases. As shown in Table 2, compounds 12a–12d displayed moderate cytotoxic
activities against HT-29 and MDA-MB-231 cell lines, but not to A549 cell line. While, compounds 7a–7h displayed
excellent selectivity for MDA-MB-231 cell line with IC50 values from 1 nmol/L to 0.92 mmol/L. In particular,
compounds 7b and 7e showed IC50 values in the single-digit nmol/L range against MDA-MB-231 cell line. The
preliminary structure–activity relationship (SAR) showed that the pyridyl group at position-4 of phthalazine scaffold
plays an important role in enhancing their cytotoxic activities.