Z.H. Wang et al. / Chinese Chemical Letters 21 (2010) 297–300
299
Table 1
Structures and CDK2 kinase inhibitory activities of 70-azaindirubins (1a–g) and 7-azaindirubins (2a–f).
Compd.
R
Z
Inhibition
rate (%)a
IC50
Compd.
R0
Z0
Inhibition
rate (%)a
IC50
(mmol/L)
(mmol/L)
1a
1b
1c
1d
1e
1f
CH3
O
11.5 ꢂ 0.9
10.5 ꢂ 0.7
10.5 ꢂ 0.6
10.5 ꢂ 0.7
10.5 ꢂ 0.5
10.6 ꢂ 0.5
65.0 ꢂ 2.3
ND
2a
2b
2c
2d
2e
2f
I
CH3
O
9.1 ꢂ 1.0
80.4 ꢂ 3.8
51.9 ꢂ 2.1
10.4 ꢂ 0.8
11.3 ꢂ 1.2
11.2 ꢂ 1.0
90.3 ꢂ 3.5
ND
C2H5
i-C3H7
n-C4H9
CH2Ph
i-C3H7
H
O
ND
C2H5
O
1.2 ꢂ 0.4
9.5 ꢂ 1.2
ND
O
ND
i-C3H7
n-C4H9
CH2Ph
i-C3H7
O
O
ND
O
O
ND
O
ND
NOH
O
ND
NOH
ND
1g
8.8 ꢂ 1.0
2.4 ꢂ 0.5
ND: not determined.
Determined at a final concentration of 10ꢁ5 mol/L.
a
In the primary assay, we discovered that compound 1g, 2b and 2c exhibited the higher potency for in vitro inhibition
of CDK2/cylinA kinase (percent inhibition >50%). Comparison of CDK2 kinase inhibitory activity of compounds 1b
and 2b, 1c and 2c, respectively, showed that nitrogen atom at 7-position was helpful to enhance CDK2 kinase
inhibitory activity.
In summary, a series of novel 70-azaindirubin (1a–g) and 7-azaindirubin (2a, 2c, 2e and 2f) derivatives were
synthesized and their inhibitory activity against CDK2/cylinA was evaluated. Compared to parent drug indirubin (I),
compound 2b had more potent activity. The investigation results showed that 70-azaindirubin derivatives, as 7-
azaindirubins, may be also brought to potential antineoplastic candidates for further studies. Moreover, being the first
report of 70-azaindirubin and 7-azaindirubin derivatives serving as CDKs inhibitors, these results demonstrated that the
use of a 7-azaindole coupled with an indole strategy could effectively extend the anticancer compound libraries of
indirubin family.
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[17] The data of selected compounds: 1d. 136–138 8C; ESI-MS m/z: 320.2 [M+H]+; 1H NMR (300 MHz, CDCl3): d 0.97 (t, 3H, J = 7.32 Hz, CH3),
1.38–1.43 (m, 2H, CH2), 1.65–1.74 (m, 2H, CH2), 3.83 (t, 2H, J = 7.29 Hz, N-CH2), 6.89 (d, 1H, J = 7.78 Hz, 7-H), 6.99 (dd, 1H, J = 5.05,
7.49 Hz, 50-H), 7.12 (t, 1H, J = 7.72 Hz, 5-H), 7.34 (t, 1H, J = 7.72 Hz, 6-H), 8.01 (dd, 1H, J = 0.90, 7.49 Hz, 60-H), 8.44 (d, 1H, J = 3.62 Hz, 4-
H), 8.91 (dd, 1H, J = 0.90, 7.80 Hz, 40-H), 10.87 (s, 1H, N0-H); Anal. Calcd. for C19H17N3O2 (319.3) (%): C 71.46, H 5.37, N 13.16; Found: C
71.05, H 5.37, N 13.25. 1f. mp: 275–276 8C; ESI-MS m/z: 321.2 [M+H]+; 1H NMR (300 MHz, DMSO-d6): d 1.49 (d, 6H, J = 7.05 Hz, 2CH3),
4.70–4.76 (m, 1H, N-CH), 7.02–7.12 (m, 2H, Ar-H), 7.22–7.29 (m, 2H, Ar-H), 8.29–8.31 (m, 1H, Ar-H), 8.47 (d, 1H, J = 7.53 Hz, 50-H),
8.71(d, 1H, J = 7.53 Hz, 40-H), 11.84 (s, 1H, N0-H), 13.82 (s, 1H, NOH); Anal. Calcd. for C18H16N4O2 (320.3) (%): C 67.49, H 5.03, N 17.49;
Found: C 67.40, H 5.05, N 17.27. 1g. mp: 325–327 8C; ESI-MS m/z: 261.9 [MꢁH]ꢁ; 1H NMR (300 MHz, DMSO-d6): d 6.92 (d, 1H,
J = 7.75 Hz, 7-H), 7.02–7.13 (m, 2H, Ar-H), 7.30 (dd, 1H, J = 1.16, 7.69 Hz, Ar-H), 8.11 (dd, 1H, J = 1.55, 7.51 Hz, Ar-H), 8.49 (dd, 1H,
J = 1.66, 5.02 Hz, Ar-H), 8.68 (d, 1H, J = 7.39 Hz, 40-H), 10.78 (s, 1H, N0-H), 11.01 (s, 1H, N-H); Anal. Calcd. for C15H9N3O2 (263.2) (%): C
68.44, H 3.45, N 15.96; Found: C 68.12, H 3.16, N 16.24. 2c. mp: 197–200 8C; ESI-MS m/z: 306.1 [M+H]+, 328.0 [M+Na]+, 304.2 [MꢁH]ꢁ,
C18H15N3O2 (Mr = 305.3); 1H NMR (300 MHz, CDCl3): d 1.53 (d, 6H, J = 6.93 Hz, 2CH3), 4.80–4.83 (m, 1H, N-CH), 6.89–6.98 (m, 3H, Ar-