342
J. Wang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 339–342
1 µM
G0/G1
G2/M
3 µM
DMSO Ctrl
10 µM
9
10a
10b
10c
10d
10e
10f
10g
PI-103
Figure 3. Compounds 9 and 10 induce cell cycle arrest at G1 phase.
6. Kong, D.; Yamori, T. Curr. Med. Chem. 2009, 16, 2839.
population in G1 phase increased after treatment by 9 and 10,
demonstrating that the compounds tested induced cell cycle arrest
at G1 phase, which is consistent with results obtained with the
lead compound PI103. Additionally, 9 and 10 also slightly induced
7. Ohwada, J.; Ebiike, H.; Kawada, H.; Tsukazaki, M.; Nakamura, M.; Miyazaki, T.;
Morikami, K.; Yoshinari, K.; Yoshida, M.; Kondoh, O.; Kuramoto, S.; Ogawa, K.;
Aoki, Y.; Shimma, N. Bioorg. Med. Chem. Lett. 2011, 21, 1767.
8. All compounds were characterized by 1H NMR and MS. Spectral data of
representative compounds 9, 10a–g: Compound 9: 1H NMR (300 MHz, DMSO-
d6) d 9.59 (s, 1H), 8.72 (d, J = 3.9 Hz, 1H), 8.50 (d, J = 8.1 Hz, 1H), 7.82 (m, 1H),
7.76 (m, 1H), 7.50 (s, 1H), 7.44 (dd, J = 8.5, 4.4 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H),
6.88 (d, J = 6.4 Hz, 1H), 4.22 (t, J = 4.2 Hz, 4H), 3.85 (t, J = 4.2 Hz, 4H). MS (EI): m/
z (%) 347(100, M+), 290(35). Compound 10a: 1H NMR (300 MHz, DMSO-d6) d
8.58 (dd, J = 4.3, 1.2 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.94
(m, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.64 (s, 1H), 7.44 (dd, J = 8.4, 4.3 Hz, 1H), 7.26
(dd, J = 8.3, 2.1 Hz, 1H), 4.20 (t, J = 4.9 Hz, 4H), 3.84 (t, J = 4.9 Hz, 4H), 2.28 (s,
3H). MS (EI): m/z (%) 389(100, M+), 347(40). Compound 10b: 1H NMR
(300 MHz, DMSO-d6) d 8.58 (dd, J = 4.3, 1.2 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H),
7.99 (d, J = 7.8 Hz, 1H), 7.85 (m, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.64 (s, 1H), 7.43
(dd, J = 8.4, 4.3 Hz, 1H), 7.28 (dd, J = 8.3, 2.1 Hz, 1H), 4.21 (t, J = 4.9 Hz, 4H), 3.84
(t, J = 4.9 Hz, 4H), 2.67 (q, J = 6.8 Hz, 2H), 1.32 (t, J = 6.8 Hz, 3H). MS (EI): m/z (%)
403(100, M+), 224(50). Compound 10c: 1H NMR (300 MHz, DMSO-d6) d 8.73
(dd, J = 4.3, 1.2 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.02 (m,
1H), 7.57 (t, J = 7.9 Hz, 1H), 7.53 (s, 1H), 7.44 (dd, J = 8.4, 4.3 Hz, 1H), 7.26 (dd,
J = 8.3, 2.1 Hz, 1H), 4.21 (t, J = 4.9 Hz, 4H), 3.84 (t, J = 4.9 Hz, 4H), 2.63 (t,
J = 7.3 Hz, 2H), 1.71 (dt, J = 14.7, 7.2 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H). MS (EI): m/z
(%) 417(100, M+), 347(45), 290(30). Compound 10d: 1H NMR (300 MHz, DMSO-
d6) d 8.74 (dd, J = 4.3, 1.2 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H),
7.67 (m, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.44 (s, 1H), 7.41 (dd, J = 8.4, 4.3 Hz, 1H),
7.26 (dd, J = 8.3, 2.1 Hz, 1H), 4.11 (t, J = 4.9 Hz, 4H), 3.84 (t, J = 4.9 Hz, 4H), 2.25
(td, J = 8.7, 4.1 Hz, 1H), 1.59 (m, 2H), 1.50 (ddd, J = 18.7, 10.7, 5.6 Hz, 2H), 1.40
(m, 4H), 0.94 (t, J = 7.3 Hz, 6H). MS (EI): m/z (%) 473(100, M+), 347(35).
Compound 10e: 1H NMR (300 MHz, DMSO-d6) d 8.58 (dd, J = 4.3, 1.2 Hz, 1H),
8.02 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.69 (m, 1H), 7.57 (t, J = 7.9 Hz,
1H), 7.53 (s, 1H), 7.44 (dd, J = 8.4, 4.3 Hz, 1H), 7.26 (dd, J = 8.3, 2.1 Hz, 1H), 6.38
(d, J = 4.3 Hz, 2H), 6.08 (t, J = 4.0 Hz, 1H), 4.21 (t, J = 4.9 Hz, 4H), 3.84 (t,
J = 4.9 Hz, 4H). MS (EI): m/z (%) 401(100, M+), 347(40). Compound 10f: 1H NMR
(300 MHz, DMSO-d6) d 8.58 (dd, J = 4.3, 1.2 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.97
(d, J = 7.8 Hz, 1H), 7.89 (m, 1H), 7.85 (d, J = 4.0 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H),
7.57 (s, 1H), 7.52 (d, J = 4.1 Hz, 1H), 7.44 (dd, J = 8.4, 4.3 Hz, 1H), 7.26 (dd,
J = 8.3, 2.1 Hz, 1H), 6.68 (t, J = 4.0 Hz, 1H), 4.21 (t, J = 4.9 Hz, 4H), 3.84 (t,
J = 4.9 Hz, 4H). MS (EI): m/z (%) 441(20, M+), 224(70), 56(100). Compound 10g:
1H NMR (300 MHz, DMSO-d6) d 8.81 (d, J = 4.5 Hz, 2H), 8.63 (dd, J = 4.3, 1.2 Hz,
1H), 8.58 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.91 (m, 4H), 7.62 (t,
J = 7.9 Hz, 1H), 7.54 (s, 1H), 7.42 (dd, J = 8.4, 4.3 Hz, 1H), 7.38 (dd, J = 8.3, 2.1 Hz,
1H), 4.21 (t, J = 4.9 Hz, 4H), 3.84 (t, J = 4.9 Hz, 4H). MS (EI): m/z (%) 452(100,
M+).
apoptosis in Rh30 cell at the concentration of 10
strated by a small sub-G1 peak in Figure 3.
In summary, structural modification of PI-103 led to the
discovery of 4-(2-arylpyrido[30,20:3,4]pyrrolo[1,2-f][1,2,4]triazin-
4-yl)morpholine derivatives 9 and 10 as novel PI3K inhibitors. 9,
lM, as demon-
10a, 10d, 10e had the IC50 against PI3Ka comparable with
PI-103. All of the compounds showed selectivity over 15 tested pro-
tein kinases and anti-proliferative activity at micromolar concen-
tration against several cancer cell lines. More importantly, this
modification may provide a useful scaffold for further optimization
of PI3K inhibitors.
Acknowledgments
This work was financially supported by the National Natural
Science Foundation of China (20772138, 90713034, 81021062),
and by Shanghai Municipality Science and Technology Develop-
ment Fund 09JC1416600. Knowledge Innovation Program of
Chinese Academy of Sciences (KSCX2-EW-Q-3).
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