Discovery and bioactivity of 4-(2-arylpyrido[3′,2′:3,4] pyrrolo[1,2-f][1,2,4]triazin-4-yl) morpholine derivatives as novel PI3K inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.11.003

PI3K is a promising therapeutic target for cancer. With PI-103 as the lead compound, we designed and synthesized 4-(2-arylpyrido[3′,2′:3,4] pyrrolo[1,2-f][1,2,4]triazin-4-yl)morpholine derivatives. 9, 10a, 10d, 10e had the IC₅₀ against PI3Kα comparable with PI-103. All of the compounds showed selectivity over 15 tested protein kinases and anti-proliferative activity at micromolar concentration against several cancer cell lines.

Full text of DOI:10.1016/j.bmcl.2011.11.003

Bioorganic & Medicinal Chemistry Letters 22 (2012) 339–342
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery and bioactivity of 4-(2-arylpyrido[30,20:3,4]pyrrolo[1,2-f][1,2,4]-
triazin-4-yl) morpholine derivatives as novel PI3K inhibitors
⇑
Jia Wang , Xiang Wang , Yanhong Chen, Simeng Chen, Guang Chen, Linjiang Tong, Linghua Meng ,
Yuyuan Xie, Jian Ding, Chunhao Yang
⇑
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, SIBS, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
PI3K is a promising therapeutic target for cancer. With PI-103 as the lead compound, we designed and
synthesized 4-(2-arylpyrido[30,20:3,4]pyrrolo[1,2-f][1,2,4]triazin-4-yl)morpholine derivatives. 9, 10a,
Received 12 August 2011
Revised 20 October 2011
Accepted 2 November 2011
Available online 9 November 2011
10d, 10e had the IC50 against PI3Ka comparable with PI-103. All of the compounds showed selectivity
over 15 tested protein kinases and anti-proliferative activity at micromolar concentration against several
cancer cell lines.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
PI3K
Cancer
PI-103 analogs
O
N
Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid
kinases that phosphorylate the hydroxyl group at position 3 on
the inositol ring to generate the second messengers phosphatidyl-
inositol 3,4,5-trisphosphate (for class I PI3Ks), phosphatidylinositol
3,4-bisphosphate (for class II PI3Ks) or phosphatidylinositol 3-
phosphate (for class III PI3K) and then initiate the PI3K mediated
signaling.1 Among the various subtypes of PI3Ks identified to date,
class I PI3Ks are known to play critical roles in cell growth and sur-
vival mainly through downstream components Akt and mTOR.2
PI3K signaling is negatively regulated by PTEN.3 Hyper-activation
of PI3Ks and/or inactivation of PTEN occur frequently in human
cancers. Therefore targeting PI3Ks is a promising approach for can-
cer therapy4 and significant efforts have been made to develop
PI3K inhibitors.5
O
N
N
OH
N
PI-103
O
N
N
N
N
O
N
R
Piramed pharma’s PI-103 is a dual PI3K/mTOR inhibitor, which
exhibitedpotent antitumor activity in human tumor xenograft mod-
els as a single agent or in combination with other anticancer drugs.
PI-103 induced cell cycle arrest at G1 phase at submicromolar
concentration and its anti-angiogenic activity was also reported.6
Morpholine, phenol, and pyridine moieties in PI-103 were presumed
to play an importantrolein theirinteraction with PI3K.7 Utilizingthe
structural information available and bioisostere, we designed 3-(4-
morpholinopyrido[30,20:3,4]pyrrolo[1,2-f][1,2,4]triazin-2-yl)phenol
(Fig. 1), which maintained the conformation of PI-103 and changed
9
R = H
Figure 1. The structures of PI-103 and the designed compounds.
furan to pyrrole. Futhermore, phenol moiety was modified to ester,
wishing to improve the pharmacological properties.
The designed compound 9 and its derivatives 10a–g were
synthesized as Scheme 1.8 The intermediate ethyl 1H-pyrrolo[3,
2-b]-pyridine-2-carboxylate 4 was synthesized from 2-chloro-3-
nitropyridine 1 by three steps according to the literature.9 Com-
pound 4 was reacted with the fresh solution of NH2Cl in ether. After
4 was consumed completely, the reaction solution was quenched by
saturated Na2S2O3 aqueous solution, extracted by AcOEt and con-
centrated to give the crude product 5, which was used without puri-
fication at once because it was labile. Annulation of 5 with ethyl
⇑
Corresponding authors. Tel./fax: +86 21 50806770.
E-mail addresses: lhmeng@mail.shcnc.ac.cn (L. Meng), chyang@mail.shcnc.ac.cn
(C. Yang).
These authors contributed equally.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.11.003

340
J. Wang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 339–342
O
HO
OEt
N
N
Cl
N
N
(a)
(b)
(c)
(d)
(g)
OEt
N
H
NO2
NO2
NO2
(f)
O
1
2
3
4
Cl
OH
N
N
(e)
N
N
N
OEt
N
O
N
O
N
N
N
NH2
O
7
6
5
O
N
O
O
N
N
N
(i)
OH
(h)
N
N
N
N
N
N
N
N
O
N
O
R1
N
N
O
10a-g
8
9
10a. R1 = CH3, 10b. R1 = CH3CH2,
10c. R1 = CH3CH2CH2,
10d. R1 = (CH3CH2CH2)2CH,
10e. R1 = CH2=CH,
10f. R1 = 2-furyl,
10g. R1= 4-pyridyl.
Scheme 1. Reagents and conditions: (a) Na, CH2(CO2Et)2, 90 °C, 7 h, then H2SO4, 105 °C, 7 h, 80%; (b) Na, (COOEt)2, EtOH, rt, 8 h, 81%; (c) TiCl4, SnCl2 2H2O, EtOH, 80 °C, 8 h,
67%; (d) NH2Cl, KOtBu, DMF, 0 °C to rt, 4 h, 83%; (e) ethyl 3-methoxybenzimidate hydrochloride, EtOH, 80 °C, 8 h, 26%; (f) POCl3, 110 °C, 3 h, 88%; (g) morpholine, THF, 70 °C,
5 h, 90%; (h) BBr3, CH2Cl2, rt, 2 h, 62%; (i) R1COOH, DCC, CH2Cl2, rt, 8 h, 78–83%.
Table 1
various carboxylic acids under the condition of DCC/CH2Cl2 afforded
10a–g.
Inhibitory activity against PI3K
a of 9 and 10
We first detected the effect of the compounds on the kinase
Compound
IC50 (nM)
Compound
IC50 (nM)
activity of PI3K
The results were summarized in Table 1. 9 inhibited PI3K
a
using Kinase-GloÒ Luminescent Kinase Assays.
9
33.6
49.7
544.0
510.5
60.7
10e
10f
10g
PI-103
47.8
424.7
421.3
16.8
a
with
10a
10b
10c
10d
an IC50 of 33.6 nM, showing a two-fold decrease in potency com-
pared with PI-103. Acetylation of 9 resulted in almost similar po-
tency (10a: IC50 = 49.7 nM). Replacement of acetyl with propionyl
or butyryl decreased the PI3K
(10b: IC50 = 544.0 nM, 10c: IC50 = 510.5 nM), whereas 2-propyl-
pentanoate and acrylate retained similar PI3K inhibitory activity
(10d: IC50 = 60.7 nM, 10e: IC50 = 47.8 nM) with 10a. Heteroaryl car-
boxylate such as isonicotinate and furan-2-carboxylate showed
unsatisfied inhibitory activity (10f: IC50 = 424.7 nM, 10g:
IC50 = 421.3 nM).
a inhibitory potency by about 10-fold
a
3-methoxybenzimidate hydrochloride in refluxing EtOH gave inter-
mediate 6. Chlorination of 6 with phosphorus oxychloride followed
by substitution with morpholine afforded 8. Demethylation of 8 by
BBr3 in CH2Cl2 gave the desired product 9. Condensation of 9 with
Table 2
The inhibitory activity against 15 protein kinases of 9 and 10
Compound
Inhibitory rate at the concentration of 10 lM
Flt-1
KDR
c-Kit
PDGFR
a
PDGFRb
RET
EGFR
ErbB2
c-Src
EPH-A2
EPH-B2
c-Met
RON
IGF1R
FGFR1
9
10a
10b
10c
10d
10e
10f
10g
Su11248
Lapatinib
Dasatinib
Su11274
AG538
Su5402
45.7
28.1
60.6
53.4
34.1
39.3
40.0
49.1
88.0
ND
39.2
23.1
25.0
25.6
29.1
28.4
24.7
35.4
94.2
ND
49.4
24.7
29.0
25.4
24.9
18.9
26.9
45.2
84.8
ND
41.2
21.8
13.0
14.0
28.7
29.4
22.2
40.0
93.0
ND
42.4
0
11.8
5.1
13.6
6.3
13.5
34.7
90.6
ND
37.8
19.0
43.0
25.8
14.4
31.9
22.8
28.9
84.8
ND
17.4
4.6
10.9
7.1
65.3
40.0
52.8
48.2
49.8
56.2
47.9
67.2
ND
ND
93.6
ND
ND
ND
53.2
22.8
32.9
22.7
15.7
19.0
37.8
41.2
ND
ND
94.5
ND
ND
ND
44.0
37.2
48.6
53.0
49.2
53.4
35.8
53.8
ND
ND
89.2
ND
ND
ND
43.8
29.0
31.7
33.9
29.0
32.8
32.5
34.8
ND
ND
ND
61.8
ND
ND
37.0
9.4
17.6
7.4
23.1
3.3
4.2
27.2
ND
ND
ND
52.2
ND
35.2
33.4
23.7
15.6
32.7
41.1
29.2
39.8
ND
ND
ND
ND
82.2
ND
39.2
27.2
37.4
32.9
37.2
40.8
43.0
40.3
ND
ND
ND
ND
ND
26.8
16.0
20.2
17.8
11.8
6.2
12.5
12.5
25.6
21.3
23.6
23.3
ND
78.0
ND
ND
NDa
97.7
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
78.6
a
ND means not determined.

J. Wang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 339–342
341
Figure 2. Modulation of p-Akt and p-p70s6k1.
Table 3
Furthermore, the effect of these compounds on the downstream
signal was examined by Western blot. The results (shown in Fig. 2)
suggested that these compounds inhibited PI3K-Akt-mTOR path-
way in a dose-dependent manner. The phosphorylated Akt and
p70S6K1 levels were significantly down regulated by all com-
The anti-proliferative activity of 9 and 10 in several human tumor lines
Compound
IC50 (lM)
ECV-304
BEL-7402
MCF-7
HT-29
9
6.7
3.8
4.0
1.4
2.5
4.0
6.0
10.0
6.3
13.1
12.1
8.6
3.6
5.6
7.9
9.3
13.3
7.0
22.7
14.4
18.7
6.1
22.3
>50
pounds except 10f and 10g at the concentration of 3 lM.
10a
10b
10c
10d
10e
10f
The anti-proliferative activity of these derivatives was evalu-
ated in several human tumor cell lines. As shown in Table 3, all
of these derivatives, especially 10c and 10d, exerted comparable
or even stronger anti-proliferative activity than the lead compound
PI-103 in human bladder cancer ECV-304 cells, human hepatoma
BEL-7402 cells, human breast cancer MCF-7 cells and human colon
carcinoma HT-29 cells. It should be notable that 10b, 10c, 10f and
10g displayed superior anti-proliferative activity than 9, while they
30.4
16.4
37.5
29.9
21.6
28.0
>50
7.3
15.3
12.8
20.0
22.4
10g
PI-103
PI103 has been shown previously to be a selective inhibitor to-
wards class I PI3Ks among a panel of 70 protein kinases represent-
possessed weaker activity against PI3Ka (Table 1). The inconsis-
tency might be due to the hydrolysis of the ester moieties in cells.
As different from the purified kinase experiment using kinase-Glo
assays, the cancer cell assays provided full cell-machinery to exe-
cute such hydrolysis, thus increasing the likelihood of metabo-
lism-driven hydrolysis of the compounds 10a–10g.
ing of the human kinome.10 To examine selectivity for PI3K
a, the
inhibitory activity of these compounds was then evaluated against
15 protein tyrosine kinases. As shown in Table 2, most of these
compounds showed weak inhibitory activity, with the inhibitory
rate lower than 50% at the concentration of 10
lM, indicating
Finally, the effect of the compounds on cell cycle distribution
was determined by flow cytometer. As shown in Figure 3, cell
selective inhibitory activity against PI3Ka 1
.

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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