2-Guanidinoquinazolines as new inhibitors of the STAT3 pathway

Article abstract of DOI:10.1016/j.bmcl.2014.09.001

Synthesis and SAR investigation of 2-guanidinoquinazolines, initially identified in a high content screen for selective STAT3 pathway inhibitors, led to a more potent analog (11c) that demonstrated improved anti-proliferative activity against a panel of HNSCC cell lines.

Full text of DOI:10.1016/j.bmcl.2014.09.001

Bioorganic & Medicinal Chemistry Letters 24 (2014) 5081–5085
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
2-Guanidinoquinazolines as new inhibitors of the STAT3 pathway
a
a
b
b,c,d
Matthew G. LaPorte a, , Dimas José da Paz Lima , Feng Zhang , Malabika Sen , Jennifer R. Grandis
,
⇑
Daniel Camarco e, Yun Hua e, Paul A. Johnston c,e, John S. Lazo f, Lynn O. Resnick a, Peter Wipf a,c,e
,
Donna M. Huryn a,e,
⇑
a University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260, USA
b Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15260, USA
c University of Pittsburgh Cancer Institute, Pittsburgh, PA 15260, USA
d Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA
e Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA
f Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2014
Revised 28 August 2014
Accepted 1 September 2014
Available online 15 September 2014
Synthesis and SAR investigation of 2-guanidinoquinazolines, initially identified in a high content screen
for selective STAT3 pathway inhibitors, led to a more potent analog (11c) that demonstrated improved
anti-proliferative activity against a panel of HNSCC cell lines.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
STAT3 pathway
Guanidinoquinazolines
Skraup synthesis
Structure–activity relationships
Cancer cell line screening
Despite recent advances in early detection methods and treat-
ment regimens, cancer continues to be a major health threat,
responsible for over 25% of deaths annually in the U.S. alone.1 Head
and neck squamous cell carcinomas (HNSCC) are particularly chal-
lenging therapeutic targets2 as evidenced by the fact that the
monoclonal antibody Cetuximab (Erbitux), an epidermal growth
factor receptor (EGFR) inhibitor,3 was the only new drug approved
for this indication in the last several decades. To address this issue,
a wide range of signaling pathways that control cell proliferation
have been interrogated as potential therapeutic strategies for
HNSCC, including the family of signal transducers and activators
of transcription (STATs).4–6 STAT3 is a tumor promoting transcrip-
tion factor that has been shown to be constitutively activated in
numerous cancers, and suppression of STAT3 leads to inhibition
of tumor growth in both in vitro and in vivo experiments. In con-
trast, the related transcription factor, STAT1, activates genes that
promote tumor suppression. Therefore, molecules that selectively
inhibit STAT3-mediated pathways with no effect on STAT1 path-
ways, have the potential to be highly effective anti-tumor agents.
Several small organic molecules that inhibit the STAT3 pathway
have been reported in the literature.7 One strategy has been to
design molecules that directly target the Src homology 2 (SH2)
domain in STAT3 (1–4, Fig. 1).8 Other approaches included focusing
on inhibiting kinases operative in the STAT3 pathway, such as
Janus activated kinases (JAKs), and identified quinolones, pyri-
dones, and the pyridine carboxamide, sorafenib (5, 6 and 7, respec-
tively, Fig. 1).9 Additionally, natural products, including STA-21 (8),
curcumin (9), and cucurbitacin Q (10), inhibit the STAT3 pathway;
however, specific inhibitory mechanisms are still being elucidated
(Fig. 2).5b Finally, anti-sense oligonucleotides (AZD9150) and decoy
nucleotides directed at STAT3 also exhibit promising anti-prolifer-
ative activities in cellular assays.5,10
By using a high content phenotypic screen (HCS) to identify
selective inhibitors of IL-6 induced activation of the STAT3 path-
way,11 we identified the quinazoline 11a (Fig. 3). In Cal33 head
and neck tumor cells, 11a inhibited IL-6-induced STAT3 tyrosine
phosphorylation and nuclear translocation (IC50 = 15.7
had no effect on IFN -induced activation of the STAT1 pathway
at 50 M (Fig. 3). Western blot analysis indicated a 69% decrease
in phospho-STAT3 (pSTAT3) levels upon treatment of 11a at
39.6 M concentration (Fig. 4, A and B). Unlike the JAK inhibitor
6 that displayed nanomolar potencies against both STAT3 and
lM), but
c
l
⇑
Corresponding authors. Tel.: +1 412 624 8004 (M.G.L.), +1 412 737 3225
(D.M.H.).
l
E-mail addresses: mgl12@pitt.edu (M.G. LaPorte), huryn@pitt.edu (D.M. Huryn).
http://dx.doi.org/10.1016/j.bmcl.2014.09.001
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

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M. G. LaPorte et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5081–5085
NH2
O
O
O
H
N
N
NHBn
O
O
O
O
F
F
O
O
O
HN
NH
P
O
O
O
O
O
H
N
H2N
BnOCONH
N
2
O
1
OPO3H2
F
F
F
O
O
O
O
N
N
S
F
O
O
F
CO2H
3
OH
CO2H
4, BP-1-102
F
F
O
N
F
F
CO2Et
O
N
AcHN
O
Cl
O
t-Bu
F
F
HN
N
H
N
F
N
H
N
CF3
F
H
6, pyridone 6
7, sorafenib
5
F
F
Figure 1. SH2 targeted phosphopeptide mimetics and JAK inhibitors of the STAT3 pathway.
O
O
O
HO
O
O
O
O
O
H
O
H
H
OH
HO
HO
HO
OH
OH
OMe
OMe
STA-21 (8)
curcumin (9)
cucurbitacin Q (10)
Figure 2. Natural product STAT3 inhibitors.
Our initial strategy was to incorporate modest structural modifi-
cations onto the 2-guanidinoquinazoline core in order to establish
preliminary structure-activity relationships. Using established syn-
thetic procedures,16 the dihydroquinolines 13 were generated
through the treatment of the substituted anilines 12 with acetone
under modified Skraup conditions (Scheme 1).17 Conversion to the
guanidines 14 occurred by reaction with cyanoguanidine under
aqueous acidic conditions.18 The final products, dihydropyrimidi-
nyl-aminoquinazolines 11a–d, were formed via thermal cyclodehy-
drations using mesityl oxide in DMSO. The structure of 11b was
confirmed by X-ray analysis (Scheme 1).16 In this subset of analogs
(Table 1), it was apparent that structural modification was tolerated
and modulated the biological profile; the C6-methyl (11b) and C6-
,C8-dimethyl (11c) analogs exhibited improved potency (4- and
30-fold, respectively) while maintaining selectivity versus STAT1
compared to the original hit 11a. Unlike 11a, 11b and 11d, which
EtO
STAT3 IC50 = 15.7 5.4 μM
STAT1 IC50 > 50 μM
N
N
=
N
N
H
N
H
STAT1/STAT3 = > 3
GI50 (HNSCC) 17-37
M
μ
11a
MW = 325
HBA = 4.7
HBD = 2.0
cLogP = 4.0
PSA = 60
# rotatable bonds = 4
Figure 3. Guanidinoquinazoline hit 11a.
STAT1 (data not shown),11 compound 11a selectively inhibited
STAT3 compared to STAT1 and displayed no effects on JAK1/JAK2
as determined by Western blot analysis (Figs. 3 and 4, panels C
and D). In addition, 11a exhibited anti-proliferative activities
(IC50’s = 17–37 lM in four HNSCC cell lines (CAL33, FADU, 686
LN, OSC19, Fig. 3). Examination of the literature and PubChem
revealed limited examples of biological effects for this chemotype,
and Lipinski and Veber parameters fell into the generally desirable
ranges (Fig. 3).12–15 While the specific mode of action of 11a was
not determined, its apparent lack of activity in the STAT1 assay
likely rules out direct binding to SH2 domains. Furthermore, this
hit compound did not exhibit any significant activity against a
panel of >80 kinases (data not shown). The promising selectivity
for STAT3, the notable anti-proliferative activity and desirable
physical properties made this compound an attractive lead struc-
ture for further medicinal chemistry optimization, and herein we
report the results of these efforts.
failed to show any inhibition of IFN
c-induced STAT1 activation at
50 M, 11c exhibited an IC50 of 5.9
l
lM for STAT1 but still main-
tained a good selectivity index (Table 1).
Efforts to examine a simplified pharmacophore focused on the
preparation of 2-aminoquinazolines of general structure 17
(Scheme 2). The pivotal 2-chloro intermediate 16 was prepared
in three steps19 and subjected to amination under microwave con-
ditions to provide the corresponding quinazoline derivatives 17a–i.
All of these compounds were devoid of activity and therefore
established the importance of quinazoline substitutions as well
as the C2-linked nitrogenous heterocycle (Table 2).11

M. G. LaPorte et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5081–5085
5083
69%
11a
A
B
pSTAT3Tyr705
STAT3
-tubulin
C
D
11a
11a
Figure 4. Inhibition of STAT3 phosphorylation using Western blot analysis of compound 11a versus vehicle in interleukin 6 (IL6, 50 ng/mL)-stimulated CAL33 cells (A & B).
Compound 11a did not show any effects on pJAK1/JAK1 (C) or pJAK2/JAK2 (D).
NCN
R1
R2
12
R1
R2
R1
R2
H2N
NH2
t-butylcatechol, I2
N
NH
N NH2
NH2
acetone, MgSO4
HCl, H2O
R3
N
14
N
H
13
H
R3
R3
O
R1
R2
N
N
N
N
N
H
DMSO
H
R3
11a-d
N
N
N
H
N
H
N
11b
Scheme 1. Preparation of 2-guanidinoquinazolines 11a–d and X-ray structure of 11b (CCDC 1020633).
Table 1
STAT3 and STAT1 Activity of 2-guanidinoquinazolines 11a–d
R1
R2
R3
STAT3
IC50
STAT1
IC50
SIa
O
Compd#
1. NH4OAc
DMSO,
11
11
(
lM)
(
lM)
(STAT1/STAT3)
RNH2, K2CO3
N
N
MeCN, μW
11a
11b
11c
11d
OEt
Me
Me
H
H
H
H
OEt
H
H
Me
H
15.7 5.4
7.9 2.8
0.8 0.6
20.7 3.0
>50
>50
5.9 0.9
>50
>3
>6
>7
>2
2. POCl3
dimethylaniline
NH
N
Cl
N
NHR
16
17a-i
O
CCl3
15
a
Selectivity index ratio.
Scheme 2. Preparation of 2-aminoquinazolines (17a–i).

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M. G. LaPorte et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5081–5085
Table 2
pounds in this series and their activities are shown in Table 3. Sev-
Inhibitory potencies of 2-aminoquinazolines (17a–i)
eral substitutions (e.g., entries 19a, b, g, h) slightly improved
potency and selectivity compared to the original hit (11a), whereas
other substitution patterns (e.g., 19e, o, p, r) completely abolished
activity. With the exception of 19p, all 5,6-dimethylpyrimidinones
(19b, 19f, 19l, 19n) demonstrated inhibition of pSTAT3 at less than
10 lM concentration and maintained at least a 3-fold selectivity
against pSTAT1. All new compounds were fully characterized,
and all tested compounds had LC/MS/ELSD purities exceeding 91%.
Compd#
R
STAT311
STAT111
IC50
(l
M)
IC50
(
lM)
17a
17b
>30
>30
∗
∗
>30
>30
>30
>30
>30
>30
H
N
17c
17d
Table 4
∗
Growth inhibition of selected analogs on HNSCC cell lines 686LN, CAL33, FADU and
OSC19
O
O
N
∗
Compd#
686LN IC50
M)
CAL33 IC50
M)
FADU IC50
M)
OSC19 IC50
(lM)
O
(
l
(
l
(
l
∗
17e
17f
>30
>30
>30
>30
11a
11b
11c
19a
19g
19h
6
37.5 11.1
49.3a
2.4 0.6
18.0 10.4
37.8a
29.4 5.9
19.7 0.5
1.2 0.3
12.9 0.9
11.1a
18.8 5.3
11.0 0.1
1.9 0.1
30.9 14.9
17.9a
17.0 4.6
12.8 0.9
3.2 0.4
11.2a
∗
O
19.0a
43.7 0.7
> 5
>50
1.3 0.4
27.4 13.3
2.4 0.6
>50
7.7 4.7
17g
>30
>30
∗
a
Results from a single experiment.
17h
17i
>30
>30
>30
>30
∗
∗
The ability of the most potent analogs to inhibit the prolifera-
N
tion of a panel of HNSCC cell lines is shown in Table 4. While a
strict correlation between STAT3 inhibition and cell growth inhibi-
tion potency was not evident, compound 11c, which exhibited the
most potent activity in our STAT3 assays, also displayed the most
potent anti-proliferative effects.
In summary, 6-ethoxy-4-methylquinazoline-2-amino-dihydro-
trimethylpyrimidine 11a, a structurally novel, selective inhibitor
of STAT3-mediated signaling, was further optimized through three
rounds of SAR studies. Modest structural changes established the
O
O
O
N
R4
OEt
(18)
R1
R2
R5
R4
R1
R2
N
R5
N
NH
NH2
N
N
N
H
N
N
NaHCO3, DMSO
H
R3
H
R3
19a-t
14
preferred quinazoline substitutions. Most notably,
a 20-fold
improvement in STAT3 inhibition, while maintaining selectivity
over STAT1, was obtained with the 6,8-dimethyl substituted analog
11c. More substantial changes to the dihydropyrimidine moiety led
to complete loss of activity; however, substitution of the quinazo-
line with dihydropyrimidinones also retained potency and selectiv-
ity. The most promising lead structures, 11b, 11c, and 19a exhibited
low-micromolar potency against STAT3, at least a 2-fold selectivity
Scheme 3. Preparation of 2-aminoquinazoline dihydropyrimidones (19a–t).
To investigate substituent effects on the pyrimidine, we also
synthesized pyrimidinones of general structure 19. The reaction
of guanidines 14 with substituted acetoacetic esters (Scheme 3)20,21
afforded the dihydropyrimidones 19a–t. Representative com-
Table 3
Inhibitory potencies of 2-amino-quinazolinyl-dihydropyridimidones 19a–t
R1
R2
R3
R4
R5
STAT3 IC50
(lM)
STAT1 IC5
(lM)
0
SIb (STAT1/STAT3)
11
11
Compd#
19a
19b
19c
19d
19e
19f
19g
19h
19i
19j
19k
19l
19m
19n
19o
19p
19q
19r
19t
Me
Me
Me
Me
OEt
OEt
OEt
OEt
OMe
OMe
H
H
Me
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Ph
Me
Me
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
H
5.0 1.8
6.4 1.6
14.3 0.9
11.2 2.1
>50
11.7 5.7
3.4 0.6
2.7 2.5
34.9 2.7
34.7a
19.1 1.3
10.5 0.2
24.7 0.5
10.4 1.3
>50
12.1 0.9
>50
>50
>50
>50
>50
>50
>50
>50
>2
>7
>3
>4
—
>4
>14
>18
>1
>1
>1
>3
>2
>4
—
Me
Allyl
H
H
Me
H
Bn
H
Bn
H
Me
H
Me
H
50
39.7 1.6
35.2 1.1
>50
>50
>50
>50
>50
>50
>50
Me
–OCH2O–
–OCH2O–
–OCH2O–
–OCH2O–
H
Me
H
Bn
H
>50
13.0 1.4
>50
—
>3
—
H
H
Me
Me
OMe
33.9 1.8
>1
a
Results from a single experiment.
Selectivity index ratio.
b

M. G. LaPorte et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5081–5085
5085
7. For recent reviews, see: (a) Siveen, K. S.; Sikka, S.; Surana, R.; Dai, X.; Zhang, J.;
Kumar, A. P.; Tan, B. K. H.; Sethi, G.; Bishayee, A. Biochim. Biophys. Acta 1845,
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41, 1181.
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over STAT1, and anti-proliferative activity in the 1–50 lM range.
Additional SAR iterations will be needed to increase the activity
of these compounds to the sub-micromolar level; however, 11b,
11c, and 19a represent attractive tool compounds to investigate a
kinase- and STAT1-independent downregulation of the STAT3 path-
way. Studies on the mechanism of action of this class of compounds
as well as the biological data and medicinal chemistry of other
STAT3 HCS hits will be reported in due course.
Acknowledgments
9. (a) Pedranzini, L.; Dechow, T.; Berishaj, M.; Comenzo, R.; Zhou, P.; Azare, J.;
Bornmann, W.; Bromberg, J. Cancer Res. 2006, 66, 9714; (b) Swiatek-Machado,
K.; Mieczkowski, J.; Ellert-Miklaszewska, A.; Swierk, P.; Fokt, I.; Szymanski, S.;
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11. Johnston, P. A.; Sen, M.; Hua, Y.; Camarco, D.; Shun, T. Y.; Lazo, J. S.; Grandis, J.
R. Assay Drug Dev. Technol. 2014, 12, 55.
12. (a) Holloway, G. A.; Charman, W. N.; Fairlamb, A. J.; Brun, R.; Kaiser, M.;
Kostewicz, E.; Novellow, P. M.; Parisot, J. P.; Richardson, J.; Street, I. P.; Watson,
K. G.; Baell, J. B. Antimicrob. Agents Chemother. 2009, 53, 2824; (b) Ciustea, M.;
Silverman, J. E. Y.; Shudofsky, A. M. D.; Ricciardi, R. P. J. Med. Chem. 2008, 51,
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13. Pubchem (http://pubchem.ncbi.nlm.nih.gov) activity for 11a indicates 21
active assays (6-confirmatory) in 666 bioassays tested: Down Regulation
Insulin Promoter (AID 1628); Cytotoxicity MIN6 cells (AID 2122); Cruzain
Inhibition (AIDs 1476, 1478); FEN1 Endonuclease inhibition (AIDs 588795,
720498).
The authors would like to thank Dr. Steven J. Geib for the X-ray
analysis of 11b, Mr. Pete Chambers for LCMS/ELS analyses, Dr. Tong
Ying Shun for data processing, and Ms. Mary Liang and Ms. Shelby
Anderson for sample handling, procurement, registration, and dis-
tribution. We also thank Drs. Mark Schurdak and D. Lansing Taylor
(University of Pittsburgh Specialized Applications Center), Drs. Bill
Moore (Leidos), Beverly Teicher (NCI) and Shizuko Sei (Leidos) for
their helpful discussions. This project was funded in whole or in
part with federal funds from the National Cancer Institute, National
Institutes of Health, under Chemical Biology Consortium Contract
No. HHSN261200800001E. The content of this publication does
not necessarily reflect the views or policies of the Department of
Health and Human Services, nor does mention of trade names,
commercial products, or organizations imply endorsement by the
U.S. Government.
14. (a) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery
Rev. 1997, 23, 3; (b) Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward,
K. W.; Kopple, K. D. J. Med. Chem. 2002, 45, 2615.
Supplementary data
15. Physicochemical Properties were Calculated Using: Maestro 8.5.207-QikProp 2.1,
Schrödinger, LLC: New York, NY, USA.
16. Shikhaliev, K. S.; Falaleev, A. V.; Ermolova, G. I.; Solov’ev, A. S. Chem. Heterocycl.
Compd. 2002, 38, 210.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.09.001.
17. Fotie, J.; Kaiser, M.; Delfin, D. A.; Manley, J.; Reid, C. S.; Paris, J.-M.; Wenzler, T.;
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