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Published in final edited form as:
Bioorg Med Chem Lett. 2014 November 1; 24(21): 5081–5085. doi:10.1016/j.bmcl.2014.09.001.
2-Guanidinoquinazolines as new inhibitors of the STAT3
pathway
Matthew G. LaPortea,*, Dimas José da Paz Limaa, Feng Zhanga, Malabika Senb, Jennifer R.
Grandisb,c,d, Daniel Camarcoe, Yun Huae, Paul A. Johnstonc,e, John S. Lazof, Lynn O.
Resnicka, Peter Wipfa,c,e, and Donna M. Huryna,e,*
aUniversity
of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA
15260, USA
bDepartment
cUniversity
of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15260, USA
of Pittsburgh Cancer Institute, Pittsburgh, PA 15260, USA
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dDepartment
of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA
15260, USA
eDepartment
of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA
fDepartment
of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
Abstract
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.
Keywords
STAT3 pathway; Guanidinoquinazolines; Skraup synthesis; Structure–activity relationships;
Cancer cell line screening
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Despite recent advances in early detection methods and treatment 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
challenging 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 transcription factor that
© 2014 Elsevier Ltd. All rights reserved.
*
Corresponding authors. Tel.: +1 412 624 8004 (M.G.L.), +1 412 737 3225 (D.M.H.). mgl12@pitt.edu (M.G. LaPorte),
huryn@pitt.edu (D.M. Huryn)..
Supplementary data
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.
LaPorte et al.
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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
contrast, the related transcription factor, STAT1, activates genes that promote tumor
suppression. Therefore, molecules that selectively inhibit STAT3-mediated pathways with
no effect on STAT1 pathways, 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 include focusing on inhibiting
kinases operative in the STAT3 pathway, such as Janus activated kinases (JAKs), and
identified quinolones, pyridones, and the pyridine carboxamide, sorafenib (5, 6 and 7,
respectively, 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 antiproliferative activities in cellular assays.5,10
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By using a high content phenotypic screen (HCS) to identify selective inhibitors of IL-6
induced activation of the STAT3 pathway,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 μM), but had no effect on IFNγinduced activation of the STAT1 pathway at 50 μM (Fig. 3). Western blot analysis indicated
a 69% decrease in phospho-STAT3 (pSTAT3) levels upon treatment of 11a at 39.6 μM
concentration (Fig. 4, A and B). Unlike the JAK inhibitor 6 that displayed nanomolar
potencies against both STAT3 and 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 structure for further medicinal chemistry
optimization, and herein we report the results of these efforts.
Our initial strategy was to incorporate modest structural modifications onto the 2guanidinoquinazoline core in order to establish preliminary structure-activity relationships.
Using established synthetic 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 cyano-guanidine
under aqueous acidic conditions.18 The final products, dihydropyrimidinylaminoquinazolines 11a-d, were formed via thermal cyclodehydrations using mesityl oxide
in DMSO. The structure of 11b was confirmed by X-ray analysis (Scheme 1).16 In this
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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 failed to
achieve ≥50% inhibition of IFNγ-induced STAT1 activation at 50 μM, 11c exhibited an IC50
of 5.9 μM for STAT1 but still maintained a good selectivity index (Table 1).
Efforts to examine a simplified pharmacophore focused on the preparation of 2aminoquinazolines of general structure 17 (Scheme 2). The pivotal 2-chloro intermediate 16
was prepared in three steps19 and subjected to amination under microwave conditions 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
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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 compounds in this
series and their activities are shown in Table 3. Several 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) 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%.
The ability of the most potent analogs to inhibit the proliferation of a panel of HNSCC cell
lines is shown in Table 4. While a strict correlation between STAT3 inhibition and cell
growth inhibition potency was not evident, compound 11c, which exhibited the most potent
activity in our STAT3 assays, also displayed the most potent anti-proliferative effects.
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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 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 quinazoline with dihydropyrimidinones also retained
potency and selectivity. The most promising lead structures, 11b, 11c, and 19a exhibited
low-micromolar potency against STAT3, at least a 2-fold selectivity over STAT1, and antiproliferative activity in the 1–50 μM 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 STAT1independent downregulation of the STAT3 pathway. 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.
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Supplementary Material
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Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
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 distribution. 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.
References and notes
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Figure 1.
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SH2 targeted phosphopeptide mimetics and JAK inhibitors of the STAT3 pathway.
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Figure 2.
Natural product STAT3 inhibitors.
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Figure 3.
Guanidinoquinazoline hit 11a.
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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).
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Scheme 1.
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Preparation of 2-guanidinoquinazolines 11a–d and X-ray structure of 11b (CCDC 1020633).
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Scheme 2.
Preparation of 2-aminoquinazolines (17a–j).
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Scheme 3.
Preparation of 2-aminoquinozoline dihydropyrimidones (19a–t).
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Table 1
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STAT3 and STAT1 Activity of 2-guanidinoquinazolines 11a–d
Compd#
R1
R2
R3
STAT3
IC5011 (µM)
STAT1
IC5011 (µM)
a
SI (STAT1/STAT3)
11a
OEt
H
H
15.7 ± 5.4
>50
>3
11b
Me
H
H
7.9 ± 2.8
>50
>6
11c
Me
H
Me
0.8 ± 0.6
5.9 ± 0.9
>7
11d
H
OEt
H
20.7 ± 3.0
>50
>2
a
Selectivity index ratio.
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Table 2
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Inhibitory potencies of 2-aminoquinazolines (17a–j)
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STAT311
STAT111
IC50 (µM)
IC50 (µM)
17a
>30
>30
17b
>30
>30
17c
>30
>30
17d
>30
>30
17e
>30
>30
17f
>30
>30
17g
>30
>30
17h
>30
>30
Compd#
R
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Compd#
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17i
R
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STAT311
STAT111
IC50 (µM)
IC50 (µM)
>30
>30
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Table 3
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Inhibitory potencies of 2-amino-quinazolinyl-dihydropyridimidones 19a–t
Compd#
R1
R2
R3
R4
R5
STAT3 IC5011 (µM)
STAT1 IC5110 (µM)
b
SI (STAT1/STAT3)
19a
Me
H
Me
Me
H
5.0 ± 1.8
12.1 ± 0.9
>2
19b
Me
H
Me
Me
Me
6.4 ± 1.6
>50
>7
19c
Me
H
Me
Me
Allyl
14.3 ± 0.9
>50
>3
19d
Me
H
Me
Ph
H
11.2 ± 2.1
>50
>4
19e
OEt
H
H
Me
H
>50
>50
–
19f
OEt
H
H
Me
Me
11.7 ± 5.7
>50
>4
19g
OEt
H
H
Ph
H
3.4 ± 0.6
>50
>14
19h
OEt
H
H
Me
Bn
2.7 ± 2.5
>50
>18
19i
OMe
H
H
Me
H
34.9 ± 2.7
>50
>1
a
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19j
OMe
H
H
Me
Bn
34.7
50
>1
19k
H
Me
H
Me
H
19.1 ± 1.3
39.7 ± 1.6
>1
19l
H
Me
H
Me
Me
10.5 ± 0.2
35.2 ± 1.1
>3
19m
Me
Me
H
Me
H
24.7 ± 0.5
>50
>2
19n
Me
Me
H
Me
Me
10.4 ± 1.3
>50
>4
19o
−OCH2O−
H
Me
H
>50
>50
–
19p
−OCH2O−
H
Me
Me
>50
>50
–
19q
−OCH2O−
H
Ph
H
13.0 ± 1.4
>50
>3
19r
−OCH2O−
H
Me
Bn
>50
>50
–
19t
H
H
Me
H
33.9 ± 1.8
>50
>1
OMe
a
Results from a single experiment.
b
Selectivity index ratio.
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Table 4
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Growth inhibition of selected analogs on HNSCC cell lines 686LN, CAL33, FADU and OSC19
Compd#
686LN IC50
(µM)
CAL33 IC50
(µM)
FADU IC50
(µM)
OSC19 IC50
(µM)
11a
37.5 ± 11.1
29.4 ± 5.9
18.8 ± 5.3
17.0 ± 4.6
11b
49.3
a
19.7 ± 0.5
11.0 ± 0.1
12.8 ± 0.9
11c
2.4 ± 0.6
1.2 ± 0.3
1.9 ± 0.1
3.2 ± 0.4
19a
18.0 ± 10.4
12.9 ± 0.9
30.9 ± 14.9
11.2
19g
37.8
11.1
17.9
19.0
19h
43.7 ± 0.7
>50
27.4 ± 13.3
>50
6
>5
1.3 ± 0.4
2.4 ± 0.6
7.7 ± 4.7
a
a
a
a
a
a
Results from a single experiment.
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