Targeting epidermal growth factor receptor with ferrocene-based kinase inhibitors

Article abstract of DOI:10.1021/om300974d

A series of ferrocene analogues based on a 6,7-dimethoxy-N- phenylquinazolin-4-amine template has been synthesized, and two compounds were characterized in the solid state by X-ray crystallography. The compounds have been tested for in vitro anticancer activity, against epidermal growth receptor (EGFR), and submicromolar IC₅₀ values have been determined.

Full text of DOI:10.1021/om300974d

Article
pubs.acs.org/Organometallics
Targeting Epidermal Growth Factor Receptor with Ferrocene-Based
Kinase Inhibitors
Jahangir Amin,† Irina Chuckowree,† Graham J. Tizzard,‡ Simon J. Coles,‡ Minghua Wang,§
John P. Bingham,∥ John A. Hartley,∥ and John Spencer*,†
†Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex BN1 9QJ, U.K.
‡UK National Crystallography Service, School of Chemistry, University of Southampton, Highfield, Southampton SO171BJ, U.K.
§Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada
∥CRUK Drug−DNA Interactions Research Group, UCL Cancer Institute, Paul O’Gorman Building, 72 Huntley Street, London
WC1E 6DD, U.K.
S
* Supporting Information
ABSTRACT: A series of ferrocene analogues based on a 6,7-
dimethoxy-N-phenylquinazolin-4-amine template has been
synthesized, and two compounds were characterized in the
solid state by X-ray crystallography. The compounds have
been tested for in vitro anticancer activity, against epidermal
growth receptor (EGFR), and submicromolar IC50 values have
been determined.
with its aryl congeners).2 Others have explored ferrocene
INTRODUCTION
■
analogues of tamoxifen3a (where the ferrocene can significantly
Protein kinase inhibitors (PKIs) are used clinically for the
enhance the activity of the drug) as well as chloroquine
treatment of a number of cancers.1 Compounds 1 and 2 act as
derivatives, where drug resistance is significantly diminished.3b
epidermal growth factor receptor (EGFR) inhibitors, combin-
We now report a synthesis of simplified ferrocene analogues
ing a quinazoline unit, mimicking the adenosine in ATP, a
of 1 and 2. The reasons for this are numerous:
solvent-exposed region composed of a solubilizing ether or
(i) The introduction of a ferrocene unit can have beneficial
or detrimental consequences in terms of biological
activity in comparison with its organic congener, as
noted above.
(ii) An organometallic unit, by virtue of its heavy-metal atom,
can be used as a biological probe for cocrystal studies for
protein structure determination.4
(iii) Compounds 1 and 2 contain elaborated side chains and
require a multistep synthesis to introduce these
solubility-enhancing groups. As a direct comparative
study, simpler methoxy-substituted quinazolines were
readily accessible (6d,e; see below).5 Moreover, the latter
are easier to synthesize yet still display excellent
biological activity.
amine side chain, and a substituted anilide function (in red,
Figure 1), serving as a hydrophobic pocket binding group,
which imparts selectivity to the PKI.1
We have successfully employed ferrocenes as aryl bioisosteres
(“bioequivalents”) in a number of applications ranging from
histone deacetylase inhibitors (HDACis, where the ferrocene
leads to changes in enzyme isoform selectivity in comparison to
its phenyl congener) to kinase inhibitors (where a loss of kinase
activity is observed, attributed to steric effects, in comparison
We have now applied this principle to the design of
compounds 6, whereby the aniline moiety has been replaced by
an aminoferrocene bioisostere. In standing with our aims of
synthesizing molecules rapidly with minimum workup bottle-
necks, following standard conversion of 6,7-dimethoxyquinazo-
lin-4(3H)-one 3 to the chloroquinazoline 4, a microwave-
mediated6 nucleophilic displacement of 4 with aminoferrocene
5a or anilinoferrocenes 5b,c afforded the corresponding
products 6a−c (Scheme 1). The last species were characterized
Figure 1. Clinically approved PKIs (general pharmacophore shown in
box).
Received: October 18, 2012
Published: January 10, 2013
© 2013 American Chemical Society
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Scheme 1. General Method of Synthesis of 6
by NMR spectroscopy and elemental analysis. The two non-
ferrocene products 6d,e were also synthesized as positive
controls for comparison of EGFR inhibition.5
molecules are overlaid. The crystal structure consists of stacked
1-D “cross-hatch tapes” comprising H-bonded quinazoline
molecules (N101···N203 = 2.989(7) Å; ∠D−H···A = 158.4°;
N201···N103 = 2.942(7) Å; ∠D−H···A = 156.0°) propagating
along the crystallographic b axis. The solvent dichloromethane
molecules reside in the voids created as these stacks pack along
the c axis. The structure of 6c (determined using a synchrotron
source due to its poor diffraction using our standard
equipment) was found to be monoclinic, space group P21/c,
and contained a water of crystallization. The crystal structure
consists of 1-D “corrugated tapes” of water-mediated H-bonded
quinazoline molecules (N1···O1W = 2.967(7) Å, ∠D−H···A =
165.1°; O1W···N3 = 2.752(2) Å, ∠D−H···A = 174(3)°)
propagating along the crystallographic c axis. These tapes stack
along the b axis and are interleaved with an inverted stack such
that weak H bonds exist between the water molecules of one
layer and the amine N atoms of the adjacent inverted layer
(O1W···N1 = 3.232(2) Å, ∠D−H···A = 160(3)°). Tables S1
and S2 (Supporting Information) summarize important bond
lengths and angles as well as structural parameters for both
compounds.
The two ferrocene analogues 6a,c were studied in the solid
state by X-ray crystallography (Figures 2 and 3, respectively).
6a was found to crystallize in the monoclinic crystal system,
space group P21/n, with two quinazoline molecules and one
molecule of dichloromethane in the asymmetric unit. The two
quinazoline molecules display a negligible difference in
conformation, as shown by the results in Table S1 (Supporting
Information) and the RMS deviation of 0.1720 when the
Next, the complexes were evaluated for biological activity in
in vitro assays against EGFR, since this is the target of the
inhibitors 1, 2, and 6d,e (Table 1).5 Complex 6b exhibited an
impressive submicromolar activity against EGFR, whereas 6a,c
gave essentially micromolar inhibition. However, EGFR
inhibitory activity was substantially weaker than the controls
6d,e, which displayed very low nM affinities. Indeed, compound
6d (termed PD 153035) is reported to have an IC50 value of
0.025 nM.5b
Next, the compounds were tested for in vitro activity in K562
cells. Neither the organometallic complexes 6a,b nor the
organic entities 6d,e showed any appreciable activity, with IC50
values >20 μM. It has been reported that EGFR inhibition is
dependent on the number of EGF receptors expressed as well
as the type of cell line used, many of which show IC50 values of
the same magnitude.9a Moreover, EGFR is not expressed in
K562 cells.9b Only complex 6c showed cellular activity with
Figure 2. ADP plot for complex 6a with ADP ellipsoids drawn at the
50% probability level.
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Figure 3. ADP plot for 6c with ADP ellipsoids drawn at the 50% probability level.
Table 1. Biological Evaluation of 6
region. Of the organometallic complexes, only 6b can be
docked with its core in a close position to that of 6e (Figure
4b). It can thus form the H bond and places the (aniline-
substituted) phenyl group in the correct orientation, hence
accounting for 6b having the best activity among the ferrocenes
studied. However, 6a,c can only be docked with a shifted core,
leading to binding penalties (Figure 4c,d). This is probably
because these particular ferrocene substitution patterns hinder
binding to the pocket.
a
b
compd
IC50 (nM) vs EGFR
in vitro IC50 (μM)
6a
6b
6c
6d
6e
1800
133
905
<5
>20
>20
16
>20
>20
4.6
a
b
In vitro assay (Reaction Biology Corp. US),7 average of two runs. In
K562 cells,8 average of two runs.
CONCLUSION
■
IC50 = 16 μM, which is highly likely to be due to off-target
effects.7b
Three ferrocene analogues containing a quinazoline skeleton
have been synthesized. Two have been further characterized in
the solid state. Biological evaluation of the complexes showed
them to be effective EGFR inhibitors with micromolar or
submicromolar potencies, which are significantly weaker than
those of their related organic prototypes. Docking studies have
accounted for the good in vitro EGFR inhibition observed for
the ferrocene 6b. Bioorganometallic complexes remain
important as tool compounds in the study of kinases, and we
are actively pursuing this area of research.10
In order to rationalize the biological activity of these
compounds, they were studied by molecular modeling.
Compound 6e can be docked in a conformation (Figure 4a)
with its core close to that of the reported cocrystallized ligand
(erlontinib (pdb code: 4hjo)). A nitrogen atom in the
quinazoline forms an expected hydrogen bond with a backbone
NH of a methionine in the kinase receptor. The two rings
(quinazoline and phenyl) both fit well in the hydrophobic
Figure 4. Docking pose of compounds in the ATP pocket of EGFR (pdb code: 4hjo): (a) 6e; (b) 6b; (c) 6a; (d) 6c. Color scheme for the atom
types: carbon, yellow; nitrogen, blue; oxygen, red; iron, cyan. Methods have been previously reported.2b
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Compound 6c. Crystallization using 1/19 ethyl acetate/hexane
afforded 6c (0.12 g, 87%) as a bright orange solid. Mp: 200−202 °C.
EXPERIMENTAL PROCEDURES
■
Experimental and spectroscopic methods2 as well as biological
experiments (K562, MTT assay)11 have been outlined in previous
papers.
1
IR (thin film): νmax 1030 cm−1 (CN stretch). H NMR (δ, 270.0
MHz, CDCl3): 4.03 (3H, s, OCH3), 4.04 (3H, s, OCH3), 4.06 (5H, s,
C5H5), 4.31 (2H, t, J = 2.7 Hz, Fc), 4.63 (2H, t, J = 2.7 Hz, Fc), 7.06
(1H, s, ArCH), 7.27 (2H, m, ArCH), 7.50 (2H, d, J = 5.4 Hz, ArCH),
7.62 (2H, d, J = 5.4 Hz, ArCH), 8.68 (1H, s, NH). 13C NMR (δ, 100.5
MHz, CDCl3); 56.3, 56.4, 66.3 (2C), 68.9 (2C), 69.6 (5C), 85.1 (ipso-
Fc), 99.5, 107.7, 109.0, 121.9 (2C), 126.6 (2C), 135.4, 136.4, 147.2,
149.5, 153.5, 154.7, 156.3. HRMS (m/z, HNESP): [M + H]+ for
C26H24FeN3O2 calcd 466.1212, observed 466.1255; Anal. Calcd for
C26H23N3O2Fe·0.2CH2Cl2; C, 65.2; H, 4.9; N, 8.7. Found, C, 65.2; H,
5.2; N, 8.6.
Reactions were carried out under argon using reagent grade solvents
and reagents. Compounds 6d (PD 153035) and 6e were made by
literature routes.5
Synthesis of 4-Chloro-6,7-dimethoxyquinazoline 4. In an
oven-dried three-necked round-bottom flask (250 mL) equipped with
a stirrer and reflux condenser 6,7-dimethoxy-3H-quinazoline-4-one (3;
1.00 g, 4.85 mmol) was added followed by phosphoryl chloride (2.70
mL, 29.1 mmol) and N,N′-diethylaniline (0.51 mL, 3.20 mmol). With
vigorous stirring the reaction mixture was heated to reflux for 5 h.
After this time had elapsed, the hot reaction mixture was carefully
poured into a slurry of ice/water (100 mL), ensuring no precipitate
formed at this stage. The cooled crude mixture was extracted using
methylene chloride (30 mL) and washed with brine (30 mL). The
organic layer was dried using magnesium sulfate and then filtered
through fluted filter paper. The solvent was removed under reduced
pressure. The crude mixture was purified using silica gel column
chromatography with 1/99 methanol/methylene chloride as eluent to
give the white solid 4 (0.31 g, 28%). 1H NMR (δ, 270.0 MHz,
CDCl3): 4.08 (6H, s, 2 × CH3), 7.35 (1H, s, ArCH), 7.40 (1H, s,
ArCH), 8.86 (1H, s, ArCH). 13C NMR (δ, 67.0 MHz, CDCl3): 56.5,
56.6, 102.7, 107.0, 119.6, 149.2, 151.5, 152.6, 156.8, 159.1.
General Procedure for the Synthesis of 6. In an oven-dried
microwave tube (35 mL) equipped with a stirrer, 4 (0.07 g, 0.31
mmol) was dissolved in anhydrous 1,4-dioxane (1 mL). A portion of
HCl (in 1,4-dioxane) (4 M, 0.25 mL) was then added dropwise at
room temperature, and the mixture was stirred for 15 min before the
addition of ferrocenylamine (5a), (2-aminophenyl)ferrocene (5b), or
(4-aminophenyl)ferrocene (5c); 3-bromoaniline (5d) and 4-bromoa-
niline (5e) were heated in tert-butyl alcohol (0.31 mmol scale). The
reaction mixture was heated (ramped) to 150 °C at 150 W and held at
this temperature for 30 min with microwave moderation of power.
The reaction mixture was then quenched with saturated sodium
hydrogen carbonate (10 mL). The crude reaction mixture was then
extracted using methylene chloride (10 mL), and the aqueous layer
was sonicated before being extracted with methylene chloride (10
mL). The organic layer wa washed with saturated brine (10 mL)
before being dried using magnesium sulfate and filtered. The filtrate
was removed under reduced pressure. The following purification
protocols were employed with final yields for the compounds
indicated.
X-ray Crystallography. Single-crystal X-ray diffraction analyses
were performed using either a Bruker APEXII CCD diffractometer
mounted at the window of a Bruker FR591 rotating anode (λMo Kα
=
0.710 73 Å) and equipped with an Oxford Cryosystems cryostream
device (6a) or at Station I19 of the Diamond Light Source (λ = 0.6889
Å), using a Crystal Logics κ-geometry diffractometer and a Rigaku
Saturn 724+ CCD detector with a Cryostream cooler (at 120 K) and
CrystalClear-SM Expert 2.0 r7 used to record images12 (6c). Data
were processed using either the Collect package13 (6a) or
CrystalClear-SM Expert 2.0 r7 (6c), and unit cell parameters were
refined against all data. An empirical absorption correction was carried
out using SADABS14 (6a) or CrystalClear-SM Expert 2.0 r7 (6c). The
structures were solved by direct methods using SHELXS-97 and
refined on Fo2 by full-matrix least-squares refinements using SHELXL-
97.15 All non-hydrogen atoms were refined with anisotropic
displacement parameters. Hydrogen atoms were added at calculated
positions, except those of the water molecule in 6c, which were located
and restrained to a reasonable geometry. All hydrogen atoms were
refined using a riding model with isotropic displacement parameters
based on the equivalent isotropic displacement parameter (Ueq) of the
parent atom. Figures were produced using OLEX2.16 The CIF files for
the crystal structures of 6a,c have been deposited with the CCDC and
have been given the deposition numbers 906133 and 906134,
respectively.
ASSOCIATED CONTENT
* Supporting Information
■
S
Tables and CIF files giving crystallographic data for 6a,c. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Compound 6a. Silica gel column chromatography (1:99 MeOH/
AUTHOR INFORMATION
Corresponding Author
*Fax: +44 (0)1273 876687. E-mail: j.spencer@sussex.ac.uk.
Notes
■
DCM) afforded 6a (0.06 g, 50%) as an orange solid. Mp: 240−242 °C
1
dec. IR (Nujol mull): νmax 1025 cm−1 (CN stretch). H NMR (δ,
270.0 MHz, CDCl3); 3.97 (3H, s, OCH3), 4.01 (3H, s, OCH3), 4.14
(2H, s, Fc), 4.20 (5H, s, C5H5), 4.78 (2H, s, Fc), 6.57 (1H, brs, NH),
6.91 (1H, s, ArCH), 7.24 (1H, s, ArCH), 8.67 (1H, s, ArCH). 13C
NMR (δ, 67.0 MHz, CDCl3): 56.2 (2C), 63.4 (2C), 65.3 (2C), 69.5
(5C), ipso-Fc not observed, 99.7, 107.8, 108.8, 147.2, 149.0, 153.8,
154.4, 157.0. HRMS (m/z, HNESP): [M + H]+ for C20H20FeN3O2
calcd 390.0891, observed 390.0890. Anal. Calcd for C20H19FeN3O2: C,
61.7; H, 4.9; N, 10.8. Found, C, 61.7; H, 5.0; N, 10.6.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Royal Society of Chemistry is thanked for a Research Fund
(J.S.); the EPSRC Mass Spectrometry Service (University of
Swansea) is thanked for HRMS measurements. J.A.H. acknowl-
edges support from the CRUK (C2259/A9994). S.J.C. and
G.J.T. acknowledge funding from the EPSRC for X-ray facilities
at Southampton.17 The reviewers are thanked for constructive
comments.
Compound 6b. Crystallization using 1/19 ethyl acetate/hexane
afforded 6b (0.06 g, 44%) as bright orange needles. Mp: 198−200 °C.
1
IR (thin film): νmax 1023 cm−1 (CN stretch).; H NMR (δ, 270.0
MHz, DMSO-d6); 3.90 (3H, s, OCH3), 4.01 (3H, s, OCH3), 4.23 (5H,
s, C5H5), 4.39 (2H, t, J = 2.7 Hz, Fc), 4.53 (2H, t, J = 2.7 Hz, Fc), 6.81
(1H, s, ArCH), 7.13 (1H, dt, J = 8.1, 1.2 Hz, ArCH), 7.23 (1H, s,
ArCH), 7.36 (1H, dt, J = 8.1, 1.8 Hz, ArCH), 7.77−7.80 (2H, m, 2 ×
ArCH), 8.50 (1H, dd, J = 10.8, 1.2 Hz, ArCH), 8.68 (1H, s, NH). 13C
NMR (δ, 67.0 MHz, DMSO-d6): 56.1, 56.2, 68.7 (2C), 69.5 (2C), 69.7
(5C), 84.9 (ipso-Fc), 99.4, 108.0, 109.4, 121.8, 123.3, 127.4, 128.4,
130.9, 136.7, 147.4, 149.3, 153.7, 154.5, 156.0. HRMS (m/z, HNESP):
[M + H]+ for C26H24FeN3O2 calcd 466.1212, observed 466.1205.
Anal. Calcd. for C26H23N3O2Fe·0.2CH2Cl2; C, 64.8; H, 4.9; N, 8.6.
Found, C, 64.8; H, 4.9, N; 8.5.
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