Quinazoline and tetrahydropyridothieno[2,3-d]pyrimidine derivatives as irreversible EGFR tyrosine kinase inhibitors: Influence of the position 4 substituent

Article abstract of DOI:10.1039/c3md00118k

Herein, we describe new quinazoline and tetrahydropyridothieno[2,3-d] pyrimidine derivatives with an acrylamido group at positions 6 and 7 respectively, and with variable anilino, sulfonamido and cycloalkylamino substituents at position 4. The lipophilic and steric properties of the position 4 substituent seem crucial for activity. Several compounds were more active than gefitinib in inhibiting the wild type EGFR enzyme, the autophosphorylation of the mutant EGFR expressing cell line (H1975), and the growth of cell lines with wild type and mutant EGFR tyrosine kinase. Moreover, a novel synthesis of the quinazoline nucleus from a formimidate derivative is described.

Full text of DOI:10.1039/c3md00118k

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Quinazoline and tetrahydropyridothieno[2,3-d]-
pyrimidine derivatives as irreversible EGFR tyrosine
kinase inhibitors: influence of the position 4
substituent†
Cite this: Med. Chem. Commun., 2013,
4, 1202
Mostafa M. Hamed,abc Dalal A. Abou El Ella,de Adam B. Keeton,f Gary A. Piazza,f
a
Matthias Engel,bc Rolf W. Hartmannbc and Ashraf H. Abadi
*
Herein, we describe new quinazoline and tetrahydropyridothieno[2,3-d]pyrimidine derivatives with an
acrylamido group at positions 6 and 7 respectively, and with variable anilino, sulfonamido and
cycloalkylamino substituents at position 4. The lipophilic and steric properties of the position 4
substituent seem crucial for activity. Several compounds were more active than gefitinib in inhibiting
the wild type EGFR enzyme, the autophosphorylation of the mutant EGFR expressing cell line (H1975),
and the growth of cell lines with wild type and mutant EGFR tyrosine kinase. Moreover, a novel
synthesis of the quinazoline nucleus from a formimidate derivative is described.
Received 19th April 2013
Accepted 2nd July 2013
DOI: 10.1039/c3md00118k
www.rsc.org/medchemcomm
which are designed mainly to target the ATP binding pocket of
the kinase domain.6
Introduction
Members of the epidermal growth factor receptor (EGFR) family
were found to play a vital role in lung tumorigenesis being
overexpressed in 40–80% of non-small cell lung carcinoma
(NSCLC) tumors.1–4 A series of downstream signaling events
results from EGFR activation and can mediate cancer cell
growth, proliferation, motility, adhesion, invasion, apoptosis
inhibition and metastasis as well as resistance to chemo-
therapy. Accordingly, EGFR inhibitors would be valuable in
cancer treatment.1,2
Getinib, erlotinib, and lapatinib (Fig. 1) are examples of
small molecules, acting as kinase inhibitors, that have been
approved in cancer treatment.5 They are used clinically in the
treatment of EGFR/HER2-dependent tumors which occur in
non-small cell lung cancer (NSCLC) or breast cancer.6 They
belong to a class of compounds known as 4-anilinoquinazolines
The quinazoline core is reported to be among the best
scaffolds for the development of EGFR inhibitors.7 This was
justied by a hypothesis explaining the importance of quina-
zoline N3 in the formation of a water-mediated hydrogen bond
to the side chain of the gatekeeper Thr790 of the EGFR.8,9 This
aided successfully in designing reversible and irreversible EGFR
and HER2 kinase inhibitors.10–13
The tetrahydropyridothieno[2,3-d]pyrimidine nucleus is also
among the scaffolds showing EGFR inhibitory activity.4 The
4-(phenylamino) quinazoline core has also been used to develop
several irreversible EGFR inhibitors by introducing a Michael
acceptor functional group such as the acrylamide group attached
at the C-6 or C-7 positions, e.g. I & II (Fig. 1). These groups form a
covalent linkage with the sulydryl group of the Cys797 of EGFR
and these compounds proved to be potent inhibitors of tumor
growth relying on the overexpression of the EGFR.14,15
aDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology,
German University in Cairo, Cairo 11835, Egypt. E-mail: ashraf.abadi@guc.edu.eg;
Fax: +20 2-27581041
bPharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-
¨
66123 Saarbrucken, Germany
cHelmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2.3, D-
¨
66123 Saarbrucken, Germany
dDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams
University, Egypt
eDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz
University, Saudi Arabia
fMitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Suite
3029, Mobile, AL 36604, USA
† Electronic supplementary information (ESI) available: Experimental procedures
and analytical data for all compounds. See DOI: 10.1039/c3md00118k
Fig. 1 Reversible and irreversible EGFR tyrosine kinase inhibitors.
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Drug resistance was found to develop in approximately half synthesized quinazoline derivatives having an acrylamido
of the NSCLC cases that showed an initial response to reversible substituent at position 6 and with diverse substituents at
EGFR tyrosine kinase inhibitors. This was associated with the position 4. The acrylamido substituent is intended to poten-
emergence of a secondary mutation leading to the substitution tially alkylate cysteine (C797) in the ATP binding site of the
of a single amino acid threonine 790 by methionine (T790M) in EGFR, to help in overcoming the mutation-associated drug
the ATP binding pocket of the EGFR.16–18 Several other mecha- resistance. Varied substituents at position 4 were added, namely
nisms of resistance to reversible EGFR inhibitors have also been haloanilines, alicyclic amines, alkylanilines, alkoxyanilines, and
reported.19,20
sulfonamide containing aniline derivatives 4a–4o. Furthermore,
The Thr790 residue in the EGFR is present at the entrance of a new cost-effective modication for the synthesis of the qui-
the deep hydrophobic pocket of the ATP binding site. Therefore, nazoline nucleus is described. In addition, another series of
its substitution with the bulkier methionine residue caused compounds 10a–10f was synthesized by replacing the quina-
resistance towards the reversible tyrosine kinase inhibitors zoline nucleus with a tetrahydropyridothieno[2,3-d]pyrimidine
such as getinib and erlotinib and this was attributed to an scaffold with also the same acrylamido substituent at position 7
increased enzyme affinity for ATP.21 Several studies reported while keeping the position 4 substituents showing potent
that the irreversible inhibitors22–24 are able to overcome this inhibitory activity towards the quinazoline nucleus. All acryl-
mutation-associated drug resistance.18,25–28
amido derivatives 4a–4o and 10a–10f have been tested for their
Although the T790M mutation takes place in Thr790 which is inhibitory activity on the recombinant wild type EGFR kinase as
present in the deep pocket that is occupied mainly by the well as cell growth inhibition versus cancer cell lines, with
position 4 substituents of quinazoline derivatives, the intro- mutant EGFR (H1975) and with wild type (SKBR3). In addition,
duction of a Michael acceptor group at position 6 of the qui- cell based autophosphorylation inhibition was done for
nazoline has proven to overcome this mutation-associated drug selected compounds.
resistance. While the role of Michael acceptor groups in over-
coming this resistance is justied and clear, the signicant role
of the position 4-substituents in the inhibition of the mutant
Chemistry
EGFR in the presence of Michael acceptor groups is still not Synthesis of the quinazoline nucleus was started by reuxing 2-
clear.
amino-5-nitrobenzonitrile with triethyl orthoformate in the
Therefore, we strived to investigate the effect of position 4 presence of drops of acetic anhydride to yield the formimidate
substituents on the potency of our potential irreversible inhib- derivative 1 (Scheme 1). Compound 1 was conrmed from its IR
itors. In this study we aimed to provide a better understanding spectrum showing a band at 2228.6 cmÀ1 indicating the exis-
of the signicant role of the nature and size of the position 4 tence of the (C^N) group. The 1H-NMR spectrum of 1 in DMSO-
substituents – that can be attached to a quinazoline scaffold in d6 revealed signals at 8.22 ppm (N]CH–) as a singlet, quartet at
the presence of a potential covalent interaction – on the inhi- 4.36 ppm (CH2) and triplet at 1.35 ppm (CH3).
bition of the mutant as well as the wild type EGFR kinase. In
The second step in Scheme 1 shows a novel modication for
addition, the importance of the quinazoline core was also tested the synthesis of the quinazoline nucleus, whereby the for-
by replacing it with a tetrahydropyridothieno[2,3-d]pyrimidine mimidate derivative 1 was reuxed in acetic acid with different
nucleus. Accordingly, for application in our study we amines to yield the nitroquinazoline derivatives 2a–2o and the
Scheme 1 Reagents and conditions: (i) TEOF, (Ac)2O, reflux, 24 h; (ii) R–NH2, CH3COOH, reflux, 1 h; (iii) SnCl2, MeOH, reflux, 1 h; (iv) CH2]CHCOCl, NaHCO3, acetone or
DMF, 0 ꢀC, 30 min.
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cyclization was conrmed from the IR spectrum by the disap-
Reduction of the nitroquinazoline derivatives was done by
pearance of the band for the cyano group. This novel modi- reuxing with SnCl2 in methanol to yield the aminoquinazoline
cation is cost-effective since the quinazoline nucleus is derivatives 3a–3o, which then reacted with acryloyl chloride in
synthesized from the formimidate derivative which is prepared acetone or DMF at 0 ꢀC in the presence of NaHCO3 to yield the
from the much cheaper triethyl orthoformate instead of the acrylamide derivatives 4a–4o (Scheme 1).
usual N,N-dimethylformimidamide derivative prepared from
the more expensive DMF–dimethyl acetal.29
Synthesis of the tetrahydropyridothieno[2,3-d]pyrimidine
derivatives is outlined in Scheme 3 according to the reported
The suggested mechanism for the formation of the quina- procedure.4 It started by condensing the 4-oxo-piperidine-1-
zoline nucleus from the formimidate derivative 1 is described in carboxylic acid tert-butyl ester with ethyl cyanoacetate under
Scheme 2 as reported in the literature for a similar derivative.30 basic conditions followed by cyclization through a Gewald
It is assumed that the aromatic amines or the cyclohexylamine reaction31 to construct the thiophene core. The construction of
rstly attacks the carbon of the ethoxy resulting in ejection of the thieno[2,3-d]pyrimidine ring system 6 was done using a
the ethoxy group. An amidine intermediate is then formed modied Niementowski quinazoline synthesis by condensation
which cyclizes into the quinazoline skeleton via Dimroth rear- of 5 with formamidine acetate. This was followed by chlorina-
rangement where the endocyclic and exocyclic nitrogen atoms tion of pyrimidone 6 with phosphorus oxychloride which gave
switched place to afford the 4-substituted aminoquinazoline.
the intermediate 7. Nucleophilic reaction of 7 with appropriate
Scheme 2 Suggested mechanism for the formation of the quinazoline nucleus.
Scheme 3 Reagents and conditions: (i) NCCH2COOEt, S8, Et3N, rt, 16 h; (ii) formamidine acetate, DMF, 100 ꢀC, 16 h; (iii) POCl3, Et3N, 60 ꢀC, 3 h; (iv) R–NH2, EtOH, reflux,
8 h; (v) TFA, CH2Cl2, 0 ꢀC / rt, 2 h; (vi) CH2]CHCOCl, NaHCO3, acetone, 0 ꢀC, 30 min.
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Table 1 IC50 for the inhibition of recombinant EGFR (active) kinase, cell growth
inhibitory activity, EGFR autophosphorylation inhibition in the mutant EGFR-
expressing cell linea
amines gave 8a–f, which were then subjected to Boc depro-
tection using TFA resulting in the intermediates 9a–f. The
desired compounds 10a–f were obtained by reacting the inter-
ꢀ
mediates 9a–f with acryloyl chloride in acetone at 0 C in the
presence of sodium bicarbonate to yield the acrylamide deriv-
atives 10a–f.
Biological results and discussion
All synthesized acrylamide derivatives 4a–4o and 10a–10f were
tested for their ability to inhibit isolated recombinant wild type
EGFR kinase. This was followed by testing the cell growth
inhibitory activity on cancer cell lines withwild type EGFR(breast
cancer cell line SKBR3) and the getinib-resistant (H1975)
NSCLC cell line harboring the L858R and T790M mutations. In
addition, to correlate the cell growth inhibition with the mutant
EGFR kinase inhibition, selected compounds were tested for
their ability to inhibit EGFR autophosphorylation in the mutant
EGFR expressing cell line (H1975) (Table 1).
From the results, it can be seen that several compounds
show signicant inhibitory activity on the wild type as well as
the mutant EGFR kinase which is correlated with the cell growth
inhibition. Compounds like 4a, 4b and 4f were the most potent
versus both cancer cell lines having mutant and wild type EGFR.
Concerning the inhibitory activity on the recombinant wild
type EGFR enzyme, it was generally observed that the potent
activity was accompanied by di-substitution on the 4-aniline
ring, either with dihalo or alkyl halo groups as in 4a, 4b and 4e.
In addition, this is the rst report that replacing the usual
aniline derivatives with a cyclohexyl amine as in compound 4o
resulted in an active and potent compound towards the wild
type EGFR.
It has also been found that ortho substitution on the
4-phenyl ring with uorine is tolerable as in 4b and 4e which are
the most potent compounds. Bulkier groups like “Br” or “Me”
at the ortho position, as in 4a and 4c, are also still tolerable
while the potency decreased by further increasing the chain
length like with the ethyl or methoxy groups, as in 4h and 4g. In
addition, extended substituents at the para position like ethyl,
methoxy, sulfonamide or substituted sulfonamide generally
lead to a decrease in activity. This indicates that steric
hindrance is a limiting factor to substituents at the ortho or para
IC50 (mM)
autophosphorylation
inhibition
IC50 (mM)
growth
inhibition
IC50 (nM)
Recombinant
EGFR
Compound kinase
SKBR3 H1975 Mutant
cells
cells
EGFR(H1975)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
10a
10b
10c
10d
10e
10f
Getinib
I
2.2
2.1
2.2
2.3
1.5
2.5
53.6
18.9
2.7
0.23
0.51
0.63
1.42
1.86
0.36
6.89
7.70
2.82
1.14
2.50
>40
4.00
0.39
0.40
1.4
0.26
0.28
1.86
1.82
0.39
0.40
13.87
15.96
0.68
15.69
>40
>40
>40
>40
>40
33.8
>40
>40
23.8
15.2
>40
11.39
0.44
ND
0.036
ND
ND
111.0
ND
0.931
2.0
0.275
ND
ND
ND
ND
4.39
2.8
0.28
ND
ND
3.2
76.5
53.3
43.7
9.8
3.4
3.95
3.71
4.40
8.73
7.38
>150
4
2.3
>40
3.2
ND
6.2
0.13
>5.0
13.98
0.028
>40
5.36
0.20
3.5
a
SE # 5%, ND: not determined.
positions. Similarly, compounds with a sole ethyl substitution substituents such as sulfonamide or substituted sulfonamide
at the meta position gave a more potent compound than at the anilines as well as the cyclohexylamine which destroy the
para or ortho position.
activity, while bulky substituents at the para or ortho positions
Polar substituents such as the sulfonamide group were such as 2,4-dimethoxy, p-ethyl or o-ethyl as well as the tetrahy-
found to signicantly decrease the activity, but when dropyridothieno[2,3-d]pyrimidine derivatives signicantly
substituted with heterocylic rings such as pyridine, the activity decrease the activity towards the mutant EGFR.
increased and resulted in highly potent compounds. Further-
Generally, concerning the cell growth inhibitory activity, it
more, replacing the quinazoline nucleus with the tetrahy- was found that the dihalo substituted anilines at position 4 as
dropyridothieno[2,3-d]pyrimidine nucleus resulted in less 4a and 4b are the most potent compounds. Also it was clear that
potent compounds.
replacing the methyl group in 4d by a methoxy group in 4f
Concerning the activity on the mutant EGFR, several enhanced the activity at the cellular level against both cell lines.
substituents signicantly enhanced the activity such as dihalo The 3-ethyl group in 4i was also optimum in producing a potent
in 4a and 4b, uoro methyl in 4e, bromo methoxy in 4f and m- compound towards the mutant EGFR-expressing cell line.
ethyl in 4i. Some other substituents were found to affect the
Docking of the most active compounds 4a, 4b, 4e together
mutant EGFR potency and should be avoided. This includes with getinib and compound I was done to give a better
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understanding of their binding modes in the ATP binding site substituent of all compounds accommodates the deep hydro-
of the double mutated and wild type EGFR. Fig. 2 clearly phobic pocket of the ATP-binding site. The Michael acceptor
demonstrates that getinib as well as the most active groups at position 6 of 4a, 4b, 4e and I form a covalent inter-
compounds exhibit a similar binding mode as the co-crystal- action with Cys797, while the side chain of getinib extends
lized ligand I towards the wild type EGFR. The 4-anilino towards the surface of the pocket.
Fig. 3 shows that compounds 4a, 4b, 4e and I, having a
Michael acceptor group that can potentially form a covalent
interaction with Cys797, exhibit a similar binding mode while
getinib exhibits a totally different binding mode which could
explain its much lower activity towards the double mutated
EGFR. The gure also demonstrates that in the presence of a
covalent interaction the 4-anilino substituent can still accom-
modate the back hydrophobic pocket of the mutated EGFR
which was not the case with getinib.
Conclusions
A series of 6-acrylamide-4-substituted quinazoline derivatives
and
a series of 7-acrylamide-4-substituted tetrahydropyr-
idothieno[2,3-d]pyrimidine derivatives have been synthesized.
Several potent compounds were obtained and were able to
overcome the mutation associated drug resistance. Compounds
4a, 4b and 4f were the best compromise showing potent growth
inhibitory activities towards cancer cells with mutant or wild
type EGFR kinase. Although it is clear that the presence of a
potential covalent interaction is the limiting factor and is
responsible for retaining the activity towards the mutant EGFR,
the modications in the substituents at position 4 still have a
signicant inuence towards this inhibitory activity which
should be taken into consideration to achieve highly potent
compounds. Several substituents showed potent inhibitory
activity against both mutant and wild type EGFR containing
cancer cell lines, while other substituents lead to more potent
compounds towards either cell lines such as m-ethyl in 4i, or
uoro methyl in 4e were more potent towards mutant EGFR
expressing cell line. Among the new ndings is that substitu-
ents like the cyclohexyl amine in 4o as well as the pyridyl
sulfonamide aniline in 4n resulted in active and potent
compounds towards the wild type EGFR while they were not
active towards the mutant EGFR. The quinazoline nucleus still
remains among the best scaffolds since replacing it with a tet-
rahydropyridothieno[2,3-d]pyrimidine scaffold did not seem to
be benecial towards the EGFR inhibitory activity.
Fig. 2 Docked pose of compounds 4a “cyan”, 4b “magenta”, 4e “yellow”, gefi-
tinib “green” and the co-crystallized ligand I “red” in the ATP binding site of wild
type EGFR (PDB entry 2J5F). All compounds exhibit a similar binding mode as the
co-crystallized ligand I. The 4-anilino moiety of all compounds accommodates the
deep hydrophobic pocket of the ATP-binding site of wild type EGFR. The position
6 side chain of compounds 4a, 4b, 4e and I forms a covalent interaction with
residue Cys797 “grey” while that of gefitinib extends to the surface of the pocket.
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