Quinazoline-1-deoxynojirimycin hybrids as high active dual inhibitors of EGFR and α-glucosidase

Article abstract of DOI:10.1016/j.bmcl.2017.08.035

A series of novel quinazoline-1-deoxynojirimycin hybrids were designed, synthesized and evaluated for their inhibitory activities against two drug target enzymes, epidermal growth factor receptor (EGFR) tyrosine kinase and α-glucosidase. Some synthesized compounds exhibited significantly inhibitory activities against the tested enzymes. Comparing with reference compounds gefitinib and lapatinib, compounds 7d, 8d, 9b and 9d showed higher inhibitory activities against EGFR (IC₅₀: 1.79–10.71 nM). Meanwhile the inhibitory activities of 7d, 8d and 9c against α-glucosidase (IC₅₀ = 0.14, 0.09 and 0.25 μM, respectively) were obvious higher than that of miglitol (IC₅₀ = 2.43 μM), a clinical using α-glucosidase inhibitor. Interestingly, compound 9d as a dual inhibitor showed high inhibitory activity to EGFR^wt tyrosine kinase (IC₅₀ = 1.79 nM), also to α-glucosidase (IC₅₀ = 0.39 μM). The work could be very useful starting point for developing a new series of enzyme inhibitors targeting EGFR and/or α-glucosidase.

Full text of DOI:10.1016/j.bmcl.2017.08.035

Accepted Manuscript
Quinazoline-1-deoxynojirimycin hybrids as high active dual inhibitors of EGFR
and α-glucosidase
Yaling Zhang, Hongliang Gao, Renjie Liu, Juan Liu, Li Chen, Xiabing Li, Lijun
Zhao, Wei Wang, Baolin Li
PII:
S0960-894X(17)30837-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.08.035
BMCL 25229
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 June 2017
15 August 2017
16 August 2017
Please cite this article as: Zhang, Y., Gao, H., Liu, R., Liu, J., Chen, L., Li, X., Zhao, L., Wang, W., Li, B.,
Quinazoline-1-deoxynojirimycin hybrids as high active dual inhibitors of EGFR and α-glucosidase, Bioorganic &
Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.2017.08.035
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Quinazoline-1-deoxynojirimycin hybrids as high active dual inhibitors of EGFR
and α-glucosidase
Yaling Zhang, Hongliang Gao, Renjie Liu, Juan Liu, Li Chen, Xiabing Li*, Lijun Zhao, Wei Wang, Baolin Li*
Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry; National
Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China; School of Chemistry &
Chemical Engineering, Shaanxi Normal University, Xi’an, 710062, P. R. China
* Corresponding author. E-mail address: baolinli@snnu.edu.cn, xiabingli@snnu.edu.cn
Abstract: A series of novel quinazoline-1-deoxynojirimycin hybrids were designed, synthesized and
evaluated for their inhibitory activities against two drug target enzymes, epidermal growth factor
receptor (EGFR) tyrosine kinase and α-glucosidase. Some synthesized compounds exhibited
significantly inhibitory activities against the tested enzymes. Comparing with reference compounds
gefitinib and lapatinib, compounds 7d, 8d, 9b and 9d showed higher inhibitory activities against EGFR
(IC50: 1.79 ~ 10.71 nM). Meanwhile the inhibitory activities of 7d, 8d and 9c against α-glucosidase
(IC50 = 0.14, 0.09 and 0.25 µM, respectively) were obvious higher than that of miglitol (IC50 = 2.43
µM), a clinical using α-glucosidase inhibitor. Interestingly, compound 9d as a dual inhibitor showed
high inhibitory activity to EGFRwt tyrosine kinase (IC50 = 1.79 nM), also to α-glucosidase (IC50 = 0.39
µM). The work could be very useful starting point for developing a new series of enzyme inhibitors
targeting EGFR and/or α-glucosidase.
Keywords: Quinazoline; 1-Deoxynojirimycin; Hybrids; Epidermal growth factor receptor (EGFR);
α-Glucosidase; Enzyme inhibitors.
Cancer and diabetes are common diseases with tremendous impact on human health. People with
diabetes are at significantly higher risk for many forms of cancer.1, 2 Diabetes is typically divided into
two major subtypes, type 1 and type 2 diabetes.1, 3, 4 Type 2 diabetes, previously referred to as
“noninsulin-dependent diabetes” or “adult-onset diabetes”, accounts for 90-95% of all diabetes,4 and
there is no specific treatment algorithm that is appropriate for all patients.5 Pharmacological agents,
9
such as metformin,6 orlistat,7 acarbose, voglibose and miglitol (α-glucosidase inhibitors),8,
pioglitazone, rosiglitazone and troglitazone (thiazolidinediones),10 have each been shown to decrease
incident diabetes to various degrees.11 Likewise, cancer is typically classified by its anatomic origin, of
which there are over 50 types, e.g., lymphoma, leukemia, lung and breast cancer etc.1 Lung cancers are
malignant tumors with poor prognoses and ranked as the top cause of cancer-related deaths in the
world.12, 13 In 2014, approximately 1.5 million new lung cancer cases were diagnosed globally, and 80%
of the patients were non-small cell lung cancer (NSCLC),14, 15 which was a major cause of death from
cancer.15, 16 Despite the availability of the conventional treatments, including surgery, radiotherapy, and
chemotherapy, there was still tremendous mortality, which can be due to two reasons: first, a high
proportion of lung cancer patients are only diagnosed at an advanced stage, and second, a large
population of patients manifests drug resistant, and local or distant metastasis.17 Along with the wide
recognition of genomic alterations such as epidermal growth factor receptor (EGFR) mutations, EGFR
tyrosine kinase inhibitors (TKI) known as adjuvant therapy were widely used in cancer patients with an
activating EGFR mutation, and its high efficacy could potentially improve the cure rate.15 EGFR, also
1

known as ErbB1/HER1, a member of the ERBB family of receptor tyrosine kinases (TK),18-20 has been
found to be amplified in NSCLC,21 also, it showed a significantly higher expression level in squamous
cell carcinoma with diabetics versus without diabetics.22
Cancer and diabetes are diagnosed within the same individual more frequently than would be
expected by chance.1 Only in the year of 2005, 321 incident lung cancer were diagnosed in 114915
diabetes patients in the Taiwanese general population.23 In 2002 - 2009, there were 30 diabetes patients
in 159 patients with clinical stage III NSCLC in Japan.24 From the Veterans Integrated Services
Network 16 (VISN 16) data warehouse, there were 87678 male patients diagnosed to have diabetes,
and of them, 1371 had lung cancer.25 Hence, great interest is currently focused on the development of
new series of compounds that can not only promote the regression rate of type 2 diabetes, but also
improve the cure rate of cancer. Regression of type 2 diabetes has been confirmed during treatment of
chronic myeloid leukemia with imatinib, a known inhibitor of the c-kit and platelet-derived
growth-factor receptor (PDGFR) tyrosine kinases.26, 27 Especially, the improvement of type 2 diabetes
in a lung cancer patient treated with erlotinib was observed.28
1-Deoxynojirimycin (1-DNJ) and miglitol (Fig. 1) were the potent inhibitors of α-glucosidase.8, 29
Notably, 1-DNJ was the best known naturally occurring azasugars, and gained great attention in
biochemistry and pharmacology because it acted not only as a therapeutic drug for diabetes,30 but also
33
for
cancer31
and
viral
infections,32
including
HIV.29,
As
reported,
N-(8-(3-ethynylphenoxy)octyl-1-DNJ was a potent inhibitor of α-glucosidase.13 Hybrids of 1-DNJ and
5-aryl-1,2,3-triazole were potential bi-functional inhibitors of α-glucosidase and methionine
aminopeptidase 2 (MetAP2).34 On the other hand, gefitinib and erlotinib (Fig. 1) were
4-arylaminoquinazoline inhibitors of EGFR tyrosine kinase and have been approved for treatment of
NSCLC.35-37 They showed very potent and selective inhibition profiles to the two most frequently
observed activating mutations in EGFR kinase, including the single amino acid mutant L858R, caused
by asomatic mutation in exon 21, and the delE746-A750 deletion in exon 19.20, 38, 39 Meanwhile
lapatinib (Fig. 1), as a 4-arylaminoquinazoline derivative, was a dual EGFR and human epidermal
growth factor receptor-2 (HER2, also known as ErbB2) TKI.40, 41 In view of above statements, we
would like to hybridize 1-DNJ with quinazoline backbone for new bioactive compounds. Herein,
quinazoline was selected as the core structure, 1-DNJ unit and three different arylamine groups,
including
3-chloro-4-fluorophenylamine groups, were introduced to the 6- or 7- and 4-position of the core
structure, respectively. The designed novel quinazoline-1-deoxynojirimycin hybrids
3-chloro-4-(3-fluorobenzyloxy)phenylamine,
3-ethynylphenylamine
and
(quinazoline-1-DNJ hybrids) were shown in Fig. 1 and Table 1, and the compounds were synthesized,
as well as evaluated for their inhibitory activities against wild type EGFR (EGFRwt) TK and
α-glucosidase.
2

Fig. 1. Structures of enzyme inhibitors and design of novel quinazoline-1-DNJ hybrids.
The target compounds were prepared through two synthetic routes as shown in Scheme 1 and
Scheme 2. To synthesize 6,7-disubstituted quinazoline derivatives
(Scheme 1),
R1,R2-disubstituted-2-nitrobenzonitriles (1a-1d) were selected as starting materials, and were reduced
with Na2S2O4 to yield R1,R2-disubstituted-2-aminobenzonitriles (2a-2d) in 86.7% - 93.0% yield. Then,
2a-2d were reacted with dimethylformamide-dimethylacetal (DMF-DMA) in toluene in the presence of
acetic acid to give compound 3a-3d in 79.5% - 92.0% yield, which were then reacted with three
different arylamines through the Dimroth rearrangement in acetic acid to give the intermediates 4a-4d,
5d-5d and 6a-6d in 74.9% - 95.2% yield. Finally, 4a-4d, 5d-5d and 6a-6d were treated with 1-DNJ
hydrochloride in DMF in the presence of potassium iodide and potassium carbonate to afford the desired
quinazoline-1-DNJ hybrids 7a-7d, 8d-8d and 9a-9d in 19.2% - 37.7% yield.
3

Scheme 1. Synthetic route of quinazoline-1-DNJ hybrids 7a-7d, 8a-8d and 9a-9d.
Reagents and conditions. i. (1) Na2S2O4, EtOH/H2O, 50 ℃, 30 min, (2) HCl, 50 ℃, 2 h, (3) NaOH/H2O, 86.7% - 93.0%; ii.
toluene, DMF-DMA, acetic acid, 35 - 40 ℃, 15 min, 79.5% - 92.0%; iii. (1) 3-chloro-4-(3-fluorobenzyloxy)phenylamine, AcOH,
130 ℃ , 30 min, 84.1%
- 95.2%; (2) 3-ethynylphenylamine, AcOH, 130 ℃ , 30 min, 74.9% - 91.1%; (3)
3-chloro-4-fluorophenylamine, AcOH, 130 ℃, 20 min, 85.3% - 91.1%; iv. 1-DNJ·HCl, KI, K2CO3, DMF, 70 – 75 ℃, 7 - 8 h,
19.2% - 37.7%.
Scheme 2. Synthetic route of quinazoline-1-DNJ hybrids 15a-15c.
Reagents and conditions. (i) NH4I-H2O2, AcOH, r.t., 12 h, 92.6%; (ii) DMF-DMA, AcOH, 35 ℃, 0.5 h, 89.3%; iii. (1)
3-chloro-4-(3-fluorobenzyloxy)phenylamine, AcOH, 130 ℃, 15 min, 92.5%; (2) 3-ethynylphenylamine, AcOH, 130 ℃, 15 min,
84.3%; (3) 3-chloro-4-fluorophenylamine, AcOH, 130 ℃, 15 min, 86.1%; (iv) 5-formylfuran-2-yl boronic acid, Pd/C, Et3N,
DME-MeOH, 50 ℃, 0.5 h, 65.2% - 83.4%; (v) 1-DNJ·HCl, NaBH3CN, MeOH/DMF, r.t., 48 h, 30.5% - 34.8%.
The synthetic route of 6-substituted quinazoline derivatives was followed our previous reports.39,
42 As shown in Scheme 2, 2-aminobenzonitrile (10) as the starting material was reacted with the mixture
of ammonium iodide (NH4I) and hydrogen peroxide (H2O2) in acetic acid to give
2-amino-5-iodobenzonitrile (11) in 92.6% yield. Then, the reaction of 11 with DMF-DMA gave
compound 12 in 89.3% yield. Dimroth rearrangement was used to form quinazoline core. Three
4

4-arylamino-6-iodoquinazolines (13a-13c) were obtained from the reaction of 12 with three different
substituted anilines respectively in acetic acid in 84.3% - 92.5% yield. Then, Suzuki coupling was
employed to prepare compound 14a-14c. The mixture of 13 and 5-formylfuran-2-yl boronic acid were
refluxed at 50 ℃for 30 min in dimethoxyethane-methanol (DME-MeOH) in the presence of Pd/C and
triethylamine (Et3N) to give compound 14a-14c in 65.2% - 83.4% yield. The target compounds 15a-15c
were generated from the reductive amination of 14 and 1-DNJ hydrochloride in the presence of
NaBH3CN in 30.5% - 34.8% yield. The structures of all target compounds were identified by 1H NMR,
13C NMR), IR and HRMS (see Supplementary materials).
The inhibitory effects of these new hybrids against recombinant EGFRwt tyrosine kinase were
evaluated by ELISA methods as our previous reported,39, 43 gefitinib and lapatinib were used as
reference compounds. Firstly, we determined the inhibitory rate of compounds in 50 nM final
concentrations against EGFRwt, and the results were shown in Fig. 2. All the tested compounds showed
certain inhibitory activities. Notably, the inhibitory effects of compound 7b, 7d, 8b, 8d, 9b, 9d, and 15c
were all higher than lapatinib. Compound 7b, 7d, 8b, 8d, 9b and 9d had
3-((2R,3R,4R,5S)-2-hydroxymethyl-3,4,5-trihydroxy-1-piperidyl)propoxy unit at the 6- or 7-position of
quinazoline
core,
whereas,
compound
7a,
7c,
8a,
8c,
9a,
and
9c
had
2-((2R,3R,4R,5S)-2-hydroxymethyl-3,4,5-trihydroxy-1-piperidyl)ethoxy unit at the same position of the
quinazoline core, which indicated the carbon chain containing three carbon atoms between 1-DNJ
moiety and the oxygen atom can give a better inhibitory activities against EGFRwt, which is consistent
with our former results against human tumor cell lines for the 4-arylaminoquinazoline derivatives
attaching a (E)-propen-1-yl moiety.44 It is noteworthy that compound 8d, 9b and 9d were more potent
than gefitinib, and 9b and 9d, harboring 3-Cl, 4-F at the 4-aniline moeity of quinazoline core, were the
most potent agents in all tested and reference compounds. Moreover, compound 15c also exhibited
potent inhibitory activity against EGFR. Hence, the carbon chain containing three carbon atoms
between 1-DNJ moiety and the oxygen atom, and the 3-Cl, 4-F in 4-aniline moiety of these novel
quinazoline-1-DNJ hybrids can give more potent inhibitory activities against EGFRwt. In next,
compound 7d, 8d, 9b and 9d were selected to generate IC50 values against EGFRwt using ELISA
method. The concentration ranges of the tested compounds were designed from 6 pM to 100 nM, and
the final concentration of EGFRwt was set in 50 ng/mL. As shown in Table 1, compound 7d, 8d, 9b and
9d (with IC50 values of 4.53, 4.87, 10.71 and 1.79 nM, respectively) were all more potent than lapatinib
(IC50 = 27.06 nM). Compound 9d was the most potent one among all the tested compounds, and its
IC50 value was lower than gefitinib (IC50 = 3.22 nM). This suggested 9d was a potent EGFRwt inhibitor.
5

Table 1
Inhibitory activities of synthesized quinazoline-1-DNJ hybrids against EGFRwt and α-glucosidase enzyme in vitro.a
IC50 (nM)
IC50 (µM)
Inhibition Rate (%)b
Comp.
R3
R4
R5
(against EGFRwt, comp. in 50 nM)
EGFRwt
α-glucosidase
Gefitinib
Lapatinib
82.48±2.90
73.32±4.68
3.22±1.45
>100
N.D.
27.06±3.77
3-Cl,
7a
7b
7c
7d
8a
8b
8c
8d
9a
9b
9c
66.55±0.50
74.87±3.02
N.D.
N.D.
N.D.
64.09±6.56
21.23±4.54
N.D.
4-(3-fluorobenzyloxy)
3-Cl,
4-(3-fluorobenzyloxy)
3-Cl,
N.D.
4-(3-fluorobenzyloxy)
3-Cl,
78.24±5.20
56.42±5.31
79.64±0.40
53.45±5.91
83.18±2.62
65.20±0.32
83.55±2.16
53.70±7.52
4.53±0.10
N.D.
0.14±0.03
7.18±0.54
6.19±0.56
6.25±1.04
0.09±0.01
8.40±0.57
4.34±0.53
0.25±0.07
4-(3-fluorobenzyloxy)
3-ethynyl
3-ethynyl
3-ethynyl
3-ethynyl
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
N.D.
N.D.
4.87±2.80
N.D.
10.71±1.32
N.D.
9d
85.31±2.27
50.64±0.46
1.79±0.96
N.D.
0.39±0.12
N.D.
3-Cl,
15a
4-(3-fluorobenzyloxy)
3-ethynyl
15b
15c
27.07±2.01
78.03±0.64
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
3-Cl, 4-F
1-DNJ·HCl
Miglitol
0.07±0.01
2.43±0.32
N.D.
a The values are mean±SD from three independent experiments. b The Inhibition Rate (%) was obtained from the 50 nM of the
synthesized compounds against recombinant EGFRwt TK by ELISA analysis. N.D. indicated inhibition rate or IC50 was not
determined.
6

100
80
60
40
20
0
Gefitinib 7a
7b
7d
8a
8b
8c
8d
9a
9b
9c
9d
15a
15b
15c lapatinib
Compounds (50 nM)
Fig. 2. Inhibition rate of target compounds in 50 nM against recombinant EGFRwt TK (in 50 ng/mL) from ELISA analysis.
Each bar represented the mean (±SD) of the inhibition rate from at least three independent experiments. The red dot line
indicated compounds showed higher inhibitory effects compared to lapatinib. The blue dot line indicated compounds showed
higher inhibitory effects compared to gefitinib.
Meanwhile, the inhibitory effects of these new compounds against α-glucosidase were also
investigated by anti-α-glucosidase analysis.45 1-DNJ and miglitol were selected as reference
compounds. The final concentration range of the tested compounds and reference compounds were
adjusted from 1 nM to 100 µM, and the final concentration of α-glucosidase was set in 7.2 mg/mL in
96-well plates to achieve the absorbance in the range of 0.2 - 1.2 units at 405 nm measured with
multi-well spectrophotometer. As shown in Table 1, except gefitinib, all tested compounds showed
certain inhibitory effects against α-glucosidase. Less than 50% inhibition was observed when
α-glucosidase was treated with 100 µM gefitinib. Compound 7a and 7b were less active agents among
tested compounds, and their IC50 values were 64.09 and 21.23 µM, respectively. Compound 8a, 8b, 8c,
9a and 9b exhibited moderate inhibitory activities (with IC50 values of 7.18, 6.19, 6.25, 8.40 and 4.34
µM, respectively) compared with 1-DNJ hydrochloride (IC50 = 0.07 µM) and miglitol (IC50 = 2.43 µM).
However, compared with miglitol, compound 7d, 8d, 9c and 9d were more potent agents against
α-glucosidase, and the IC50 values were 0.14, 0.09, 0.25 and 0.39 µM, respectively. Especially, the IC50
value of compound 8d was almost equal to 1-DNJ hydrochloride against α-glucosidase. Notably, it is a
contributing factor to the highest inhibitory activities that 1-DNJ moiety was linked at the 7-position of
quinazoline core by propoxy.
In summary, a series of novel quinazoline-1-DNJ hybrids were designed and synthesized, and the
structures of these new synthesized compounds were confirmed by 1H NMR, 13C NMR, IR and HRMS.
Moreover, the preliminary enzyme inhibitory activities of these hybrids against EGFRwt and
7

α-glucosidase were evaluated in vitro. The results indicated that most of synthesized compounds
exhibited moderate to excellent inhibitory effects against EGFR and/or α-glucosidase. Compound 7d
and 9c (IC50 = 0.14 and 0.25 µM, respectively) exhibited more potent inhibitory effects on
α-glucosidase compared to miglitol. Compound 8d was the most potent agent against α-glucosidase
(IC50 = 0.09 µM). Especially, compound 9d not only demonstrated strong inhibitory activity against
recombinant EGFRwt tyrosine kinase (IC50 = 1.79 nM), but also showed potent inhibitory activity toward
α-glucosidase (IC50 = 0.39 µM). Hence, compound 7d, 8d and 9c were the potent α-glucosidase
inhibitors, and compound 9d was a highly active dual enzyme inhibitor of EGFRwt tyrosine kinase and
α-glucosidase. Given these facts, some of quinazoline-1-DNJ hybrids would serve as potential
anti-enzyme agents with modifications on pharmacophore. Specifically, hybrid 9d presented as a
promising agent for the further studies regarding a high active dual inhibitor of EGFR and
α-glucosidase.
Acknowledgments
This work was financially supported by the National Natural Science Foundation of China (Grant
number 21272144), and the Fundamental Research Funds for the Central Universities of Shaanxi Normal
University (Grant number X2015YB06).
Supplementary material
Supplementary data associated with this article can be found, in the online version, at
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