DABCO-catalyzed one-pot three component synthesis of dihydropyrano[3,2-c]chromene substituted quinazolines and their evaluation towards anticancer activity

Article abstract of DOI:10.1016/j.bmcl.2016.07.003

A facile DABCO promoted one-pot three component synthesis of a new series of C–C linked bis-heterocycle containing dihydropyrano[c]chromene as highly fused oxa-heteryl group at C-2 position of quinazoline was developed. Quinazoline-2-carbaldehyde, substituted 4-hydroxycoumarin and ethyl cyanoacetate were used as key components in the Knoevenagel–Michael addition reaction to get the titled compounds. These compounds were screened for anti-cancer activity against the breast cancer cell lines of MDA-MB 231, and MDA-MB 453.

Full text of DOI:10.1016/j.bmcl.2016.07.003

Accepted Manuscript
DABCO-catalyzed one-pot three component synthesis of dihydropyrano[3,2-
c]chromene substituted quinazolines and their evaluation towards anticancer
activity
Sumathi Vodnala, A.K.D. Bhavani, Ramakrishna Kamutam, V.G.M. Naidu,
Promila, Ch. Prabhakar
PII:
S0960-894X(16)30704-1
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.07.003
BMCL 24047
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
11 March 2016
16 June 2016
1 July 2016
Please cite this article as: Vodnala, S., Bhavani, A.K.D., Kamutam, R., Naidu, V.G.M., Promila, Prabhakar, Ch.,
DABCO-catalyzed one-pot three component synthesis of dihydropyrano[3,2-c]chromene substituted quinazolines
and their evaluation towards anticancer activity, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://
dx.doi.org/10.1016/j.bmcl.2016.07.003
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DABCO-catalyzed one-pot three component synthesis of
dihydropyrano[3,2-c]chromene substituted quinazolines and their
evaluation towards anticancer activity
a
a,
a
b
Sumathi Vodnala , A. K. D. Bhavani *, Ramakrishna Kamutam , V. G. M.Naidu ,
c
c
Promila , Ch. Prabhakar
a
Department of Chemistry, University College of Science, Saifabad,
Osmania University, Hyderabad, India-500004.
b
National Institute of Pharmaceutical Education and Research (NIPER),
Balanagar, Hyderabad, India.
c
Department of Chemistry, National Institute of Technology,
Kurukshetra-36119, India.
*Corresponding Author: Mobile: 919177389748; E-mail: akdbhavaniou@yahoo.com
A facile DABCO promoted one-pot three component synthesis of a new series of C-C linked
bis-heterocycle containing dihydropyrano[c] chromene as highly fused oxa-heteryl group at
C-2 position of quinazoline was developed. Quinazoline-2-carbaldehyde, substituted 4-
hydroxycoumarin and ethyl cyanoacetate were used as key components in the Knoevenagel-
Michael addition reaction to get the titled compounds. These compounds were screened for
anti-cancer activity against the breast cancer cell lines of MDA-MB 231, and MDA-MB 453.
Keywords: Multicomponent reaction, Knoevenagel-Michael reaction, Quinazoline, 4-
hydroxycoumarin, DABCO, anti-cancer.
Quinazoline scaffold is consistently regarded as privileged structural moiety owing to its
1
-5
medicinal and pharmacological importance in various therapeutic agent , especially in anti-
6
cancer agents . Further, the oxa-heteryl quinazolines, wherein, the oxygen heterocyclic
moiety linked at various position of quinazoline are well known for efficient medicinal
properties, some of them even marketed as drugs. A class of 6-oxa-heteryl quinazolines, such
7
8
8
as Lapatinib (1a) , Selatinib (1b) and Icotinib (1c) are marketed as anticancer drugs
Figure 1). Especially, 2-tetrahydrofuranyl / furanyl / benzofuranyl / morpholinyl /
benzoxazinyl quinazolines exhibit pharmacological activities like anti-cancer by inhibiting
(
9
10
tyrosine kinase , reactivation of mutant p53 protein , anticholinergic activity by inhibiting
1
1
cyclic guanosine 3', 5'-mono-phosphate phosphodiesterase , used for control of mRNA
1
2, 13
splicing by inhibiting clk4
. Quinazoline derivative also acts as DPP-4 inhibitor for
1
4
treating type-II diabetes . Additionally, quinazoline bis-heterocyclic derivatives are used to
treat schizophrenia, depression, anxiety, migraine, hallucinations, and insomnia by
1
5
antagonizing the 5-HT2A receptor . A literature survey on 2-substituted oxa-heteryl

quinazoline derivatives revealed that a very few reports were found. Till date, particularly at
-position of quinazoline synthesis and their activity, only benzofuran or benzoxazine as
2
fused oxa-heterocycles were constructed.
O
O
S
H3C
CH3
S
O
O
O
F
F
HN
HN
N
Cl
HN
N
Cl
HN
O
N
O
N
Lapatinib, 1a
Selatinib, 1b
HN
N
O
O
O
O
N
Icotinib, 1c
Figure 1. Marketed anticancer drugs of quinazoline derivatives
We have initiated a program for the synthesis of designed hybrid molecules that contains
dihydropyrano[c]chromene motif as highly fused oxa-heterocyclic unit at C-2 position of
quinazoline ring. Also, we are aware that the dihydropyrano[c]chromene compounds have a
privileged medicinal scaffold owing to rigid heterocyclic ring system that has a possibility for
inserting different functional groups to improve their efficacies as a result of binding to
specific sites in the target. Furthermore, these compounds attracted interest over the years due
to their varied biological properties, such as anti-cancer, spasmolytic, anti-coagulant, diuretic,
1
6-18
anti-anaphylactic activities and also potassium channel activating properties
. 1,4-
Diazobicyclo [2.2.2] octane (DABCO) is an inexpensive, commercially available and most
1
9
common catalyst in organic reactions . DABCO was also considered as one of the best
2
0
catalysts in the multi-component synthesis of dihydropyrano[c]chromene derivatives .
Herein, we wish to report the DABCO catalyzed three-component reaction leading to a new
series of C-C linked bis-heterocycles containing dihydropyrano [c] chromene, quinazoline
scaffolds using 4-(benzyloxy)quinazoline-2-carbaldehyde, various substituted coumarins and
ethyl cyanoacetate. Subsequently, the anticancer activities of the synthesized compounds
were evaluated against MDA-MB 231 (Estrogen independent) and MDA-MB 453 (Breast
adeno carcinoma) cell lines.

Initially, the required key precursor 4-(benzyloxy)quinazoline-2-carbaldehyde 5 was
synthesized in four steps (over all yield 40%) starting from anthranilic acid 2 and acetamide
as shown in Scheme 1. The cyclo condensation of anthranilic acid 2 with acetamide in
2
1
paraffin oil at 220 °C for 2h led to quinazoline 3 . The hydroxy compound 3 was treated
with benzyl bromide in the presence of K CO in dry acetone to give O-benzyl derivative 4,
which upon oxidation with SeO afforded the carbaldehyde derivative 5 (Scheme 1). The
2
3
2
1
13
1
compound 5 was characterized by H, C NMR and Mass spectra. In H NMR spectrum, the
compound 5 exhibited the characteristic aldehyde proton at δ 9.65 as singlet.
Scheme 1
Primarily, the evaluation of DABCO catalyst loading was studied using quinazoline-2-
carbaldehyde 5 (1.0 equiv) substituted coumarin 6a (1.1 equiv) and ethyl cyanoacetate 7 (1.1
equiv) refluxing in EtOH. Employing 5, 10 and 15 mol% DABCO resulted in the required
2
2
compound 8a with inferior yields. The optimum catalyst loading for this knoevenagel-
Michael reaction found to be 20 mol% of DABCO to afford the titled compound in high
yields (82%). Loading 30 mol% of catalyst has no effect on the yields of the required
compound 8a. In the absence of catalyst, the reaction did not proceed at all and only starting
materials were recovered (Table 1).

Table 1. Optimized conditions for 8a compound with different mol % of DABCO in EtOH.
Entry
Catalyst (mol %)
DABCO (5 mol %)
DABCO (10 mol %)
DABCO (15 mol %)
DABCO (20 mol %)
DABCO (30 mol %)
No catalyst
Time
2h
2h
2h
2h
(%)Yield
1
2
3
4
5
6
15
25
35
82
82
2h
2h
No reaction
After optimization of the reaction conditions, the three component reactions of coumarins
6
b-g were carried out under standard protocol and the corresponding products 8b-g were
obtained in good to high yields (Table 2). The structures of compounds 8a-g were deduced
1
13
from their H NMR, C NMR, and IR spectral data. The molecular formulas for the
+
compounds 8a-g were determined by HRMS from the corresponding [M+H] ion peaks.
Table 2. DABCO catalyzed synthesis of dihydropyrano[c]chromenes 8a-g via multicomponent
b, c
reaction.

a
Entry
Compound
Substituent
3
% Yield
m.p °C
258-260
218-220
229-231
242-245
262-264
245-247
1
2
1
2
3
4
5
6
8b
8c
8d
8e
8f
R = Me, R = Me, R = H
80
77
74
79
83
72
1
2
3
R = OMe, R = H, R = H
1
2
3
R = H, R = F, R = H
1
2
3
R = OMe, R = Cl, R = H
1
2
3
R = H, R = Cl, R = Cl
1
2
3
8g
R = H, R = Cl, R = Br
a
Isolated yields but not optimized.
All compounds were characterized by IR, H NMR, C NMR, Mass and HRMS
All the reactions are carried out using 0.75 mmol of 5.
b
c
1
13
Anti-cancer activity against Breast cancer cell lines
The target compounds 8a-g were evaluated for their cytotoxicity activity against two breast
cancer cell lines, namely: MDA-MB 231 (Estrogen independent) and MDA-MB 453 (Breast
adeno carcinoma cell line). Anti-cancer activities of the compounds were determined by a
well-known colorimetric MTT assay based on mitochondrial reduction of yellow MTT
4
tetrazolium salt dye to a highly colored violet-blue formazan product. Briefly, 1 x 10 cells
(
(
counted by Trypan blue exclusion dye method) were seeded in 96 well plates using DMEM
Dulbecco's Modified Eagle's Medium) with 10% FBS (Fetal Bovine Serum) medium and
incubated for 24h before the treatment. After 24h, cells were treated with series of
concentrations of each compound and incubated for 48h at 37°C in DMEM with 10% FBS
medium. After 48h of incubation, media was replaced with 90 µL of fresh serum free media
and 10 µL of MTT reagent (prepared in 5mg/ml in 1X PBS) and plates were incubated at
3
7°C for 4h. Then, media was removed carefully without disturbing the formazan crystals
formed at the bottom of the plate and added with 200 µL DMSO and incubated at 37°C for

1
0-15 min to dissolve the formazan crystals. The absorbance at 570 nm was measured with a
background deduction at 690 nm on a spectrophotometer (spectra max, Molecular Devices,
USA). IC50 values were determined from plot with 50% cell viability (compared with control
cells which received only DMSO+DMEM) versus concentration.
Compounds 8a-f did not show toxicity even with 100µM concentrations in both MDA-MB
4
53 and MDA-MB 231 cell lines. However, the compound 8g showed inhibition of breast
cancer cell growth as reflected by its IC50 values. The compound 8g showed an IC50 values at
5.7µM and 28.3µM concentrations in MDA-MB 453 and MDA-MB 231 cell lines
4
respectively (Table 3). Also, we have performed a dose-dependent toxicity study in both the
cell lines for compound 8g and results are plotted in the form of graph (Figure 2). We found
that compound 8g showed ~80% cell growth inhibitory effects at 50 µM and further at 100
µM concentration inhibit more than 95% cell growth (Figure 2) in MDA-MB 231 cells.
Furthermore, 8g showed its effective inhibition ~65% at 100µM concentration in MDA-MB
4
53 cells. This data suggests that 8g derivative appears to have anti-cancer activity in breast
cancer cells, MDA-MB 231. Although, the anticancer activity of 8g is not comparable as
standard activity, but functional group modifications at quinazoline-2-carbaldehyde 5 and
substituted coumarins can guide to develop the drug leads and that will be future
investigations from this laboratory.
Table 3. In vitro anticancer activity (IC50) of compounds 8a-g against breast cancer cell lines (MDA-
MB 453, MDA-MB 231)
Entry
MDA-MB 453
MDA-MB 231
a
a
(
µM)
(µM)
8
8
8
a
b
c
>100
>100
>100
>100
>100
>100
8
8
8
d
e
f
>100
>100
>100
>100
>100
>100
8
g
45.7 ± 2.47
28.3 ± 1.33
a
represents the concentration of the compound that causes cell growth inhibition.

Figure 2. Concentration dependent anti-cancer activity of compound 8g in breast cancer cells (MDA-
MB 231and MDA-MB 453).
Molecular Docking studies:
In breast cancer cells Estrogens Receptor alpha (ERα) protein is highly expressed. In order to
know the level of anticancer activity of 8g against breast cancer lines (MDA-MB 231, MDA-
MB 453), the molecular docking studies have been performed by using Glide (Schrödinger
Release 2015-3: Maestro, version 10.3, Schrödinger, LLC, New York, NY, 2015) software.
Crystal structure of ER protein has downloaded from protein data bank [PDB deposition
2
3
number :3UUD, 1.60A] .
The affinity of 8g at the receptor site of ERα protein and the best ligand binding poses were
identified using the lowest binding energy, high docking score and the number of H-bonding,
residue π- π interactions, hydrophobic interactions at receptor site (Figure 3 – 6). The Table 4
represents the docking score and binding energies of 8a-g. From the Table 4, it is evident that
8
g possess low binding energy (-44.69) and considerable high docking score (-3.521). As
shown in Figure 3, the compound 8g was found to be best in fitting into the active site of
receptor. This may be due to possible hydrogen bonding interaction that formed with Leu-409
and - interaction with Tyr-331 of receptor. The hydrogen bonding was formed between
backbone -NH of Leu-409 and oxygen of C=O of ester group in 8g and it is observed as
ꢀ
.ꢁꢂꢃ (Figure 4). The - interaction is indicated between Tyr-331 of receptor and olefinic
bonds of pyran ring in 8g as shown in Figure 6.
Table 4. Showing docking score and Binding energy of 8a-g

Docking
Structure score
Binding
energy(Kcal/mol)
8
8
8
8
8
8
8
a
b
c
d
e
f
-2.683
-2.642
-1.998
-2.582
-3.207
-2.854
-3.521
-37.694
-35.392
-38.355
-33.841
-35.251
-35.612
-44.685
g
Figure 3. Illustrates compound 8g (In stick) with ERα protien (3 UUD) and showing how it fits into
the pocket. The protein is presented as cartoon and coloured spectrum. 8g in active site (H bonding
was shown by dotted pink line and pi-pi interactions are in sky blue dotted line)
Figure 4. Showing H bonding distance( pink dotted line),
shown between backbone –NH of Leu 409 of receptor
and –CO of ester in 8g
Figure 5. 8g involved in hydrophobic interactions
by fluorescent green colour) and polar
interactions (shown shown in cyan)
(

Figure 6. The - interaction is indicated between Tyr-331 of receptor and olefinic bonds of
pyran ring in 8g.
The derivative 8g, along with H bonding and - interactions shows other type of
interactions like hydrophobic interaction (takes place with pro-333, Phe-337, Pro-406 , Tyr-
3
28 , Tyr-331, Leu-408, Leu-403, Ala-405 and Leu-410 amino acids), and polar interaction
with amino acids Thr-334, Gln-414 and Asn-407) (Figure 5). Bromo and chloro substituents
in phenyl group oriented towards the hydrophobic pockets appear to be a positive influence in
(
2
4
binding affinity with protein as indicated by their high glide score and least binding energy.
These docking studies revealed that the various possible interactions between 8g and receptor
site makes the compound easy to fit into the active site and it gives supporting evidence for
the best anticancer activity of the compound.
In summary, we accomplished syntheses of a library of new series of quinazoline based C-C
linked bis-heterocyles 8a-g in which the C-2 position is occupied dihydropyrano[c]chromene
moiety. The titled compounds were screened for their anticancer activity against breast
cancer cell lines (MDA-MB 231, MDA-MB 453). Substitution at phenyl ring of oxa-heteryl
moiety with bromine and chlorine atoms emerged as active compound 8g in both breast
cancer cell lines. Further, it was evidenced by the molecular docking studies. Hence, it is a
strong impetus us to synthesize halo substituted derivative of quinazoline based C-C linked
bis-heterocyles as good leads for further study. Study towards this direction is currently
underway.
Acknowledgments: VS is grateful to Department of chemistry, Osmania University for
providing research facilities. The authors express their gratitude and thanks to the BIOSYN

Research Chemicals (P) Ltd., Hyderabad, India for providing substituted 4-
hydroxycoumarins. ChP thank to SERB- New Delhi, India for financial support under Young
Scientist Start- up Research Grant.
Supplementary data
Supplementary data associated with detailed experimental procedures for the synthesis and
spectral data of the synthesized compounds included as separate file
.
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2
2. Procedure for the synthesis of compound 8a: 4-Benzyloxy-quinazoline-2-carbaldehyde
5
6
(0.2g, 0.75 mmol), ethyl cyanoacetate 7 (0.087ml, 0.83 mmol), 4-hydroxycoumarin
a (0.83 mmol) and DABCO (20 mol %) were added to ethanol taken in R.B flask.
The reaction mixture was refluxed for 35 min. Then resulted reaction mixture was
°
cooled to 15 C, the solid separated out, filtered. The compound was recrystallised by
EtOH as solvent, if necessary crude solid was passed through a silica gel column using
EtOAc/hexane 3:7 mixture as eluent to yield the corresponding product 8a. Yellow
-1
1
solid; IR (KBr, υmax, cm ): 3377, 1706, 1670, 1649 ; H NMR (400 MHz, DMSO-
): δ ꢁ.64 (d, ꢀH, J = ꢁ.5 Hz, ArH), ꢁ.24 (dd, ꢀH, J = 6.2 Hz, J = ꢀ.5 Hz, ArH), 7.ꢁ7
t, 1H, J = 8.7 Hz, J = 7.0 Hz, ArH), 7.59-7.49 (m, 3H, ArH), 7.29-7.22 (m, 2H, ArH),
d
6
(
6
3
.90-6.88 (m, 3H, PhH), 6.81-6.77 (m, 2H, PhH), 6.57 (s, 2H, NH ), 5.14 (AB-q, 2H),
2
3
13
.86-3.81 (m, 2H,), 3.46 (s, 1H, 4(sp )-H), 0.71 (t, 3H, J = 7.0 Hz); C NMR (100
): δ ꢀ65.6, ꢀ62.ꢀ, ꢀ5ꢁ.ꢀ, ꢀ52.4, ꢀ43.4,ꢀ37.ꢀ, ꢀ36.3, ꢀ34.ꢂ, ꢀ3ꢀ.ꢁ,
28.7, 127.6, 126.1, 124.6, 124.4, 123.4, 123.3, 116.7, 116.0, 115.5, 95.3, 58.4 47.0,
MHz, DMSO-d
6
1
1
5
+
3.3. ESI-HRMS: [M+H] m/z calculated for C30
21.1651.
H
24
N
3
6
O : 521.1660; found at
2
2
3.
4.
Delfosse, V.; Grimaldi, M.; Pons, J. L.; Boulahtouf, A.; le Maire, A.; Cavailles, V.;
Labesse, G.; Bourguet, W.; Balaguer, P. Proc. Natl .Acad. Sci. U S A. 2012, 109,
1
4930.
Manivannan, E.; Chaturvedi, S. C. Bioorg. Med. Chem. 2012, 20, 7119.

Graphical abstract
DABCO-catalyzed one-pot three component synthesis of dihydropyrano[3,2-
c]chromene substituted quinazolines and their evaluation towards anticancer activity
Sumathi Vodnala, A. K. D. Bhavani*, Ramakrishna Kamutam, V. G. M.Naidu,
Promila, Ch. Prabhakar
The novel carbon-carbon linked dihydropyrano[3,2-c]chromene substituted quinazolines were
achieved via DABCO induced Knoevenagel-Michael addition reaction and resulting derivatives were
evaluated towards anticancer activity.