Synthesis and Biological Screening of Pyrano[3,2- c] quinoline Analogues as Anti-inflammatory and Anticancer Agents

Article abstract of DOI:10.1021/acsmedchemlett.7b00545

A series of pyrano[3,2-c]quinoline based structural analogues was synthesized using one-pot multicomponent condensation between 2,4-dihydroxy-1-methylquinoline, malononitrile, and diverse un(substituted) aromatic aldehydes. The synthesized compounds were

Full text of DOI:10.1021/acsmedchemlett.7b00545

Note
Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Synthesis and Biological Screening of Pyrano[3,2‑c]quinoline
Analogues as Anti-inflammatory and Anticancer Agents
Kuldip D. Upadhyay,*,† Narsinh M. Dodia,‡ Rupesh C. Khunt,‡ Ravi S. Chaniara,§ and Anamik K. Shah∥
†ICMR-National Institute of Occupational Health, Ahmedabad-380016, Gujarat, India
‡Department of Chemistry, Saurashtra University, Rajkot-360005, Gujarat, India
§Wockhardt Research Centre, Aurangabad-431136, Maharashtra, India
∥National Facility for Drug Discovery (NFDD), Saurashtra University, Rajkot-360005, Gujarat, India
S
* Supporting Information
ABSTRACT: A series of pyrano[3,2-c]quinoline based structural analogues was synthesized using one-pot multicomponent
condensation between 2,4-dihydroxy-1-methylquinoline, malononitrile, and diverse un(substituted) aromatic aldehydes. The
synthesized compounds were evaluated for their anti-inflammatory and cytotoxicity activity. Initially, all the compounds were
evaluated for the percent inhibition of cytokine release, and cytotoxicity activity and 50% inhibitory concentrations (IC50) were
also determined. Based on the primary results, it was further studied for their ability to inhibit TNF-α production in the human
peripheral blood mononuclear cells (hPBMC) assay. The screening results revealed that compound 4c, 4f, 4i, and 4j were found
most active candidates of the series against both anti-inflammatory and anticancer activity. The structure−activity relationship is
discussed and suggested that 3-substitution on the aryl ring at C4 position of the pyrano[3,2-c]quinolone structural motif seems
to be an important position for both TNF-α and IL-6 inhibition and anticancer activity as well. However, structural diversity with
electron withdrawing, electron donating, sterically hindered, and heteroaryl substitution sincerely affected both the inflammation
and anticancer activities.
KEYWORDS: Pyrano[3,2-c]quinoline, TNF-α, IL-6, anti-inflammatory, anticancer
hronic inflammation is associated with many types of
cancers, where most of solid tumors were shown inflam-
Additionally promising anticancer activity of structurally diverse
chromene scaffolds (Figure 2) were described in a number of
recent publications and patents.8−18 These agents exhibit high
potency against taxoland vinblastine-resistant P-glycoprotein
overexpressing cell types and inhibit tubulin polymerization and
induce apoptosis in cancer cells.11 Moreover, they interrupt
tumor vasculature in various human solid tumor xenografts and
currently they are in development as anticancer agents9,10
A series of pyrano[3,2-c]pyridine and related fused hetero-
cyclic scaffolds were patented for their promising activity against
apoptosis, antiproliferation, and vascular disruption in an animal
study19,20 With this background and on the basis of the pre-
established correlation between inflammation with cancer cell
C
matory indication. Immune cells play an important role in initi-
ation, growth and progression of tumors. A number of these
effects are regulated by proinflammatory cytokines like tumor
necrosis factor (TNF)-α and interleukin 6 (IL-6). As master
regulators of tumor-related inflammation and tumorigenesis,
TNF-α and IL-6 become attractive targets for adjuvant treatment
in cancer.1 In therapeutic context, quinoline analogues exhibit
diversified biological activities depending on the structure type.2
As a part of the number of natural products 2,4-dihydroxy quin-
olines are important compounds and also exhibit a variety of
interesting pharmacological properties.3 Alkaloids with pyrano-
[3,2-c]pyridone and pyrano[3,2-c]quinolone moieties reveal
broad spectrum of biological activities.4 Many of these alkaloids
(Figure 1) like fusaricide,5 melicobisquinolinone-B,6 zanthosi-
muline, and huajiaosimuline7 exhibit cytotoxicity against cancer
cells and referred as potential anticancer agents.
Received: December 28, 2017
Accepted: February 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.7b00545
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ACS Medicinal Chemistry Letters
Note
Figure 1. Pyrano[3,2-c]pyridine- and pyrano[3,2-c]quinolone-based anticancer alkaloids.
Figure 2. Chromenes investigated as anticancer agents.
Scheme 1. Reaction Scheme for Synthesis of 2-Amino-6-methyl-5-oxo-4-sub(aryl)-5,6-dihydro-4H-pyrano[3,2-c]quinoline-
3-carbonitrile (4a−v)
growth, we have set a hypothesis that whether the fusion of the
potent quinoline alkaloids with structurally diverse bioactive
chromene scaffolds can lead to the identification of the potent new
chemical entities, which can be targeted for both inflammatory and
cytotoxicity indications. Consequently, we have designed and syn-
thesized a series of pyrano[3,2-c]quinolone derivatives using multi-
component reaction. All candidates of this heterocyclic privilege
were screened for their anti-inflammatory and cytotoxicity activity.
The potential candidates of the series shown promising results
against TNF-α and IL-6 inhibition and anticancer activity.
Results and Discussion. Chemistry. The synthesis of the
2-amino-6-methyl-5-oxo-4-sub(aryl)-5,6-dihydro-4H-pyrano-
[3,2-c]quinoline-3-carbonitrile derivatives 4(a−v) is shown in
Scheme 1. 2,4-Dihydroxy-1-methylquinoline (1, Scheme 1) was
prepared by thermal cyclization between N-methyl aniline and
diethyl malonate as a literature procedure.21 In the next step, a
reaction mixture of an equal molar proportion of 2,4-dihydroxy-
1-methylquinolin (1, Scheme 1), aromatic aldehyde (2, Scheme 1),
malononitrile (3, Scheme 1), and catalytic amount of triethylamine
was refluxed in absolute ethyl alcohol to give the final product.
The proposed mechanism of reaction involves a base-catalyzed
Knoevenagel condensation between un(substituted) aromatic
aldehydes (2, Scheme 1) and malononitrile (3, Scheme 1)
resulting into cinnamic nitrile derivative in situ. The latter, on
reaction with 2,4-dihydroxy-1-methylquinolin (1, Scheme 1),
undergoes Michael addition followed by cyclization to end up
B
DOI: 10.1021/acsmedchemlett.7b00545
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Table 1. Anti-inflammatory and Antiproliferative Activity Data
anti-inflammatory activity
%cytotoxicity/antiproliferative activity
comp ID
subn. (Ar)
phenyl
% yield
87
conc
% TNF- α inh
% IL-6 inh
% tox
A-549
ACHN
MDA-MB-231
MIA-PACA-2
4a
1
10
1
0
0
0
66
0
0
13
0
34
73
12
81
71
52
19
44
21
36
74
71
0
61
82
48
82
81
68
45
69
49
68
79
83
9
0
61
0
45
41
26
69
63
38
21
63
35
51
65
70
15
64
16
45
61
70
66
72
16
17
17
29
55
83
34
31
24
21
80
84
40
50
40
66
27
68
18
77
76
75
4b
4c
4d
4e
4f
2-Cl phenyl
85
86
84
67
67
77
82
87
93
88
74
78
88
91
93
93
90
83
82
93
0
10
1
12
0
0
23
3
51
53
18
0
3-Cl phenyl
0
10
1
44
0
74
0
23
0
4-Cl phenyl
10
1
42
0
75
0
37
0
12
0
2-NO2 phenyl
3-NO2 phenyl
4-NO2 phenyl
4-F phenyl
10
1
36
11
43
0
78
0
6
18
53
65
0
17
30
4
10
1
79
0
4g
4h
4i
10
1
27
0
0
28
0
77
0
75
27
50
73
75
69
71
0
50
0
0
10
1
0
66
0
6
22
59
78
70
67
0
24
45
54
47
51
0
3-Br phenyl
2
8
10
1
38
18
34
0
82
0
24
16
28
9
4j
3-OC6H5 phenyl
4-SCH3 phenyl
3-OH phenyl
4-OH phenyl
4-N(CH3)2 phenyl
2-OCH3 phenyl
4-OCH3 phenyl
3,4-DiOCH3 phenyl
9-anthracyl
10
1
52
0
4k
4l
10
1
28
5
37
0
21
0
5
2
10
0
0
0
10
1
4
11
0
0
5
18
55
83
41
39
37
37
78
85
38
38
25
65
6
12
23
77
20
22
22
18
70
81
20
24
19
69
12
88
16
67
66
75
4m
4n
4o
4p
4q
4r
4s
4t
0
0
13
76
10
16
14
16
73
79
23
24
10
58
0
10
1
0
0
23
0
0
0
10
1
0
0
5
0
0
0
10
1
0
32
0
14
18
3
0
10
1
0
77
0
0
0
10
1
0
43
0
13
8
0
10
1
0
0
29
0
3-OC2O5, 4-OH phenyl
3-indolyl
0
0
10
1
0
0
67
6
78
8
81
27
71
67
73
0
0
10
1
0
0
7
69
70
69
4u
3-OCH3 phenyl
0
0
−6
23
10
0
33
a
Table 2. Anti-inflammatory and Anticancer Activity Data
anti-inflammatory activity (IC50, μM)
anticancer activity (IC50, μM)
comp ID
TNF-α
IL-6
toxicity
ACHN
Panc-1
HCT-116
H-460
Calu-1
4a
4c
4f
4.9
0.5
0.3
0.5
0.2
10
<0.03
0.2
0.25
0.08
0.2
4
>10
>10
>10
10
11
30
30
6.8
0
2.8
0.1
1.5
1.0
2.5
0.8
4.7
1.9
1.0
0.3
1.3
0.3
1.2
0.5
1.6
6.6
1.9
1.1
4i
0.9
0.9
0.8
0.8
4j
3.4
5.1
1.4
1.8
4m
4p
4t
1.8
0.6
1.2
1.1
12.8
11
1.7
1.4
58
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
7 HF (1 μM)
44
dexamethasone 1 μM
flavopiridol 700 nM
gemcitabine 500 nM
40
55
0
71
73
78
74
71
73
88
71
74
79
a
ACHN, renal cancer cell line; Panc1, pancreas cancer cell line; HCT-116, colon cancer cell line; H-460, nonsmall cell lung carcinoma cell line;
Calu-1, lung cancer cell line.
C
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Note
with the final product.22 The final product is precipitated directly
from the reaction mixtures, and further purification is not
required. However, the purity of the final product was confirmed
by thin layer chromatography.
The yield of the final products depends on the nature of
substituents present in hetero(aromatic) aldehyde, varying from
67 to 93% summarized in Table 1. The structures of the
pyrano[3,2-c]quinolone were characterized by 1H and 13C NMR,
IR, and mass spectral analysis.
significant antiproliferative activity against any of the used cell
lines. The rest of the structural diversity along with combination
of other substituents of the present series did not exert remark-
able activity against both inflammatory cytokine or antiprolifer-
ative inhibition. Based on these primary screenings, these com-
pounds were further evaluated for their ability to inhibit TNF-α
production in the human peripheral blood mononuclear cells
(hPBMC) assay.25 Compounds 4f and 4j (Figure 3) significantly
inhibited the production of TNF-α in a concentration-dependent
manner with IC50 value of 0.2 μM. Compound 4i inhibited the
Biology. Percent inhibition of cytokine release and percent
cytotoxicity results were summarized in Table 1, whereas 50%
inhibitory concentration (IC50) values were summarized in Table 2.
Dexomethasone was used as a reference standard for anti-
inflammatory assay;23 while flavopiridol and gemcitabine were
used as reference standards for cytotoxicity assay.24 The screening
results revealed that compound 4c with 3-chloro substituent was
found to be the most potent candidate of the series. It revealed
44 and 74% inhibition at 10 μM concentration as well as 0.5 and
0.2 μM IC50 value for TNF-α and IL-6 cytokine inhibition,
respectively, and not toxic at IC50 > 10 μM ; moreover, it showed
81 to 53% antiproliferative inhibition at 1 μM concentration with
IC50 value between 0.1 to 1.0 μM against all cancer cell lines.
3-Bromo (4i) analogue seems to be equally potent with 32 and
82% inhibition at 10 μM concentration as well as 0.5 and 0.08 μM
IC50 value for TNF-α and IL-6 cytokine inhibition, respectively,
but toxic at IC50 value 10 μM; whereas it exerted 75 to 54%
antiproliferative inhibition at 10 μM concentration with IC50
value between 0.8 to 0.9 μM against all cancer cell lines. 4-Fluoro
(4h) analogue seems to be poorly active against both inflam-
matory and proliferative inhibition. Besides this, insertion of
electronegative nitro group at 3-position of aryl ring linked on C4
of pyrano[3,2-c]quinolone skeleton influences potency against
both inflammatory cytokines and proliferative inhibition. As a
result, compound 4f exerted 43 and 79% inhibition at 10 μM
concentration as well as 0.3 and 0.25 μM IC50 value for TNF-α
and IL-6 inhibition, respectively, and not toxic at IC50 value >10 μM;
while it revealed 83 to 65% cytotoxicity at 10 μM concen-
tration with IC50 value between 1.1 to 6.6 μM against all cancer
cell lines. In contrast, electron-donating 3-methoxy analogue
was neither active against inflammatory cytokine nor against
proliferative inhibition. Beyond this insertion of sterically hin-
dered 3-phenoxy substitution at C4 position does not alter the
orientation of bioactive conformer of pyrano[3,2-c]quinolone.
Compound 4j showed 34% and 52% inhibition at 10 μM con-
centration as well as IC50 value of 0.2 μM for both TNF-α and IL-6
inhibition and toxicity at IC50 value 11 μM; whereas it exerts
72 to 51% antiproliferative inhibition at 10 μM concentration
along with IC50 value between 1.4 to 5.1 μM against all cancer cell
lines. Introduction of hetero aryl 3-indolyl ring (compound 4t)
imparts loss of potency for TNF-α inhibition with 11 μM but
sustain IL-6 inhibition along with 1.4 μM IC50 value; whereas it
showed 77 to 66% cytotoxicity at 10 μM concentration against all
cancer cell lines. However, unsubstituted phenyl ring at C4 posi-
tion of phenyl ring compound 4a exhibited moderate potency
with 66% inhibition at 10 μM concentration against IL-6 as well
as 4.9 and <0.03 μM IC50 value for TNF-α and IL-6 inhibition,
respectively, and not toxic at IC50 value >10 μM along with
82 to 41% cytotoxicity at 10 μM concentration with IC50 value
between 1.0 to 2.8 μM against all cancer cell lines. 4-Hydroxy
phenyl and 4-methoxy phenyl analogues with toxicity IC50 value
of 30 μM seem to be moderately active against TNF-α and IL-6
cytokine inhibition with 10 and 4 μM as well as 12.8 and 1.7 μM
IC50 values, respectively; while neither of the candidates exerted
Figure 3. Effect of 4c, 4f, 4i, and 4j on the production of TNF-α by
LPS-stimulated cells in hPBMCs in vitro assay.
D
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(3) Sharp, J. Antifungal methods employing certain carbostyrils. Patent
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production of TNF-α, albeit at higher concentrations with IC50
value of 0.5 μM. Compound 4c was the least active of the four
with an IC50 value of 1.8 μM; whereas compounds 4a, 4m, 4p,
and 4t were found not active in hPBMC assay. Of note, the IC50
values for TNF-a inhibition for all four compounds were far
lower than the IC50 values for cytotoxicity.
Conclusion. A new series of the pyrano[3,2-c]quinolonine
analogues was synthesized using multicomponent reaction and
evaluated for its anti-inflammatory and anticancer activity. The
screening results revealed that compounds 4c, 4f, 4i, and 4j were
found as most active candidates of the series against both anti-
inflammatory and anticancer activity. The structure−activity
relationship is discussed and suggested that 3-substitution on the
aryl ring at C4 position of the pyrano[3,2-c]quinolone structural
motif seems to be an important position for both TNF-α and
IL-6 inhibition and anticancer activity as well. However, struc-
tural diversity with electron withdrawing, electron donating,
sterically hindered, and heteroaryl substitution sincerely affected
both the inflammation and anticancer activities. The advance
research in the same line may identify a lead molecule, which can
be developed for the clinical trial for its therapeutic use.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acsmedchemlett.7b00545.
■
S
(11) Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Wang, Y.; Zhao, J.;
et al. Discovery of 4-aryl-4H-chromenes as a new series of apoptosis
inducers using a cell- and caspase-based high-throughput screening
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Chem. 2004, 47 (25), 6299−310.
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Grundy, C.; et al. Discovery of 4-aryl-4H-chromenes as a new series of
apoptosis inducers using a cell- and caspase-based high-throughput
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Experimental details of synthesis, anti-inflammatory and
cytotoxicity activity assay, and characterization data of all
the synthesized compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: drkuldip_upadhyay@rediffmail.com.
ORCID
Kuldip D. Upadhyay: 0000-0002-0416-1923
Author Contributions
The manuscript was written through contributions of all authors.
■
(13) Cai, S. X.; Jiang, S.; Kemnitzer, W. E.; Zhang, H.; Attardo, G.;
Denis, R. Substituted 4-aryl-4H-pyrrolo[2,3-h]chromenes and analogs
as activators of caspases and inducers of apoptosis and the use thereof.
Patent WO2003097806A2, 2003 Nov 27.
Notes
(14) Cai, S. X.; Jiang, S.; Attardo, G.; Denis, R.; Storer, R.; Rej, R. 4H-
Chromenes, 2H-chromenes substitues, chromans et analogues utilises
comme activateurs de caspases et inducteurs de l′apoptose, et utilisation
de ces composes. Patent WO2003096982A2, 2003 Nov 27.
(15) Cai, S. X.; Zhang, H.; Jiang, S.; Storer, R. Substituted 4H-
chromenes and analogs as activators of caspases and inducers of
apoptosis and the use thereof. Patent WO2002092594A1, 2002 Nov 21.
(16) Cai, S. X.; Xu, L.; Storer, R.; Attardo, G. 7,8-Fused 4H-chromene
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are sincerely thankful to Dr. Somesh Sharma,
Dr.(Mrs.) Asha Almeida, Dr. R. D. Gupta, Mrs. Sapna Parikh,
Ms. Kalpna Joshi, and Mr. Anagha Damre, Piramal Life Science,
Mumbai, for anti-inflammatory and anticancer activities. The
authors genuinely acknowledge financial support of the DST
(India) under National Facility for Drug Discovery (NFDD),
Saurashtra University, Rajkot for spectral and instrumental
analysis.
(17) Cai, S. X.; Zhang, H.; Kemmitzer, W. E.; Jiang, S.; Drewe, J. A.;
Storer, R. Substituted coumarins and quinolines as caspases activators.
Patent WO2002092076A1, 2002 Nov 21.
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analogues en tant qu’activateurs de caspases et qu’inducteurs d’apoptose
ainsi que leur utilisation. Patent WO2001034591A2, 2001 May 17.
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ABBREVIATIONS
TNF, tumor nacrosis factor-α; IL, interleukin; IC50, inhibitory
concentration at 50% level; TLC, thin layer chromatography
■
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