Synthesis and antitumor activities of some 2-oxo-quinoline-3-Schiff base derivatives

Article abstract of DOI:10.14233/ajchem.2014.17186

A series of 2-oxo-quinoline-3-Schiff-base derivatives (4a₁-4n₂) have been designed and synthesized as new antitumor agents. in vitro Antitumor activities were evaluated against four cancer cell lines including MGC80-3, BEL-7404, A549 and NCI-H460. Compounds 4a₁, 4a₂, 4c₂, 4d₁, 4d₂ and 4l₂ exhibited better inhibition activities than commercial antitumor drug 5-fluorouracil (5-fluorouracil, IC₅₀ = 44 ±0.54 μM) on NCI-H460, with IC₅₀ of 35.52 ± 0.86, 16.22 ± 0.71, 11.62 ± 0.52, 5.16 ± 0.37, 7.62 ± 0.46 and 7.66 ± 0.65 μM, respectively.

Full text of DOI:10.14233/ajchem.2014.17186

Asian Journal of Chemistry; Vol. 26, No. 21 (2014), 7449-7451
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.17186
Synthesis and Antitumor Activities of Some 2-Oxo-quinoline-3-Schiff Base Derivatives
1
2
2
3,*
YILIN FANG , XIANGHUI YI , WEN QIN , YE ZHANG2,* and YONGZHI LIAO
1College of Chemistry and Chemical Engineering, Hunan University, Hunan 410082, P.R. China
2Department of Chemistry, Guilin Normal College, Guangxi 541001, P.R. China
3Guangxi Academy of Fishery Sciences, Nanning 530021, P.R. China
*Corresponding authors: Fax: +86 77 32806321; Tel: +86 77 32823285; E-mail: zhangye81@126.com; liao0777@163.com
Received: 8 February 2014; Accepted: 5 May 2014; Published online: 30 September 2014;
AJC-16159
A series of 2-oxo-quinoline-3-Schiff-base derivatives (4a1-4n2) have been designed and synthesized as new antitumor agents. in vitro
Antitumor activities were evaluated against four cancer cell lines including MGC80-3, BEL-7404, A549 and NCI-H460. Compounds 4a1,
4a2, 4c2, 4d1, 4d2 and 4l2 exhibited better inhibition activities than commercial antitumor drug 5-fluorouracil (5-fluorouracil, IC50 = 44
0.54 µM) on NCI-H460, with IC50 of 35.52 0.86, 16.22 0.71, 11.62 0.52, 5.16 0.37, 7.62 0.46 and 7.66 0.65 µM, respectively.
Keywords: 2-Oxo-quinoline-3-Schiff-base derivatives, Synthesis, Antitumor activity.
INTRODUCTION
EXPERIMENTAL
Cancer is one of the primary causes of death globally, so
searching and screening for effective new anticancer drugs
have greatly attracted bioorganic chemists' interest. Anti-
oxidants are recently fabricated as the drug candidates to
counter multifarious diseases, such as carcinogenesis, infla-
mmation, atherogenesis and aging in aerobic organisms1,2.
Therefore, screening for new antitumor drug from antioxidants
has become an important research topic in bioinorganic
chemistry.
2-Oxo-quinoline-3-Schiff-base derivatives 4a1-4n2 were
synthesized as outlined in Scheme-I, accoding to the litera-
ture11. Quinoline carbaldehydes (2) were got throughVilsmeier-
Haack-Arnold reaction, which is subjected the condensation
of acetanilides (1) with N,N-dimethylformamide (DMF) in
the presence of phosphorus oxychloride. Compounds 3 were
then obtained in good yields by the hydrolytic reaction of
compound 2 in the presence of 70 % acetic acid aqueous
solution. Compounds 4n1-4n2 were then gained in good yields
by the condensation of compound 3 with different primarily
amines or hydraziniums in hot ethanol, respectively.
Quinoline and its derivatives displays extensively bio-
logical and pharmacological activities3-6 so a great deal of
efforts have been devoted to design and synthesize functional
quinoline derivatives with better medicinal virtue over the past
decades. 2-Oxo-quinoline is a kind of alkaloid and widely
exists in nature as same as quinoline. Researchers have long
explored natural products in the search for new antioxidants
and anticancer drugs, so those compounds with a 2-oxo-
quinoline structure core have been studied and it have been
found that they own preferable biological activities such as
antioxidation, anticancer, antiproliferation and antiinfla-
mmation7-10. In our previous work, some 2-oxo-quinoline-3-
schiff-base derivatives (4a1-4n2) (Scheme-I) have been
demonstrated to have good antioxidant. Since antioxidants
have been recently forged as the anticancer drug candidates,
so the aim of the present work is to evaluate the in vitro anti-
tumor activities of compounds 4a1-4n2, employing standard
MTT assay.
The in vitro antitumor activities of compound 4a1-4n2 were
evaluated by a MTT assay12,13 on four typical human cancer
cell lines (5-fluorouracil as the positive control), including
stomach cancer cell MGC80-3, liver cancer cell BEL-7404,
lung cancer cellA549 and lung cancer cell NCI-H460. Firstly,
the in vitro antitumor activity initial screening test was done
by the respective condensation of 20 µM of compounds 4a1-4n2
with these cancer cells, respectively.
RESULTS AND DISCUSSION
As shown in Table-1, compounds 4c2, 4g2-4i2, 4k2, 4l2,
4m1, 4n1 and 4n2 showed none inhibition on stomach cancer
cell MGC80-3, while other compounds displayed weak inhibi-
tion on this cancer cell. Of these compounds, compound 4a2
exhibited the best inhibition on stomach cancer cell MGC80-
3, with a mere inhibition rate 26.21 %. In the lung cancer cell

7450 Fang et al.
Asian J. Chem.
R1
R1
CHO
O
R1
R2
N
R1
CHO
(b)
O
(a)
(c)
N
H
N
Cl
N
H
N
H
O
1
2
3
4
1a: R1 = H
2a: R1 = H
3a: R1 = H
1b: R1 = CH3
2b: R1 = CH3
3b: R1 = CH3
R1
R2
R1
R2
R1
R2
4a1
4a2
H
OH
4f1
4f2
H
CH3
H
p-OH-C6H4
p-OH-C6H4
CH6H5NH
p-NH2SO2-C6H4
4j2
CH3
4k1
NH2
NH2
OH
CH3
H
H
C4H9
C4H9
CH2Ph
CH2Ph
CH3
H
4b1
4b2
4k2
4l1
4g1
4g2
4h1
4h2
CH3
H
CH6H5NH
p-COOH-C6H4
p-COOH-C6H4
CH3
p-NO2-C6H4NH
4l2
CH3
H
H
4c1
4c2
CH3
CH3
H
4m1
4m2
4-Pridine-acetimido
4-Pridine-acetimido
p-NO2-C6H4NH
H
o-NO2-p-NO2C6H3NH
o-NO2-p-NO2C6H3NH
p-NH2SO2-C6H4
CH2CH2OH
CH2CH2OH
o-OH-C6H4
o-OH-C6H4
4i1
4i2
CH3
H
4d1
4d2
4e1
4e1
CH3
H
CH3
H
4n1
4n2
Amino-sulfoacetimido
Amino-sulfoacetimido
CH3
4j1
4j2
CH3
CH3
p-NH2SO2-C6H4
Scheme-I: Synthetic route of 2-oxo-quinoline-3-carbaldehyde schiff-base derivatives. Reagents and conditions: (a) DMF/POCl3, 90 °C; (b) 70 % acetic acid
aqueous solution, 95 °C; (c) R2-NH2, ethanol, 80 °C
A549 assay, compounds 4b1, 4b2, 4c2 and 4e2-4i2 did not show
any inhibition on this lung cancer cell and compounds 4a1,
4a2, 4c1, 4d1-4e1 and 4j1-4n2 also exhibited low inhibition on
it. Compound 4e1 displayed the best inhibition effect in this
assay, with inhibition rate (19.97 %) of less than 20 %. For
liver cancer cell BEL-7404 assay, all the compounds except
4c1 and 4i1 exhibited inhibition on this kind of cancer cell.
Compound 4g2 showed the highest inhibition on liver cancer
cell BEL-7404, with a low inhibition rate of 24.51 %. In the
lung cancer cell NCI-H460 test, compounds 4e1-4f1, 4i1-4k2
and 4n1 showed none inhibition activities on this cancer cell,
while other compounds showed various inhibition rates in this
assay. It was worthy to note that six compounds 4a1, 4a2, 4c2,
4d1, 4d2 and 4l2 exhibited better inhibition on lung cancer cell
NCI-H460, with desirable inhibition rates of 45.64, 50.26,
67.54, 75.65, 71.65 and 72.50 %, respectively. Therefore, these
six compounds were selected to do the further in vitro antitumor
activity to test against lung cancer cell NCI-H460 and their IC50
values were thus determined (Table-2). IC50 of the classic anti-
tumor drug 5-fluorouracil was also determined for comparison.
As shown in Table-2, IC50 of 4a1, 4a2, 4c2, 4d1, 4d2, 4l2
and 5-fluorouracil in lung cancer cell NCI-H460 assay were
found to be 35.52 0.86, 16.22 0.71, 11.62 0.52, 5.16
0.37, 7.62 0.46, 7.66 0.65 and 44 0.54 µM, respectively.
Markedly, these six compounds exhibited better antitumor
activity than the commercial antitumor drug 5-fluorouracil. It
was important to note that compounds 4d1, 4d2 and 4l2 showed
excellent antitumor activity, with IC50 even lower than 10 µM.
Obviously, the antitumor activity decreased in the order 4d1,
4d2, 4l2, 4c2, 4a2, 4a1, 5-fluorouracil. The order indicated that
methyl group on quinoline skeleton and hydroxyl groups
TABLE-1
INHIBITION RATES (%) OF COMPOUNDS 4a1–4n2 ON THE
CANCER CELLS LINES. BOLD VALUES REPRESENT
TO POINT OUT THE ACTIVE COMPOUNDS
Entry
4a1
MGC80–3a
19.37
26.21
9.79
8.70
15.85
NA
A549b
15.99
11.27
NA
NCI–H460b
BEL–7404c
23.59
14.51
9.051
14.68
NA
45.64
50.26
11.93
20.52
23.61
67.54
75.65
71.65
NA
4a2
4b1
4b2
4c1
4c2
4d1
4d2
4e1
4e2
4f1
NA
10.51
NA
17.00
8.12
9.51
8.86
21.85
15.34
8.33
21.94
6.55
NA
3.52
11.04
19.97
NA
9.98
6.48
NA
5.94
NA
NA
10.74
12.33
15.05
24.51
7.35
NA
19.96
4.22
11.27
9.97
29.42
NA
4f2
NA
4g1
4g2
4h1
4h2
4i1
NA
NA
NA
NA
NA
12.28
NA
NA
NA
NA
NA
NA
5.82
4i2
3.62
4.54
5.53
NA
10.95
5.95
11.39
5.33
1.73
3.40
10.88
4.53
4.45
8.41
NA
3.51
4j1
NA
7.89
4j2
NA
11.18
12.34
12.46
23.27
8.53
4k1
4k2
4l1
NA
8.58
NA
22.02
72.50
9.49
12.37
NA
4l2
NA
4m1
4m2
4n1
4n2
12.25
NA
10.38
13.15
5.34
NA
11.28
NA: no active; a Stomach cancer cell; b Lung cancer cell; c Liver cancer
cell
TABLE-2
IC50(µM) VALUES OF COMPOUNDS 4a1, 4a2, 4c2,4d1, 4d2 AND 4l2 AGAINST NCI–H460 CELLS
Entry
5-Fluorouracil
44.0 0.54
4a1
4a2
4c2
4d1
4d2
4l2
NCI–H460
35.52 0.86
16.22 0.71
11.62 0.52
5.16 0.37
7.62 0.46
7.66 0. 65

Vol. 26, No. 21 (2014)
Synthesis and Antitumor Activities of Some 2-Oxo-quinoline-3-Schiff Base Derivatives 7451
3. K. Iwasa, M. Moriyasu,Y. Tachibana, H. Kim,Y. Wataya, W. Wiegrebe,
linked with salen group may have important effect on their
antitumor activities.
K.F. Bastow, L.M. Cosentino, M. Kozuka and K. Lee, Bioorg. Med.
Chem., 9, 2871 (2001).
In conclusion, on the base of above observation, it could
be concluded that screening for new antitumor drug from 2-
oxo-quinoline-3-Schiff-base derivatives 4a1-4n2 is feasible.
4. D.L. Minor, S.D. Wyrick, P.S. Charifson, V.J. Watts, D.E. Nichols and
R.B. Mailman, J. Med. Chem., 37, 4317 (1994).
5. R. Naito, Y. Yonetoku, Y. Okamoto, A. Toyoshima, K. Ikeda and M.
Takeuchi, J. Med. Chem., 48, 6597 (2005).
6. J. Chen, X. Chen, M. Bois-Choussy and J. Zhu, J. Am. Chem. Soc.,
128, 87 (2006).
ACKNOWLEDGEMENTS
7. J. DeRuiter,A.N. Brubaker, W.L. Whitmer and J.L. Stein, J. Med. Chem.,
29, 2024 (1986).
This study was supported by the Fund of Guangxi Key
Laboratory of Functional Phytochemicals Research and
Utilization (No. FPRU2011-6; FPRU2013-6), the State Key
Laboratory Cultivation Base for the Chemistry and Molecular
Engineering of Medicinal Resources, Ministry of Science and
Technology of China (CMEMR2014-B14), the Guangxi
Natural Science Foundation (No. 2014GXNSFBA118050) and
Guangxi Department of Education Research Project (No.
2013YB283; 2013YB284).
8. P. Hewawasam, W. Fan, J. Knipe, S.L. Moon, C.G. Boissard, V.K.
Gribkoff and J.E. Starrett Jr, Bioorg. Med. Chem. Lett., 12, 1779 (2002).
9. J. Rousell, E.B. Haddad, J.C. Mak, B.L. Webb, M.A. Giembycz and
P.J. Barnes, Mol. Pharmacol., 49, 629 (1996).
10. I.V. Ukrainets, V.O. Gorokhova, A.P. Benzuglyi and V.L. Sidorenko,
Farm. Zh., 1, 75 (2000).
11. Y. Zhang, B.Q. Zou, K. Wang, Y.M. Pan, H. Liang, X.H. Yi and H.S.
Wang, Med. Chem. Res., 21, 1341 (2012).
12. S. Rubino, S. Petruso, R. Pierattelli, G. Bruno, G.C. Stocco, L. Steardo,
M. Motta, M. Passerotto, E.D. Giudice and G. Gulì, J. Inorg. Biochem.,
98, 2071 (2004).
REFERENCES
13. M. Botta, S. Armaroli, D. Castagnolo, G. Fontana, P. Pera and E.
Bombardelli, Bioorg. Med. Chem. Lett., 17, 1579 (2007).
1. B.N. Ames, M.K. Shigenaga and T.M. Hagen, Proc. Natl. Acad. Sci.
USA, 90, 7915 (1993).
2. Y.K. Tyagi, A. Kumar, H.G. Raj, P. Vohra, G. Gupta, R. Kumari, P.
Kumar and R.K. Gupta, Eur. J. Med. Chem., 40, 413 (2005).