Synthesis and antiproliferative activity evaluation of imidazole-based indeno[1,2-b]quinoline-9,11-dione derivatives

Article abstract of DOI:10.1007/s12272-013-0032-7

A series of new imidazole substituted indeno[1,2-b]quinoline-9,11-dione derivatives were synthesized and evaluated for their antiproliferative effects on HeLa, LS180, MCF-7 and Jurkat human cancer cell lines. Antiproliferative effects were evaluated using MTT assay. Prepared compounds exhibited weak to good antiproliferative activity in evaluated cell lines. Prepared compounds were more potent in Jurkat cell line when compared to LS180, HeLa and MCF-7 cell lines. Compounds 29 (IC₁₆ = 0.7 μM) and 31 (IC₁₆ = 1.7 μM) and 33 (IC₁₆ = 1.7 μM) were found to be the most potent molecules on Jurkat cell lines. Moreover; it was found that some of the tested compounds bearing imidazole-2-yl moiety on the C₁₁-position of dihydropyridine ring exhibited superior antiproliferative activity in comparison to cis-platin especially in Jurkat cell line (compounds 29, 31, and 33). It seemed that the introduction of electron-withdrawing groups on the imidazole ring enhanced the antiproliferative potential of these compounds (compounds 27, 29 and 31). The results of this study proposed that some of the imidazole substituted indeno[1,2-b]quinoline-9,11-dione compounds may act as efficient anticancer agents in vitro, emphasizing their potential role as a source for rational design of potent antiproliferative agents.

Full text of DOI:10.1007/s12272-013-0032-7

Arch. Pharm. Res. (2013) 36:436–447
DOI 10.1007/s12272-013-0032-7
RESEARCH ARTICLE
Synthesis and antiproliferative activity evaluation
of imidazole-based indeno[1,2-b]quinoline-9,11-dione derivatives
•
Hasti Sarkarzadeh Ramin Miri Omidreza Firuzi
•
•
•
Mohsen Amini Nima Razzaghi-Asl
•
•
Najmeh Edraki Abbas Shafiee
Received: 9 October 2012 / Accepted: 7 February 2013 / Published online: 26 February 2013
Ó The Pharmaceutical Society of Korea 2013
Abstract A series of new imidazole substituted indeno
[1,2-b]quinoline-9,11-dione derivatives were synthesized
and evaluated for their antiproliferative effects on HeLa,
LS180, MCF-7 and Jurkat human cancer cell lines. Anti-
proliferative effects were evaluated using MTT assay.
Prepared compounds exhibited weak to good antiprolifer-
ative activity in evaluated cell lines. Prepared compounds
were more potent in Jurkat cell line when compared to
LS180, HeLa and MCF-7 cell lines. Compounds 29
emphasizing their potential role as a source for rational
design of potent antiproliferative agents.
Keywords Synthesis ꢀ Indeno[1,2-b]quinoline-9,
11-dione ꢀ Antiproliferative ꢀ MTT assay
Introduction
(IC16 = 0.7 lM) and 31 (IC16 = 1.7 lM) and 33 (IC16
=
Dihydropyridines (DHPs) are heterocyclic structures that
have found significant attention among researchers. Many
efforts on ruling synthetic routes for DHP scaffolds began
after the first successful synthesis of symmetric 1,4-DHP
derivative via one-pot cyclocondensation reaction of
ammonia with alkylacetoacetate and aldehyde more than a
century ago (Hantzsch 1882). Since then, a variety of
synthetic procedures have been elucidated for preparation
of symmetrical and unsymmetrical DHP derivatives
(Vanden Eynde and Mayence 2003; Saini et al. 2008;
Swarnalatha et al. 2011; Hugel 2009).
1.7 lM) were found to be the most potent molecules on
Jurkat cell lines. Moreover; it was found that some of the
tested compounds bearing imidazole-2-yl moiety on the
C11-position of dihydropyridine ring exhibited superior
antiproliferative activity in comparison to cis-platin espe-
cially in Jurkat cell line (compounds 29, 31, and 33). It
seemed that the introduction of electron-withdrawing
groups on the imidazole ring enhanced the antiproliferative
potential of these compounds (compounds 27, 29 and 31).
The results of this study proposed that some of the imid-
azole substituted indeno[1,2-b]quinoline-9,11-dione com-
pounds may act as efficient anticancer agents in vitro,
Besides synthetic feature, DHPs have been looked upon
as one of the most important medicinal scaffolds possess-
ing interesting biological properties such as anti-hyper-
tensive (Nekooeian et al. 2010; Shafiee et al. 2002),
calcium channel modulating (Miri et al. 2008; Davood
et al. 2006), antituberculosis (Shafii et al. 2008), anti-
coagulant (Kumar et al. 2011), antidyslipidemic (Kumar
et al. 2010), anti-oxidant (Kumar et al. 2010; Leon et al.
2008), and multidrug resistance reversal (MDR) (Tasaka
et al. 2001) activities.
H. Sarkarzadeh ꢀ M. Amini ꢀ N. Edraki ꢀ A. Shafiee (&)
Department of Medicinal Chemistry, Faculty of Pharmacy
and Pharmaceutical Sciences Research Center, Tehran
University of Medical Sciences, 14176 Tehran, Iran
e-mail: ashafiee@ams.ac.ir
In this regard, several reports indicating anti-tumor
activity of symmetric 3,5-dicarboxamide (Sirisha et al.
2010), 3,5-diketo (Engi et al. 2006; Bazargan et al. 2008),
3,5-dicarboxylate (Engi et al. 2006; Foroughinia et al.
2008) and 3,5-dicyano (Abbas et al. 2010) derivatives of
R. Miri (&) ꢀ O. Firuzi ꢀ N. Razzaghi-Asl ꢀ N. Edraki
Medicinal and Natural Products Chemistry Research Center,
Shiraz University of Medical Sciences, PO Box 3388-71345,
71345 Shiraz, Iran
e-mail: mirir@sums.ac.ir
123

New antiproliferative indeno[1,2-b]quinoline-9,11-diones
437
1,4-DHPs have been documented in the literature.
Dexniguldipine is a prototype of the unsymmetrical 1,
4-DHPs exhibiting therapeutic activity in neuroendocrine
hamster lung tumors (Hahn et al. 1997). Rigid polycyclic
scaffolds constituted around a DHP core for which 1,8-
acridinediones are representative ones have also been
reported to possess anti-tumor activity (Jamalian et al.
2011). One possible rationalization toward the observed
antiproliferative activity of rigid polycyclic compounds is
their planar polycyclic portion which enables them to
intercalate properly with DNA molecule (Miri et al. 2012;
Brana et al. 2001; Ryabokon et al. 2005).
potentiating the cytotoxic/antiproliferative action of anti-
cancer agents (Kiue et al. 1990).
In continuation to our work on novel fused and con-
densed 1,4-DHP structures (Miri et al. 2004, 2010), we
report here the synthesis and characterization of new
indeno[1,2-b]quinoline-9,11-dione derivatives. Further-
more all the prepared compounds were subjected to in vitro
antiproliferative assay on four different human cancer cell
lines.
Materials and methods
Some in vitro assays revealed that 3,5-diketo derivatives
of 1,4-DHPs could decrease DNA damage and motivate its
repair in Raji, HL60 and peripheral blood lymphocyte
cells. Jamalian and colleagues have demonstrated that
potential DNA-intercalating activity of 1,8-acridinones
could be achieved via incorporating imidazole moiety
bearing electron-withdrawing groups (Jamalian et al.
2011). Moreover there are some reports highlighting the
effect of DHPs on potentiation of anti-tumor activity of
general cytotoxic drugs (Fedeli et al. 1989). For instance,
structural conjugation of homocamptothecins with DHP
scaffold has proven to reinforce the inhibition of DNA
topoisomerase I (Zhu et al. 2011). Such enhanced activities
have also been reported for telupidine, a DHP derivative
that was superior to veapamil in enhancing the anti-tumoral
activities of anthracyclines and vinca alkaloids in vitro
(Tolomeo et al. 1994). It is worth noting here that MDR
reversing activity of 1,4-DHPs especially those containing
aromatic rings may be of significant importance in
Chemistry
Synthesis of desired Indeno[1,2-b]quinoline-9,11-diones was
achieved following steps depicted in Figs. 1 and 2.
Indeno[1,2-b]quinoline-9,11-dione derivatives 19–31 were
achieved by molecular condensation of equivalent amounts
of corresponding aldehydes (7–11), enamines (14–17) and
1,3-indandione (18). At the next stage, oxidative aromati-
zation of the compounds 19–31 by MnO2 afforded the cor-
responding aromatized indeno[1,2-b]quinoline-9,11-diones
(32–40). The yield and some physicochemical characteristics
of final products are summarized in Tables 1 and 2.
Melting points were determined with a Reichert–Jung
hot-stage microscope and were uncorrected. All the syn-
thesized compounds were characterized by mass spectros-
1
copy, IR and H NMR. IR spectra were recorded on a
Nicolet FT-IR Magna 550 spectrophotometer. 1H NMR
spectra were determined by a Bruker FT-500 MHz
Fig. 1 General structure and
synthetic procedure for
preparation of aldehydes used in
the synthesis of indeno[1,2-
b]quinoline-9,11-dione
123

438
H. Sarkarzadeh et al.
Fig. 2 General synthetic route
to indeno[1,2-b]quinoline-9,11-
diones
spectrometer in chloroform-d1 or DMSO-d6. All the
chemical shifts were reported as d values (ppm) against
tetramethylsilane as an internal standard. The MS spectra
were recorded using a Finnigan TSQ-70 spectrometer at
70 eV.
and methylamine hydrochloride in acetic acid/1-butanol at
room temperature (m.p. 203–205 °C, 55 % yield) (Fassihi
et al. 2004). (1-methyl-1H-imidazol-5-yl) methanol (3) was
obtained from hydrogenolysis of compound 2 via refluxing
in the presence of Raney nickel in the ethanol (m.p.
115–118 °C, 93 % yield) (Amini et al. 2002). (1-methyl-2-
(methylthio)-1H-imidazol-5-yl) methanol (4) was obtained
through deprotonation using sodium hydroxide solution,
and then stirring with methyl iodide in ethanol at room tem-
perature (m.p. 81–90 °C, 17 % yield) (Amini et al. 2002).
General procedure for the synthesis of imidazolyl
aldehydes, 7–11
1H-imidazole-2-carbaldehyde (11) was obtained from a
commercial source and all other required aldehydes were
prepared via oxidation of corresponding alcohols (7–10).
For this purpose, MnO2 (10 equiv.) was added to a stirred
solution of corresponding alcohols in chloroform (1 equiv.)
The mixture was refluxed overnight and then filtered. The
filterate was dried and recrystallized from methanol
to give corresponding aldehydes (70–80 % yields) (7–10)
(Javidnia et al. 2011).
General procedure for the synthesis of
3-aminocyclohex-2-enones, 14–17
3-Aminocyclohex-2-enones (14, 15) were prepared via
reaction of ammonium acetate or aniline with 1,3-cyclo-
hexanedione (12) in benzene using a dean-stark trap
apparatus [14: 44 % yield and m.p. 103–105 °C, MS: m/z
(%) 111 (M?, 62), 84 (100), 68 (21), 56 (40); 15: 27 %
yield and m.p. 170–173 °C, MS: m/z (%) 187 (M?, 41),
159 (92), 130 (100), 92 (28), 77 (26)].
(2-Mercapto-1-methyl-1H-imidazol-5-yl) methanol (2)
used for synthesis of 7 and 8, was obtained via stirring a
mixture of dihydroxyacetone (1), potassium thiocyanate
123

New antiproliferative indeno[1,2-b]quinoline-9,11-diones
439
Table 1 Chemical structures and physical properties of indeno[1,2-b]quinoline-9,11-dione derivatives
Ar
O
O
10
9
11
8
1
7
R
2
N 5
6
R
4
R'
3
19-31
Comp. No.
MW
376
Ar
O2N
R
R0
Mp (°C)
Yield (%)
16
19
H
H
282–285
N
N
20
21
331
386
H
H
H
H
280 (decomposition)
38
57
N
N
303–305
Cl
Cl
N
HN
22
23
393
453
H
H
Ph
Ph
244–248
241–245
46
63
N
HN
N
N
S
24
404
CH3
H
300–303
43
O2N
N
N
25
26
345
359
CH3
CH3
H
H
264–265
257–260
30
53
N
HN
N
N
123

440
H. Sarkarzadeh et al.
Table 1 continued
Comp. No.
MW
414
Ar
R
R0
H
Mp (°C)
Yield (%)
49
27
CH3
281–285
Cl
Cl
N
HN
28
29
405
480
CH3
H
H
257–260
309–312
87
67
N
N
S
CH3
O2N
N
N
30
31
421
490
CH3
CH3
Ph
Ph
251–255
255–257
56
69
N
HN
Cl
Cl
N
HN
10-(1-Methyl-5-nitro-1H-imidazol-2-yl)-7,8-dihydro-5H-
indeno[3,2-b]quinoline-9,11(6H,10H)-dione (19)
(C20H16N4O4)
3-Amino-5,5-dimethylcyclohex-2-enones (16, 17) were
prepared via reaction of ammonium acetate or aniline with
5,5-dimethyl-cyclohexanedione (13) through a solvent free
procedure in oil bath [16: 91 % yield and m.p. 161–163 °C,
MS: m/z (%) 139 (M?, 22), 83 (100), 55 (50); 17: 95 %
yield and m.p. 175–185 °C, MS: m/z (%) 215 (M?, 71),
197 (29), 156 (100), 130 (15)].
1H-NMR (CDCl3): d 2.01 (m, 2H, H7), 2.32 (m, 2H, H6),
2.73 (t, 2H, H8), 4.19 (s, 3H, N–CH3), 4.93 (s, 1H, H10),
7.27–7.61 (m, 4H, H1–4), 7.91 (s, 1H, H4-imidazole), 10.69
(brs, 1H, NH); MS: m/z (%) 376 (M?, 43), 359 (27), 329
(8), 275 (22), 250 (100), 194 (21), 164 (20), 69 (14), 55
(36); IR (KBr) m (cm-1): 3503, 2930, 2853, 1680, 1649,
1511, 1368. Anal. Calcd. for C20H16N4O4: C, 63.82; H,
4.28; N, 14.89; Found: C, 63.95; H, 4.11; N, 14.66.
General procedure for the synthesis
of indeno[1,2-b]quinoline-9,11-diones, 19–23
As it is illustrated in Fig. 2, all indeno[1,2-b]quinoline-
9,11-dione derivatives (19–23) were synthesized using the
modified Hantzsch classical condensation procedure. After
stirring mixture of aldehyde (1 equiv.), corresponding
enamine (1 equiv.) (14, 15) and 1,3-indanedione (18) in
ethanol for 24 h, the mixture was cooled in ambient tem-
perature, concentrated under reduced pressure and further
purified by column chromatography with the ethyl acetate/
petroleum ether as eluent to afford compounds 19–31 in
fair to good yields (16–87 %).
10-(1-Methyl-1H-imidazol-5-yl)-7,8-dihydro-5H-
indeno[1,2-b]quinoline-9,11(6H,10H)-dione (20)
(C20H17N3O2)
1H-NMR (CDCl3): d 1.97 (m, 2H, H7), 2.29 (t, 2H, H6),
2.71 (t, 2H, H8), 3.82 (s, 3H, N–CH3), 4.65 (s, 1H, H10),
6.45 (s, 1H, H4-imidazole), 7.33–7.58 (m, 5H, H1–4 and H2
imidazole), 10.54 (brs, 1H, NH); MS: m/z (%) 331 (M?,
123

New antiproliferative indeno[1,2-b]quinoline-9,11-diones
441
100), 274 (75), 250 (66), 194 (37), 166 (53), 139 (45), 102
(38), 83 (65), 55 (13); IR (KBr) m (cm-1): 3442, 3155,
3114, 2935, 1685, 1644, 1511, 1342. Anal. Calcd. for
C20H17N3O2: C, 72.49; H, 5.17; N, 12.68; Found: C, 72.23;
H, 5.38; N, 12.89.
Table 2 Chemical structures of the aromatized indeno[1,2-b]quino-
line-9,11-dione derivatives
Ar
O
O
10
9
11
8
1
7
R
2
N
6
10-(4,5-Dichloro-1H-imidazol-2-yl)-7,8-dihydro-5H-
indeno[1,2-b]quinoline-9,11(6H,10H)-dione (21)
(C19H13Cl2N3O2)
R
5
4
3
32-40
Comp.
No.
MW Ar
374
R
Mp (°C)
Yield
(%)
1H-NMR (CDCl3): d 1.96 (m, 2H, H7), 2.30 (t, 2H, H6),
2.70 (t, 2H, H8), 4.71 (s, 1H, H10), 7.29–7.59 (m, 4H, H1–4),
10.58 (brs, 1H, NH), 13.15 (brs, 1H, imidazole NH); MS:
m/z (%) 389 [(M?4)?, 6)], 387 [(M?2)?, 39)], 385 (M?,
60), 357 (16), 327 (100), 295 (17), 248 (64), 193 (38), 163
(66), 136 (45), 102 (53), 62 (88); IR (KBr) m (cm-1): 3447,
3140, 2919, 1685, 1614, 1501, 1363, 707. Anal. Calcd. for
C19H13Cl2N3O2: C, 59.08; H, 3.39; N, 10.88; Found: C,
59.32; H, 3.61; N, 10.58.
32
H
H
245–248
54
O2N
N
N
33
315
240–243
16
N
HN
34
35
329
384
H
H
251–254
272–276
62
56
10-(1H-imidazol-2-yl)-5-phenyl-7,8-dihydro-5H-
indeno[1,2-b]quinoline-9,11(6H,10H)-dione (22)
(C25H19N3O2)
N
N
1H-NMR (CDCl3): d 1.25 (m, 2H, H7), 2.15 (m, 2H, H6),
2.38 (t, 2H, H8), 5.01 (s, 1H, H10), 5.14 (2 s, 2H, H4 and
H5-imidazole), 6.98–7.59 (m, 4H, H1–4), 7.68–7.69 (m, 5H,
N-phenyl), 11.64 (brs, 1H, imidazole NH); MS: m/z (%)
393 (M?, 95), 336 (31), 325 (53), 315 (100), 287 (31), 240
(22), 190 (17), 152 (18), 91 (19), 76 (88); IR (KBr) m
(cm-1): 3063, 2884, 1680, 1634, 1393. Anal. Calcd. for
C25H19N3O2: C, 76.32; H, 4.87; N, 10.68; Found: C, 76.56;
H, 4.68; N, 10.39.
Cl
Cl
N
HN
36
37
402
343
CH3 221–225
70
46
O2N
N
N
CH3 271–275
10-(1-Methyl-2-(methylthio)-1H-imidazol-5-yl)-5-phenyl-
7,8-dihydro-5H-indeno[1,2-b]quinoline-9,11(6H,10H)-
dione (23) (C27H23N3O2S)
N
HN
38
39
357
412
CH3 211–215
45
56
1H-NMR (CDCl3): d 1.74 (m, 2H, H7), 1.96 (m, 2H, H6),
2.33 (m, 2H, H8), 2.50 (s, 3H, S-CH3), 3.98 (s, 3H, N-CH3),
4.94 (s, 1H, H10), 6.75–7.45 (m, 5H, N-phenyl), 7.58–7.65
(m, 4H, H1–4); MS: m/z (%) 453 (M?, 100), 407 (14), 376
(36), 325 (35), 271 (15), 198 (7), 77 (9); IR (KBr) m
(cm-1): 3058, 2919, 1685, 1634, 1363, 692, 758. Anal.
Calcd. for C27H23N3O2S: C, 71.50; H, 5.11; N, 9.26;
Found: C, 71.76; H, 5.34; N, 9.19.
N
N
CH3 [300
Cl
(decomposition)
Cl
N
HN
40
403
CH3 183–187
68
General procedure for the synthesis of indeno[1,2-
b]quinoline-9,11-diones, 24–31
N
N
As it is illustrated in Fig. 2, all indeno[1,2-b]quinoline-
S
9,11-dione derivatives (24–31) were synthesized using the
123

442
H. Sarkarzadeh et al.
10-(4,5-Dichloro-1H-imidazol-2-yl)-7,7-dimethyl-7,8-
dihydro-5H-indeno[1,2-b]quinoline-9,11(6H,10H)-dione
(27) (C21H17Cl2N3O2)
modified Hantzsch classical condensation procedure. A
mixture of aldehyde (1 equiv.), corresponding enamine
(1 equiv.) (16, 17) and 1,3-indanedione (18) was refluxed
in oil bath (120 °C) and termination of the reaction was
confirmed by TLC after 3–5 h. The obtained mixture was
cooled at room temperature and poured into cold water.
The precipitated solid was filtered and washed with water
and ethanol. After dryness, recrystallization from ethanol
produced the desired products 24–31 in fair to good yields.
1H-NMR (CDCl3): d 1.04 and 1.07 (2 s, 6H, gem-dime-
thyl), 2.13 and 2.25 (2d, 2H, J = 16 Hz, H6), 2.57 and 2.61
(2d, 2H, J = 17 Hz, H8), 4.70 (s, 1H, H10), 7.28–7.59 (m,
4H, H1–4), 10.53 (brs, 1H, NH-DHP), 13.09 (s, 1H, NH-
imidazole); MS: m/z (%) 417 [M?4)?, 1], 415{(M?2)?,
6], 414 (M?, 9), 329 (17), 278 (16), 227 (15), 167 (31), 137
(38), 108 (39), 83 (58), 60 (100); IR (KBr) m (cm-1): 3144,
3088, 3032, 2848, 1751, 1705, 1624, 1363, 758. Anal.
Calcd. for C21H17Cl2N3O2: C, 66.88; H, 4.14; N, 10.14;
Found: C, 66.98; H, 4.37; N, 10.41.
7,7-Dimethyl-10-(1-methyl-5-nitro-1H-imidazol-2-yl)-7,8-
dihydro-5H-indeno[1,2-b]quinoline-9,11(6H,10H)-dione
(24) (C22H20N4O4)
1H-NMR (CDCl3): d 1.04 and 1.08 (2 s, 6H, gem-dime-
thyl), 2.09 and 2.83 (2d, 2H, J = 16 H6), 2.55 and 2.66 (2d,
2H, J = 17 Hz, H8), 4.19 (s, 3H, N–CH3), 4.93 (s, 1H,
H10), 7.29–7.60 (m, 4H, H1-4), 7.91 (s, 1H, H4-imidazole),
10.64 (brs, 1H, NH); MS: m/z (%) 404 (M?, 64), 387 (79),
317 (22), 278 (100), 231 (14), 222 (30), 193 (36), 138 (13),
80 (15), 55 (29); IR (KBr) m (cm-1): 3442, 3150, 3026,
2925, 2838, 1685, 1650, 1516, 1378. Anal. Calcd. for
C22H20N4O4: C, 65.34; H, 4.98; N, 13.85; Found: C, 65.06;
H, 5.16; N, 13.57.
7,7-Dimethyl-10-(1-methyl-2-(methylthio)-1H-imidazol-5-
yl)-7,8-dihydro-5H-indeno[1,2-b]quinoline-9,11(6H,10H)-
dione (28) (C23H23N3O2S)
1H-NMR (CDCl3): d 1.01 and 1.03 (2 s, 6H, gem-dime-
thyl), 2.16 (2d, 2H, J = 16 Hz, H6), 2.49 (2d, 2H,
J = 17 Hz, H8), 3.29 (s, 3H, S–CH3), 3.76 (s, 3H, N–CH3),
4.59 (s, 1H, H10), 6.48 (s, 1H, C4-imidazole), 7.24–7.44
(m, 4H, H1–4), 10.46 (brs, 1H, NH); MS: m/z (%) 405 (M?,
100), 390 (55), 358 (29), 330 (14), 278 (10), 221 (11), 194
(13), 128 (14); IR (KBr) m (cm-1): 3447, 3147, 3036, 2949,
2852, 1681, 1641, 1508, 1361. Anal. Calcd. for
C23H23N3O2S: C, 68.12; H, 5.72; N, 10.36; Found: C,
67.86; H, 5.48; N, 10.08.
10-(1H-imidazol-2-yl)-7,7-dimethyl-7,8-dihydro-5H-
indeno[1,2-b]quinoline-9,11(6H,10H)-dione (25)
(C21H19N3O2)
1H-NMR (CDCl3): d 0.93 and 1.02 (2 s, 6H, gem-dime-
thyl), 1.94 and 2.15 (2d, 2H, J = 15.5 Hz, H6), 2.38 and
2.49 (2d, 2H, J = 17 Hz, H8), 4.83 (s, 1H, H10), 6.67 and
6.88 (2 s, 2H, H4 and H5-imidazole), 7.27–7.42 (m, 4H,
7,7-Dimethyl-10-(1-methyl-5-nitro-1H-imidazol-2-yl)-5-
phenyl-7,8-dihydro-5H-indeno[1,2-b]quinoline-
9,11(6H,10H)-dione (29) (C28H24N4O4)
H
1–4), 11.01 (brs, 1H, NH–DHP), 13.24 (s, 1H, NH-imid-
1H-NMR (CDCl3): d 1.00 and 1.02 (2 s, 6H, gem-dime-
thyl), 2.18 (2d, 2H, J = 16 Hz, H6), 2.24 (2d, 2H,
J = 17 Hz, H8), 4.42 (s, 3H, N-CH3), 5.11 (s, 1H, H10),
6.86–7.42 (m, 4H, H1-4), 7.61–7.67 (m, 5H, N-phenyl),
7.89 (s, 1H, H4-imidazole); MS: m/z (%) 480 (M?, 35),
464 (14), 434 (7), 354 (100), 298 (7), 270 (13); IR (KBr) m
(cm-1): 3119, 2960, 2873, 1685, 1650, 1531, 1368. Anal.
Calcd. for C28H24N4O4: C, 69.99; H, 5.03; N, 11.66;
Found: C, 69.74; H, 5.29; N, 11.87.
azole); MS: m/z (%) 345 (M?, 64), 315 (9), 277 (28), 261
(56), 219 (35), 164 (39), 101 (20), 82 (27), 69 (50), 55
(100); IR (KBr) m (cm-1): 3293, 3088, 2945, 1680, 1644,
1511, 1368. Anal. Calcd. for C21H19N3O2: C, 73.03; H,
5.54; N, 12.17; Found: C, 73.31; H, 5.21; N, 12.42.
7,7-Dimethyl-10-(1-methyl-1H-imidazol-5-yl)-7,8-dihydro-
5H-indeno[1,2-b]quinoline-9,11(6H,10H)-dione (26)
(C22H21N3O2)
1H-NMR (CDCl3): d 1.03 and 1.08 (2 s, 6H, gem-dimethyl),
2.11 and 2.26 (2d, 2H, J = 16 Hz, H6), 2.54 and 2.63 (2d, 2H,
J = 17 Hz, H8), 3.84 (s, 3H, N–CH3), 4.62 (s, 1H, H10), 6.43
(s, 1H, H4-imidazole), 7.25–7.46 (m, 4H, H1–4), 7.55 (s, 1H,
H2-imidazole), 10.49 (brs, 1H, NH); MS: m/z (%) 359 (M?,
100), 329 (72), 275 (28), 246 (43), 233 (20), 164 (7), 101 (20),
55 (9); IR (KBr) m (cm-1): 3513, 3263, 3160, 3052, 2960,
1680, 1639, 1506, 1358. Anal. Calcd. for C22H21N3O2: C,
73.52; H, 5.89; N, 11.64; Found: C, 73.27; H, 5.65; N, 11.36.
10-(1H-imidazol-2-yl)-7,7-dimethyl-5-phenyl-7,8-dihydro-
5H-indeno[1,2-b]quinoline-9,11(6H,10H)-dione (30)
(C27H23N3O2)
1H-NMR (CDCl3): d 0.99 and 1.02 (2 s, 6H, gem-dime-
thyl), 2.13 (2d, 2H, J = 16 Hz, H6), 2.34 (2d, 2H,
J = 17 Hz, H8), 5.30 (s, 1H, H10), 6.83–7.12 (m, 4H, H1–4),
7.36–7.38 (2 s, 2H, H4 and H5-imidazole), 7.56–7.66 (m,
5H, N-phenyl), 9.70 (s, 1H, NH-imidazole); MS: m/z (%)
123

New antiproliferative indeno[1,2-b]quinoline-9,11-diones
443
421 (M?, 100), 393 (13), 354 (21), 345 (84), 316 (14), 270
(22), 193 (35), 169 (20), 77 (27), 45 (42); IR (KBr) m
(cm-1): 3252, 3048, 2955, 1690, 1639, 1588, 1368. Anal.
Calcd. for C27H23N3O2: C, 76.94; H, 5.50; N, 9.97; Found:
C, 77.18; H, 5.76; N, 9.68.
55 (34); IR (KBr) m (cm-1): 3411, 3140, 3058, 2963, 1709,
1687, 1360. Anal. Calcd. for C19H13N3O2: C, 77.37; H,
4.16; N, 13.33; Found: C, 77.64; H, 4.39; N, 13.07.
10-(1-Methyl-1H-imidazol-5-yl)-7,8-dihydro-6H-
indeno[1,2-b]quinoline-9,11-dione (34) (C20H15N3O2)
10-(4,5-Dichloro-1H-imidazol-2-yl)-7,7-dimethyl-5-
phenyl-7,8-dihydro-5H-indeno[1,2-b]quinoline-
9,11(6H,10H)-dione (31) (C27H21Cl2N3O2)
1H-NMR (CDCl3): d 1.24 (m, 2H, H7), 2.13 (t, 2H, H6),
2.63 (t, 2H, H8), 3.25 (s, 3H, N–CH3), 6.78 (s, 1H,
H4-imidazole), 7.61–7.78 (m, 4H, H1–4), 7.95 (s, 1H,
H2-imidazole); MS: m/z (%) 329 (M?, 85), 312 (27), 272
(20), 245 (11), 190 (22), 123 (19), 111 (28), 96 (35), 81
(77), 69 (100); IR (KBr) m (cm-1): 2945, 1721, 1685, 1547.
Anal. Anal. Calcd. for C20H15N3O2: C, 72.94; H, 4.59; N,
12.76; Found: C, 73.16; H, 4.27; N, 12.46.
1H-NMR (CDCl3): d 1.02 (s, 6H, gem-dimethyl), 2.12 (2d,
2H, J = 20 Hz, H6), 2.33 (2d, 2H, J = 18 Hz, H8), 5.20 (s,
1H, H10), 6.84–7.39 (m, 4H, H1–4), 7.54–7.66 (m, 5H,
N-phenyl), 9.98 (s, 1H, NH-imidazole); MS: m/z (%) 493
[(M?4)?, 3], 491 [(M?2)?, 18], 489 (M?, 27), 472 (36),
412 (12), 355 (14), 338 (29), 293 (13), 241 (21), 136 (20),
104 (29), 78 (79), 46 (100); IR (KBr) m (cm-1): 3222,
3068, 2960, 1690, 1634, 1552, 1363, 768. Anal. Calcd. for
C27H21Cl2N3O2: C, 66.13; H, 4.32; N, 8.57; Found: C,
66.42; H, 4.58; N, 8.32.
10-(4,5-Dichloro-1H-imidazol-2-yl)-7,8-dihydro-6H-
indeno[1,2-b]quinoline-9,11-dione (35) (C19H11Cl2N3O2)
1H-NMR (CDCl3): d 1.24 (m, 2H, H7), 2.14 (t, 2H, H6),
2.65 (t, 2H, H8), 7.48–7.92 (m, 4H, H1–4), 13.40 (brs, 1H,
NH-imidazole); MS: m/z (%) 387 [(M?4)?, 5], 385
[(M?2)?, 28] 383 (M?, 42), 355 (100), 293 (14), 265 (15),
248 (64), 202 (13), 102 (53), 45 (14); IR (KBr) m (cm-1):
3221, 2955, 2919, 1716, 1685, 1557, 773. Anal. Calcd. for
C19H11Cl2N3O2: C, 59.39; H. 2.89; N, 10.94; Found: C,
59.12; H, 3.07; N, 11.12.
General procedure for the synthesis of aromatized
indeno[1,2-b]quinoline-9,11-diones, 32–40
As it is illustrated in Fig. 2, all aromatized indeno[1,2-
b]quinoline-9,11-diones derivatives (32–40) were synthe-
sized via oxidation of indeno[1,2-b]quinoline-9,11-dione
substrates (compounds 19–31). For this purpose, 1 equiv.
of substrates was stirred with 5–10 equiv. of MnO2 in
dichloromethane at room temperature. The termination of
the reaction was monitored by TLC (5–30 min) and the
obtained product was filtered, washed with solvent and
dried to obtain the desired aromatized compounds in
moderate to good yields (16–70 %).
7,7-Dimethyl-10-(1-methyl-5-nitro-1H-imidazol-2-yl)-7,8-
dihydro-6H-indeno[1,2-b]quinoline-9,11-dione (36)
(C22H18N4O4)
1H-NMR (CDCl3): d 1.13 and 1.22 (2 s, 6H, gem-dime-
thyl), 1.55 (s, 2H, H6), 2.56 (s, 2H, H8), 3.71 (s, 3H,
N–CH3), 7.49–7.90 (m, 4H, H1–4), 8.15 (s, 1H, H4-imid-
azole); MS: m/z (%) 402 (M?, 57), 316 (100), 245 (28),
217 (21), 191 (13), 54 (20); IR (KBr) m (cm-1): 2960,
2863, 1731, 1690, 1562, 1368. Anal. Calcd. for C22H18
N4O4: C, 65.66; H, 4.51; N, 13.92; Found: C, 65.88; H,
4.73; N, 13.69.
10-(1-Methyl-5-nitro-1H-imidazol-2-yl)-7,8-dihydro-6H-
indeno[1,2-b]quinoline-9,11-dione (32) (C20H14N4O4)
1H-NMR (CDCl3): d 1.26 (m, 2H, H7), 2.49 (t, 2H, H6),
2.69 (t, 2H, H8), 3.72 (s, 3H, N–CH3), 7.63–7.89 (m, 4H,
H
1–4), 8.12 (s, 1H, H4-imidazole); MS: m/z (%) 374 (M?,
29), 372 (86), 328 (27), 285 (100), 203 (28), 162 (36), 148
(14), 53 (21); IR (KBr) m (cm-1): 3421, 3135, 1716, 1690,
1552, 1378. Anal. Calcd. for C20H14N4O4: C, 64.17;
H, 3.77; N, 14.97; Found: C, 64.02; H, 3.98; N, 14.68.
10-(1H-imidazol-2-yl)-7,7-dimethyl-7,8-dihydro-6H-
indeno[1,2-b]quinoline-9,11-dione (37) (C21H17N3O2)
1H-NMR (CDCl3): d 1.19 and 1.57 (2 s, 6H, gem-dime-
thyl), 2.79 (s, 2H, H8), 3.10 (s, 2H, H8), 7.89–7.91 (2 s, 2H,
H4 and H5-imidazole), 7.49–7.75 (m, 4H, H1–4), 12.25 (s,
1H, imidazole NH); MS: m/z (%) 343 (M?, 93), 318 (82),
288 (100), 230 (14), 178 (6), 84 (8); IR (KBr) m (cm-1):
3411, 3150, 3053, 2950, 1716, 1685, 1557, 1368. Anal.
Calcd. for C21H17N3O2: C, 73.45, H, 4.99, N, 12.24;
Found: C, 73.19; H, 5.24; N, 12.51.
10-(1H-imidazol-2-yl)-7,8-dihydro-6H-indeno[1,2-
b]quinoline-9,11-dione (33) (C19H13N3O2)
1H-NMR (CDCl3): d 1.24 (m, 2H, H7), 2.12 (t, 2H, H6), 2.63
(t, 2H, H8), 7.63–7.78 (m, 4H, H1–4), 7.93–7.95 (2 s, 2H, H4
and H5-imidazole), 12.20 (brs, 1H, NH-imidazole); MS: m/z
(%) 315 (M?, 50), 287 (100), 230 (29), 163 (28), 101 (36),
123

444
H. Sarkarzadeh et al.
7,7-Dimethyl-10-(1-methyl-1H-imidazol-5-yl)-7,8-dihydro-
6H-indeno[1,2-b]quinoline-9,11-dione (38) (C22H19N3O2)
Cell lines
HeLa (human cervical adenocarcinoma), LS180 (human
colon adenocarcinoma), MCF-7 (human breast adenocar-
cinoma) and Jurkat (human T cell leukemia) cells were
obtained from the National Cell Bank of Iran, Pasteur
Institute, Tehran, Iran. All cell lines were maintained in
RPMI 1640 supplemented with 10 % FBS, and 100 U/ml
penicillin-G and 100 lg/ml streptomycin. Cells were
grown in monolayer cultures, except for Jurkat cells, which
were grown in suspension, at 37 °C in humidified air
containing 5 % CO2.
1H-NMR (CDCl3): d 1.14 and 1.20 (2 s, 6H, gem-dimethyl),
2.49 (s, 2H, H6), 2.60 (s, 2H, H8), 3.41 (s, 3H, N–CH3), 6.91
(s, 1H, H4-imidazole), 7.51–7.71 (m, 4H, H1–4), 7.96 (s, 1H,
H2-imidazole); MS: m/z (%) 357 (M?, 100), 342 (7), 302
(8), 273 (5); IR (KBr) m (cm-1): 3063, 2945, 2868, 1721,
1680, 1547. Anal. Calcd. for C22H19N3O2: C, 73.93; H,
5.36; N, 11.76; Found: C, 74.17; H, 5.62; N, 11.48.
10-(4,5-Dichloro-1H-imidazol-2-yl)-7,7-dimethyl-7,8-
dihydro-6H-indeno[1,2-b]quinoline-9,11-dione (39)
(C21H15Cl2N3O2)
Antiproliferative effect
1H-NMR (CDCl3): d 1.18 and 1.25 (2 s, 6H, gem-dime-
thyl), 2.77 (s, 2H H8), 3.09 (s, 2H, H8), 7.51–7.90 (m, 4H,
Cell viability following exposure to synthetic compounds
was estimated by using the MTT reduction assay (Miri
et al. 2004; Javidnia et al. 2005; Jabbar et al. 1989). MCF-
7 and Jurkat cells were plated in 96-well microplates at a
density of 5 9 104 cells/ml (100 ll per well). LS180 and
HeLa cells were plated at densities of 1 9 105 and
2.5 9 104 cells/ml, respectively. Control wells contained
no drugs and blank wells contained only growth medium
for background correction. After overnight incubation at
37 °C, half of the growth medium was removed and 50 ll
of medium supplemented with four different concentra-
tions of synthetic compounds were added. All compounds
were tested at the final concentration range of 1–100 lM
except for compounds 19, 20 and 29 which were tested at
1–25 lM and compounds 22, 24 and 25, which were
tested in the range of 1–50 lM, due to lower solubility in
DMSO. Plates with Jurkat cells were centrifuged before
this procedure. Compounds were all first dissolved in
DMSO and then diluted in medium so that the maximum
concentration of DMSO in the wells was 0.5 %. Cells
were further incubated for 72 h, except for HeLa cells,
which were incubated for 96 h. At the end of the incu-
bation time, the medium was removed and MTT was
added to each well at a final concentration of 0.5 mg/ml
and plates were incubated for another 4 h at 37 °C. Then
formazan crystals were solubilized in 200 ll DMSO. The
optical density was measured at 570 nm with background
correction at 655 nm using a Bio-Rad microplate reader
(Model 680). The percentage of inhibition of viability
compared to control wells was calculated for each con-
centration of the compound and IC16 and IC50 values
(Tallarida and Murray 1987) were calculated with the
software CurveExpert version 1.34 for Windows. The
absorbance of wells containing no cells was subtracted
from sample well absorbances before calculating the
percentage of inhibition. Each experiment was repeated
four times.
H
1–4), 12.67 (s, 1H, NH–imidazole); MS: m/z (%) 415
[(M?4)?, 11], 413 [(M?2)?, 66], 4121 (M?, 100), 354
(85), 292 (21), 264 (29), 202 (21), 176 (14), 83 (13), 56
(49); IR (KBr) m (cm-1): 3220, 2945, 2919, 1721, 1685,
1557, 764. Anal. Calcd. for C21H15Cl2N3O2: C, 61.18; H,
3.67; N, 10.19; Found: C, 61.43; H, 3.89; N, 10.32.
7,7-Dimethyl-10-(1-methyl-2-(methylthio)-1H-imidazol-5-
yl)-7,8-dihydro-6H-indeno[1,2-b]quinoline-9,11-dione
(40) (C23H21N3O2S)
1H-NMR (CDCl3): d 1.15 and 1.19 (2 s, 6H, gem-dime-
thyl), 2.57 (s, 2H, H6), 2.68 (s, 2H, H8), 3.21 (s, 3H,
S–CH3), 3.31 (s, 3H, N–CH3), 6.99 (s, 1H, H4-imidazole),
7.55–7.95 (m, 4H, H1–4); MS: m/z (%) 403 (M?, 100), 370
(85), 343 (21), 286 (14), 245 (12), 219 (7), 165 (7), 57 (6);
IR (KBr) m (cm-1): 2950, 1716, 1670, 1552. Calcd. for
C23H21N3O2S: C, 68.46; H, 5.25; N, 10.41; Found: C,
68.57; H, 5.01; N, 10.17.
Biological activity
Reagents and chemicals
RPMI 1640, fetal bovine serum (FBS), trypsin and phos-
phate buffered saline were purchased from Biosera
(Ringmer, UK). 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphe-
nyltetrazolium bromide (MTT) was obtained from Sigma
(Saint Louis, MO, USA) and penicillin/streptomycin was
purchased from Invitrogen (San Diego, CA, USA). Doxo-
rubicin, cis-platin and dimethyl sulphoxide were obtained
from EBEWE Pharma (Unterach, Austria) and Merck
(Darmstadt, Germany), respectively.
123

New antiproliferative indeno[1,2-b]quinoline-9,11-diones
Results and discussion
445
Considering the data in Table 3, following rationales
may be developed:
Chemistry
1. Indeno[1,2-b]quinoline-9,11-diones derivatives exhibited
higher potency in Jurkat cancer cell lines compared to
LS180, HeLa and MCF-7 cell lines.
The structures of all synthesized indeno[1,2-b]quinoline-
9,11-diones were confirmed by spectroscopic and elemen-
tal analysis. The physical properties of synthesized
compounds are summarized in Tables 1 and 2.
2. Indeno[1,2-b]quinoline-9,11-dione derivatives were
more potent in HeLa cell lines than LS180 cell lines.
3. Aromatization of the central ring in indeno[1,2-b]quin-
oline-9,11-diones resulted in reduced antiproliferative
potential of compounds in LS180 and HeLa cell lines.
4. Although all synthesized indeno[1,2-b]quinoline-9,
11-dione compounds possessed lower antiproliferative
activity than Doxorubicin, but some compounds
showed superior activity to cis-platin (compounds 29,
31, and 33 in Jurkat cell lines, 27 in LS180 cell line)
(Table 3).
Antiproliferative activity
Prepared indeno[1,2-b]quinoline-9,11-dione derivatives
were assayed for their antiproliferative activity in four
human cancer cell lines (HeLa, LS180, MCF-7 and Jurkat)
in terms of their IC16 and IC50 values (Table 3). In HeLa
cell line, the most potent compound was 29 (IC16
=
9.2 lM). The order of decreasing activity in LS180 cell
line was found to be 27 [ 21 (IC16 values). This order was
22 [ 39 [ 31 for assayed compounds in MCF-7 cell line
(IC16 values). In Jurkat cell lines the most potent com-
pound in terms of its IC16 value was 29 followed by 31 and
33.
5. All of the compounds that exhibited superior antipro-
liferative activity to cis-platin in Jurkat cell lines,
included imidazol-2-yl substituent on their DHP ring.
This emphasizes the importance of this substitution on
antiproliferative potential of indeno[1,2-b]quinoline-
9,11-dione derivatives in Jurkat cell lines.
Table 3 Antiproliferative activity of indeno[1,2-b]quinoline-9,11-dione compounds assessed by the MTT reduction assay
Comp. No.
HeLa cells
LS180 cells
MCF-7 cells
Jurkat cells
IC16 (lM)
IC50 (lM)
IC16 (lM)
IC50 (lM)
IC16 (lM)
IC50 (lM)
IC16 (lM)
IC50 (lM)
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
[25
[25
[25
[25
[25
[25
[25
[25
[25
[25
15.7 2.5
6.5 0.5
41.8 12.1
[100
[25
[25
[25
2.5 1.6
10.8 1.6
2.3 0.7
5.7 1.0
[50
[25
15.2 2.9
[50
[100
[50
66.7 19.1
[50
17.2 5.4
4.4 0.9
[100
[100
[50
[100
[50
[100
[100
[50
[100
[50
[100
[50
[100
[50
14.6 2.9
[50
[50
[50
14.3 2.5
15.7 2.2
12.0 2.1
[100
[50
[50
[50
[50
5.6 2.1
2.1 0.2
6.1 2.5
9.9 5.4
0.7 0.1
2.3 1.5
1.7 0.8
33.0 1.5
1.7 1.1
13.4 11.1
3.4 0.8
[100
[50
[100
[100
[100
[25
[100
[100
23.5 2.4
[100
[25
21.4 4.8
[100
[100
[100
[100
[25
41.7 0.6
61.0 10.6
[100
2.8 0.5
[100
[100
9.2 1.1
11.4 2.9
10.7 2.7
[100
12.5 3.5
[100
[25
[25
[100
59.0 17.0
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
21.4 4.5
13.6 2.4
[100
[100
77.1 8.3
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
19.4 1.3
[100
95.8 42.8
[100
[100
[100
[100
70.9 24.6
[100
[100
[100
[100
25.4 5.7
91.4 82.5
40.3 5.3
11.3 2.0
[100
[100
[100
51.5 18.5
[100
[100
46.2 26.6
34.3 27.7
[100
[100
24.7 16.0
15.6 8.6
13.4 8.0
14.7 1.1
[100
[100
[100
37.4 8.1
[100
11.0 1.3
[100
[100
[100
[100
Doxorubicin 0.042 0.007 0.281 0.039 0.012 0.003 0.118 0.012 0.015 0.003 0.326 0.095 0.025 0.004 0.192 0.049
Cisplatin
5.6 1.5
16.3 2.3
5.0 1.5
43.3 9.2
4.0 1.1
82.7 24.8
1.9 0.6
11.4 3.2
123

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6. It seems that introduction of the phenyl moiety on the
nitrogen atom of the central ring may enhance antipro-
liferative effect of compounds in most cases (22:
IC16 = 4.4 lM, MCF-7 cell line and IC16 = 2.3 lM,
Jurkat cell line; 23: IC16 = 5.7 lM, Jurkat cell line; 29:
IC16 = 0.7 lM, Jurkat cell line and IC16 = 9.2 lM,
HeLa cell line; 30: IC16 = 2.3 lM, Jurkat cell line; 31:
1.7 lM, Jurkat cell line and IC16 = 19.4 lM, LS180
cell line). This finding is in agreement with previous
reported results.
7. The introduction of electron-withdrawing groups such
as nitro or chlorine on imidazole moiety positioned at
central part of the indeno[1,2-b]quinoline-9,11-dione
scaffolds, played an important role in antiproliferative
potency of these compounds (27, 29 and 31, this effect
was less pronounced for MCF-7 cell lines). For
example, in Jurkat cell line, compounds bearing nitro
(29) or two chlorine (31) substituents showed superior
activity over their analogues bearing no electronega-
tive groups (Table 3). However; this finding confirmed
our previous results (Miri et al. 2011).
Synthesized indeno[1,2-b]quinoline-9,11-diones were
found to possess weak to relatively good antiproliferative
activities in HeLa, LS180, MCF-7 and Jurkat human cancer
cell lines. Some of the compounds exhibited superior
antiproliferative activity to cis-platin especially in Jurkat
cell lines. The results of the present study may be appropriate
for further rational design of more potent anti-tumor agents
based on the indeno[1,2-b]quinoline-9,11-dione scaffold.
However considering the flattened structure of these com-
pounds, one possible antiproliferative mechanism may be
the DNA intercalation.
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Acknowledgments This work was financially supported by
research council of Shiraz University of Medical Sciences and Tehran
University of Medical Sciences.
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