Synthesis, NMR spectra and X-ray data of chloro and dichloro derivatives of 3-hydroxy-2-phenylquinolin-4(1H)-ones and their cytostatic activity

Article abstract of DOI:10.1002/jhet.5570410311

As known, some derivatives of quinolin-4(1H)-one possess interesting biological properties. The biological and cytostactic activity of 2-substituted 3-hydroxyquinolin-4(1H)-ones has not been reported yet. In this paper the synthesis of a series of chloro and dichloro 2-phenyl-3-hydroxyquinolin-4(1H)- ones and their characterization by NMR spectra and X-ray data is described. Their cytostatic properties have been evaluated and the results are reported.

Full text of DOI:10.1002/jhet.5570410311

May-Jun 2004
375
Synthesis, NMR Spectra and X-ray Data of Chloro and Dichloro
Derivatives of 3-Hydroxy-2-phenylquinolin-4(1H)-ones and their
Cytostatic Activity
Pavel Hradil*,a, Petr Krejcˇía, Jan Hlavácˇa, Iveta Wiedermannováa,
Antonín Lycˇkab, and Valerio Bertolasic
a
Department of Organic Chemistry, Palacky University, Trˇ. Svobody 8, 771 46 Olomouc, Czech Republic,
Fax:++420-68-5634405, E-mail: ph.1@tiscali.cz
b
Research Institute for Organic Syntheses, Pardubice, 532 18 Czech Republic; Antonin.Lycka@vuosas.cz
c
Università di Ferrara, Dipartimento di Chimica, Via L. Borsari, 46, 44100 Ferrara,
Italy; m38@dns.unife.it
Received November 10, 2003
As known, some derivatives of quinolin-4(1H)-one possess interesting biological properties. The biologi-
cal and cytostactic activity of 2-substituted 3-hydroxyquinolin-4(1H)-ones has not been reported yet. In
this paper the synthesis of a series of chloro and dichloro 2-phenyl-3-hydroxyquinolin-4(1H)-ones and their
characterization by NMR spectra and X-ray data is described. Their cytostatic properties have been evalu-
ated and the results are reported.
J. Heterocyclic Chem., 41, 375 (2004).
2-Phenyl-3-hydroxyquinolin-4(1H)-ones are a group of
phoric acid, the titled quinolones 1c-10c were received
(Scheme 1, Table 1 and 2).
compounds isosteric with natural flavonoids - natural com-
pounds exhibiting cytostatic and antileukemic properties.
Biological activity of flavonoids is intensively studied, on
the other hand, biological activity of substituted 3-hydrox-
yquinolin-4(1H)-ones has not been described yet. As a
part of our work at this theme we have synthesized series
of dichloro and monochloroderivatives. Their structures
and their cytostacic activity were studied.
Table 1
Characteristic Data of Chloro and Dichloro Derivatives of
Phenacyl Anthranilates 1-10b
Compound
M.P. °C
Yield. %
Formula
M.W.
Calculated /Found
%C
%H
%N
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
84-86
52
157-160
82
135-140
70
146-148
81
127
82
124-126
83
118-121
85
195-198
91
191-192
86
139-140
66
C
H
ClNO
ClNO
ClNO
ClNO
62.18 4.17
61.93 3.86
62.18 4.17
62.85 4.20
62.18 4.17
62.39 3.84
62.18 4.17
61.87 4.02
55.57 3.42
55.25 3.06
55.57 3.42
55.55 3.69
55.57 3.42
55.54 3.56
55.57 3.42
55.54 3.56
55.57 3.42
55.67 3.03
55.57 3.42
55.61 2.99
4.83
4.79
4.83
4.52
4.83
4.74
4.83
4.82
4.32
4.24
4.32
4.43
4.32
4.44
4.32
4.44
4.32
4.18
4.32
4.24
Chloro and dichloro derivatives of 3-hydroxy-2-phenyl-
quinolin-4(1H)-ones were synthesized from commercially
available chloro and dichloro anthranilic acids 1a-10a,
according to methods of preparation and cyclization of
phenacyl anthranilates previously described [1,2]. These
acids were treated with phenacyl bromide to give phenacyl
anthranilates 1b-10b. After their cyclization in polyphos-
15 12
3
3
3
3
289.73
C H
15 12
289.73
C H
15 12
289.73
C H
15 12
289.73
C H Cl NO
15 11 2
3
3
3
3
3
3
324.18
C H Cl NO
15 11 2
324.18
C H Cl NO
15 11 2
324.18
C H Cl NO
15 11 2
324.18
C
H
Cl NO
15 11
2
324.18
C
H
Cl NO
15 11
2
324.18
Structures of the compounds were confirmed by NMR.
1
The H and 13C chemical shifts were assigned using gs
(gradient selected)-H, H-COSY, gs-HSQC (optimised for
1J(13C,H) ca 145 Hz) gs-HMBC [3] (optimised for
3J(13C,H) ca 5 - 10 Hz). H,H-COSY provided proton-pro-
ton connectivity. A correlation of proton H(6) with carbon
of C(7)OO group in HMBC spectra was key information
for the assignment of proton and carbon resonances in
compounds 1b – 10b and, similarly, a correlation of proton
H(5) with carbon of C(4)=O group in HMBC spectra was

376
P. Hradil, P. Krejcˇí, J. Hlavácˇ, I. Wiedermannová, A. Lycˇka, V. Bertolasi
Vol. 41
Table 2
Characteristic Data of Chloro and Dichloro Derivatives of 3-Hydroxy-2-
phenylquinolin-4(1H)-ones 1-10c
Compound
M.P. °C
Yield. %
Formula
M.W.
Calculated /Found
%C
%H
%N
1c
2c
308-312.5
82
300-303
53
>350
95
272-274
65
314-319
45
297-300
47
171-174
45
342-346
93
C
C
C
C
C
C
C
C
C
C
H
271.71
ClNO
66.30 3.71
66.51 3.85
66.30 3.71
66.65 4.01
66.30 3.71
66.22 3.76
66.30 3.71
65.98 4.13
58.84 2.96
58.53 2.64
58.84 2.96
58.80 2.63
58.84 2.96
58.51 3.17
58.84 2.96
58.74 2.56
58.84 2.96
58.64 3.28
58.84 2.96
59.30 2.31
5.15
5.31
5.15
5.32
5.15
5.18
5.15
4.87
4.57
4.55
4.57
4.36
4.57
4.70
4.57
4.25
4.57
4.62
4.57
4.55
15 10
2
2
2
2
2
2
2
2
2
2
H
ClNO
15 10
271.71
3c
H
ClNO
15 10
271.71
4c
H
ClNO
15 10
271.71
H Cl NO
306.16
H Cl NO
306.16
H Cl NO
306.16
H Cl NO
306.16
H Cl NO
306.16
H Cl NO
5c
15
15
15
15
15
15
9
2
6c
9
2
7c
9
2
8c
9
2
9c
212-215
90
262-4
65
9
2
Figure 1b. Chain of hydrogen-bonded molecules in crystal packing of
compound 1c.
10c
9
2
306.16
key information for the assignment of proton and carbon
resonances in compounds 1c – 10c (Table 4, 5, 6 and 7 in
the experimental part).
Derivatives 1c, 7c and 9c were isolated in the form of
monocrystal and their structure was confirmed by X-ray
diffraction. It is the definitive confirmation of 2-phenyl-3-
hydroxy-4(1 H)-quinoline as a product of anomalous
cyclization of phenacyl esters of anthranilic acid in poly-
phosphoric acid instead of 2-aryl-1H- b e n z [e][1, 4]oxa-
zepin-5-ones described in previous papers [4]. Structure of
quinolones is drawn in Figure 1a, 1b, 2a, 2b and 3.
Figure 2a. ORTEP view of compound 7c showing the thermal ellipsoids
at 40% probability level.
Figure 1a. ORTEP view of compound 1c showing the thermal ellipsoids
Figure 2b. Dimer of hydrogen-bonded molecules in crystal packing of
at 40% probability level.
compound 7c.

May-Jun 2004
Synthesis, NMR Spectra and X-ray Data of Chloro and Dichloro Derivatives
377
Table 3
-4
Percent of Growth of the Cells Treated with 1.10 mol Compound
Compared to the Untreated Cells
Compound
M-CF7
NCI-H460
SF-268
1c
2c
3c
4c
5c
6c
7c
8c
9c
63
46
61
66
33
29
12
61
65
61
84
59
72
84
70
70
11
89
27
91
84
55
47
55
71
73
20
81
86
74
10c
Activity against Breast Cancer exhibit compounds 6c and
7c. Both of these compounds were active against the cell
line MCF7, log GI50 was -5.68 and –5.77.
Figure 3. Dimer of hydrogen-bonded molecules in crystal packing of
compound 9c.
Activity against melanoma was similar for both these
compounds. These compounds were active against the cell
line M147. Activity of both compounds was very similar,
log GI50 was approximately -5.50.
Both compounds 6c and 7c exhibit some activity against
Ovarian Cancer. The compound 6c was active against
the cell line IGROV1 log GI50 = -5.48. The compound 7c
As mentioned previously, biological properties of 2-sub-
stituted 3- h y d r o x y - 2 - p h e n y l q u i n o l i n - 4 ( 1H)-ones are not
known. The cytotoxic properties of some substituted
2-p h e n y l q u i n o l i n - 4 ( 1H)-ones and their affinity to
colchicin binding place were descr recently[5].
The cytostatic properties of prepared quinolinones have
been evaluated in the National Cancer Institute Bethesda.
All compounds have been screened in the 3-cell line –
breast cancer MCF7, non-small cell lung cancer NCI-
H460 and CNS cancer SF-268.
exhibits activity against the cell line OVCAR-8 log GI50
-5.50.
=
D i ffe rent activity of these compounds was observed
against Renal cancer. The compound 7c was not active.
Compound 6c exhibits activity against the cell lines
Each cell line is inoculated and preincubated on a
microtiter plate. Test agents are then added at a single con-
centration and the culture incubated for 48 hours. End-
point determination is made with alamar blue. Results of
each test agent are reported as the percent of growth of the
treated cells when compared to the untreated control cells
(Table 3). Compounds which reduce the growth of any one
of the cell lines to approximately 32% or less are passed on
for evaluation in the full panel of 60 cell lines over a 5-log
dose range.
In our case, three compounds (6 c, 7 c, 9 c) which passed
NCI's criteria were evaluated against the 60 tumor cell lines.
These compounds have limited effects on cancer lines in
lower concentration. The most active was compound 7c. It
has the most notable effects in the screen on some lines
from the colon panel and on some lines from the breast
cancer panel.
CAKI-1 and UO-31 log GI50 = -5.44 and log GI50
-5.45.
=
The compound 6c was not active against leukemia.
Compound 7c was active against most of tested leukemia
lines. Especially against the cell lines CCRF-CEM, HL-
60(TB), MOLT-4 and K-562; Log GI50 was between
-5.48 to -5.81.
The compound 7c exhibits moderate activity against
Non-Small Cell Lung Cancer. Higher activity of this com-
pound was observed against the cell lines HOP-62, NCI-
H322M, NCI-H460. Logarithm of the concentration GI50
was between -5.64 to -5.93.
The compound 7c was also active against the Colon
Cancer cell line HCC-2998 and the cell line HCT-116.
There was log GI50 = -5.77 and log GI50 = -5.62.
EXPERIMENTAL
These compounds have limited effects on cancer lines in
the lower concentration. Activity of these three com-
pounds was characterized by log GI50, where GI50 is the
concentration which causes growth inhibition of 50%.
The most active compound of this series of quinolinone
derivatives was compound 7c . Compound 9c did not
exhibit any activity where log GI50 is smaller than –5.
Melting points were determined on a Boetius stage. Infrared
spectra (KBr disks) were taken with an ATI Unicam Genesis
FTIR instrument. NMR spectra of solutions in DMSO-d (TMS
as internal standard) were measured on a Bruker Avance 300
spectrometer (300 MHz). Elemental analyses were obtained with
an EA 1108 Elemental Analyzer (Fison Instrument).
6

378
P. Hradil, P. Krejcˇí, J. Hlavácˇ, I. Wiedermannová, A. Lycˇka, V. Bertolasi
Vol. 41
Table 5
C Chemical Shifts of Phenacyl anthranilates 1-10b in DMSO-d
General Procedure of Preparation of Chloro Phenacyl
Anthranilates (b).
13
6
Acid a (13 mmol) was dissolved in dimethylformamide (10
ml) and sodium carbonate (0.69 g, 6.5 mmol) was added to the
solution. The reaction mixture was stirred for 10 minutes at labo-
ratory temperature and then the reaction mixture was heated at 65
°C for 45 min. The mixture was cooled to 25 °C and phenacyl
bromide (2.59 g, 13 mmol) was added. The reaction temperature
increased spontaneously to 30 °C. The mixture was heated up to
70 °C for 60 minutes. The hot mixture was poured onto crushed
ice and the precipitated solid was collected by suction, thoro-
ughly washed with water and dried at 60 °C. The dried product
was crystallized from hot acetone and dried at 60 °C.
No 1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
1
2
3
4
5
6
7
8
9
114.4 109.1 107.3 110.5 116.3 113.0 116.5 108.5 110.9 108.8
148.8 150.5 152.5 147.0 147.1 149.7 143.8 150.9 146.1 148.3
116.4 118.8 115.5 119.4 115.9 113.6 117.2 117.8 120.5 117.2
132.1 134.4 139.1 134.5 132.3 136.2 131.8 136.9 129.1 137.5
114.5 118.0 115.0 115.5 117.6 115.8 117.0 115.9 118.0 116.1
131.5 129.6 132.9 130.2 128.8 132.9 129.8 131.9 133.8 130.5
165.3 165.9 166.1 166.4 164.8 164.5 164.5 165.2 165.4 165.9
67.4 66.9 66.7 67.0 67.7 67.5 67.8 67.0 67.4 67.1
193.9 193.1 193.1 193.0 193.9 193.7 193.9 192.9 192.8 192.8
10 133.6 134.0 134.0 134.0 133.5 133.5 133.4 134.0 133.9 133.9
11 128.1 127.9 127.9 127.9 128.2 128.1 128.2 127.9 128.0 127.9
12 129.1 129.0 129.0 129.0 129.1 129.1 129.1 129.1 129.1 129.0
13 134.4 134.1 134.1 134.1 134.6 134.4 134.6 134.2 134.3 134.1
General Procedure of Preparation of Chloro and Dichloro 2-
Phenyl-3-hydroxyquinolin-4(1H)-ones (c).
Phenacyl anthranilate b (2.03 g, 7.2 mmol) was stirred with
polyphosphoric acid (30 g) at 100 to 110 °C for 2 h. Then the
reaction mixture was poured into water (100 ml) and the precipi-
tated solid was collected by filtration and washed with water to
neutral pH. The solid was dried at 80 °C and crystallized from 2-
methoxyethanol. The product was collected by filtration and
washed with cold acetone.
Scheme 3
NMR Spectra.
1
13
The H (500.13 MHz) and C (125.76 MHz) and NMR spec-
tra of compounds 1b,1c - 10b,10c were measured on a Bruker
Avance 500 spectrometer equipped with 5 mm broadband probe
with z-shielding and a SGI O2 computer in hexadeuteriodimethyl
Table 6
1
H Chemical Shifts of Substituted 2-Phenyl-3-hydroxyquinolinones 1-10c
in DMSO-d
13
1
6
sulfoxide at ambient temperature. The C and H chemical
13
shifts were referred to the central peak of DMSO-d (δ( C) =
6
39.60, δ( H) = 2.55). Positive values of chemical shifts denote
No 1c
2c
3c
4c
5c
6c
7c
8c
9c
10c
1
high frequency shifts with respect to standards. Two dimensional
gs (gradient selected)-H,H-COSY, gs-HSQC and gs-HMBC [6,7]
spectra were measured using standard microprograms provided
by Bruker [3].
1
-
8.67
-
8.65 8.45 8.52 8.78
-
8.80 8.82
3 11.72 11.83 11.55 11.55 11.93 11.70 10.34 11.81 10.75 10.62
5
6
7
8
-
8.15 8.21 8.22
7.31 7.34
-
-
-
-
8.27 8.14 8.19
-
-
7.73
7.51 7.66
7.26 7.81 7.82
-
7.32 7.32
-
7.86
-
7.57 [b]
-
-
-
7.85 7.71
-
7.76
-
-
7.75 7.77
7.96
Scheme
2
10 7.84 7.85 7.86 7.81 7.84 7.85 7.82 7.83 7.84 7.84
11 7.60 7.60 7.61 7.60 7.61 7.62 7.60 7.61 7.58 7.57 [b]
12 7.54 7.55 7.57 7.55 7.56 7.59 7.55 7.57 7.54 7.57 [b]
[b] Middle of the multiplet.
X-Ray crystal Structure Analysis.
Crystal data for 1c: C H ClNO ; monoclinic, space group
15 10
P2 /a, a = 13.7745(6), b = 6.4125(3), c = 14.1271(8) Å, β =
2
1
102.538(2)°, V = 1218.1(1) Å , Z = 4, D = 1.482 g cm .
Table 4
H Chemical Shifts of Phenacyl anthranilates 1-10b in DMSO-d
3
-3
c
1
6
Intensity data collected with θ ≤ 28° using Mo-Kα radiation (λ =
0.71073 Å) on a Nonius Kappa CCD diffractometer; T = 295 K,
2 9 11 independent reflections measured; 2146 reflections
observed [I ≥ 2σ(I)]; solution by direct methods [SIR92] [8]; full
No 1b 2b
3b
4b
5b
6b
7b
8b
9b 10b
2
3
4
5
6
8
6.21 6.85 6.94 6.80 6.30 6.50 6.30 6.99 6.92 7.08
2
matrix least-squares refinement, on F , using SHELXL-97 [9]
6.70 6.90 6.96
7.21 7.38
-
6.84 6.89
-
7.14
-
7.88
-
-
-
with anisotropic non-H atoms and isotropic hydrogens. Final R
index = 0.044 (observed reflections). An ORTEP view [10] of the
molecule is shown in Figure 1a. The molecules form intramolec-
ular hydrogen bond: O3-H3…O4 [O3…O4 = 2.584(2) Å, O3-
H3…O4 = 124(3)°] and chains linked by intermolecular hydro-
gen bonds assisted by resonance [11,12]: N1-H1…O4 [N1…O4
= 2.905(2) Å, N1-H1…O4 = 159(2)°] (Figure 1b).
-
7.61 7.43
-
6.78
-
-
6.81
-
-
6.65 6.71
-
-
6.79 7.44
-
6.91
7.81 7.87 7.93
-
7.96 7.78 7.90
5.88 5.74 5.74 5.79 5.91 5.88 5.94 5.75 5.80 5.79
11 8.10 8.06 8.06 8.07 8.11 8.10 8.11 8.06 8.06 8.06
12 7.63 7.63 7.63 7.62 7.64 7.63 7.65 7.63 7.64 7.62
13 7.77 7.74 7.76 7.75 7.78 7.77 7.79 7.76 7.77 7.75

May-Jun 2004
Synthesis, NMR Spectra and X-ray Data of Chloro and Dichloro Derivatives
379
Table 7
13
C Chemical Shifts of Substituted 3-Hydroxy-2-phenylquinolin-4(1H)-ones 1-10c in DMSO-d
6
No
1c
2c
3c
4c
5c
6c
7c
8c
9c
10c
2
3
4
4a
5
6
129.8
138.9
169.6
117.5
131.5
118.1
130.3
124.4
140.3
131.7
129.2
128.4
129.5
132.2
138.4
169.0
122.7
123.3
126.7
130.8
121.1
136.6
132.4
129.4
128.4
129.5
131.6
138.5
169.7
120.3
126.9
122.4
135.2
117.5
138.2
132.0
129.2
128.4
129.5
132.5
138.6
170.2
118.5
124.2
122.4
131.1
121.8
134.5
132.3
129.7
128.3
129.4
129.1
138.8
168.9
118.5
129.8
126.5
131.2
119.4
139.7
131.6
129.3
128.5
129.6
129.7
139.6
169.2
116.2
133.3
123.8
134.1
117.0
140.4
131.6
129.2
128.5
129.6
131.0
139.0
169.8
120.9
130.1
124.5
131.8
118.8
136.2
131.8
129.5
128.3
129.4
132.7
138.7
168.9
121.7
125.9
124.9
133.2
120.3
136.9
132.0
129.4
128.5
129.7
[a]
[a]
[a]
169.5
[a]
[a]
[a]
[a]
[a]
[a]
138.8
168.9
[a]
[a]
[a]
[a]
[a]
[a]
[a]
7
8
8a
9
10
11
12
[a]
129.4
128.3
[a]
129.6
128.2
129.3
[a] Broad and overlaying signals.
Crystal data for 7c: C H Cl NO ; orthorhombic, space group
P bca, a = 15.8452(3), b = 6.9292(1), c = 24.3340(5) Å, V =
202134. Copies of the data can be obtained, free of charge, on
application to CCDC, Union Road, Cambridge CB2 1EZ, UK [fax:
+(44)(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk]
15
9
2
2
3
-3
2671.74(8) Å , Z = 8, D = 1.522 g cm . Intensity data collected
c
with θ ≤ 28° using Mo-Kα radiation (λ = 0.71073 Å) on a Nonius
Kappa CCD diffractometer; T = 295 K, 3185 independent reflec-
tions measured; 2266 reflections observed [I ≥ 2σ(I)]; solution by
direct methods [SIR92][8], full matrix least-squares refinement,
Acknowledgment.
This work was financially supported by the Grant Agency of
the Czech Republic. (Grant No. 203/01/1360).
2
on F , using SHELXL-97 [9] with anisotropic non-H atoms and
isotropic hydrogens. Final R index = 0.039 (observed reflec-
tions). An ORTEP view [10] of the molecule is shown in Figure
2a. The molecules form intramolecular hydrogen bond: O3-
H3…O4 [O3…O4 = 2.668(2) Å, O3-H3…O4 = 112(2)°] and
dimers linked by intermolecular hydrogen bonds: O3-H3…O4
[O3…O4 = 2.786(2) Å, O3-H3…O4 = 160(3)°] (Figure 2b).
Crystal data for 9c: C H Cl NO ; monoclinic, space group
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C. Burla, G. Polidori and M. Camalli, Appl. Crystallogr., 2 7, 435 (1994).
[9] G. M. Sheldrick, SHELXL-97. Program for Refinement for
Crystal Structures; University of Göttingen: Göttingen, Germany.
[10] C. K. Johnson, ORTEPII, Report ORNL-5138; Oak Ridge
National Laboratory: Oak Ridge, TN (1976).
[11] V. Bertolasi, P. Gilli, V. Ferretti and G. Gilli, A c t a
Crystallogr. Sect. B, 51, 1004 (1995).
[12] V. Bertolasi, P. Gilli, V. Ferretti and G. Gilli, A c t a
Crystallogr. Sect. B, 54, 50 (1998).
15
9
2
2
P2 / c, a = 9.8478(2), b = 13.1654(2), c = 20.3946(6) Å, β =
-3
1
94.016(1)°, V = 2637.7(1) Å , Z = 8, D = 1.542 g cm . Intensity
3
c
data collected with θ ≤ 28° using Mo-Kα radiation (λ = 0.71073
Å) on a Nonius Kappa CCD diffractometer; T = 295 K, 5973
independent reflections measured; 3842 reflections observed [I ≥
2σ(I)]; solution by direct methods [SIR92] [8], full matrix least-
2
squares refinement, on F , using SHELXL-97 [9] with
anisotropic non-H atoms and isotropic hydrogens. Final R index
= 0.047 (observed reflections). An ORTEP view [10] of the
asymmetric unit built up by two independent molecules is shown
in Figure 3. These molecules form intramolecular hydrogen
bond: O3-H3…O4 [O3A…O4A = 2.728(3) Å, O3A-H3A…O4A
= 114(3)°; O3B…O4B = 2.751(3) Å, O3B-H3B…O4B =
115(3)°] and are linked in dimers by means of intermolecular
hydrogen bonds: O3-H3…O4 [O3A…O4B = 2.637(2) Å, O3A-
H 3 A …O4B = 143(3)°; O3B…O4A = 2.661(2) Å, O3B-
H3B…O4A = 147(3)°].
Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 202132, 202133,