An effective two-step synthesis, fluorescent properties, antioxidant activity and cytotoxicity evaluation of benzene-fluorinated 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-ones

Article abstract of DOI:10.1016/j.jfluchem.2015.07.006

Abstract This study describes a simple and efficient procedure to synthesize a series of benzene-fluorinated 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-ones by the PTSA-catalyzed cyclocondensation reaction of the corresponding ortho-alkynylanilines prepared by the Sonogashira reaction of fluoro-substituted 2-iodanilines with 2-methylbut-3-yn-2-ol. The photofluorescent properties (shape of bands, λ_ex, λ_em, Stokes shift) of the new compounds were investigated. It has been revealed that the 2,3-dihydroquinolinones with different number of fluoro-substituents have almost the same fluorescence properties. The cytotoxicity evaluation of the 2,3-dihydroquinolinones against human myeloma, human mammary adenocarcinoma, human hepatocellular carcinoma HepG2 epithelial tumor cells, normal mouse fibroblasts and Chinese hamster Ag 17 cells was performed. It has been found that the benzo-perfluorinated derivatives of 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-ones show enhanced cytotoxic effect against the tumor RPMI (human myeloma) cells line compared with the normal cells. Mutagenic and antioxidant properties of the compounds using Salmonella tester strain were studied. It has been shown, that the compounds are well antioxidants.

Full text of DOI:10.1016/j.jfluchem.2015.07.006

Journal of Fluorine Chemistry 178 (2015) 142–153
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
An effective two-step synthesis, fluorescent properties, antioxidant
activity and cytotoxicity evaluation of benzene-fluorinated
2,2-dimethyl-2,3-dihydro-1H-quinolin-4-ones
a
a
Larisa V. Politanskaya a, , Igor P. Chuikov , Evgeny V. Tretyakov ,
*
Vitalij D. Shteingarts a,1, Ludmila P. Ovchinnikova b, Olga D. Zakharova c,
Georgy A. Nevinsky c,
*
a N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, Ac. Lavrentiev Avenue 9, 630090 Novosibirsk,
Russian Federation
b Institute of Cytology and Genetics, Siberian Division of Russian Academy of Sciences, Lavrentiev Avenue 10, 630090 Novosibirsk, Russian Federation
c Institute of Chemical Biology and Fundamental Medicine, Siberian Division of Russian Academy of Sciences, Lavrentiev Avenue 8, 630090 Novosibirsk,
Russian Federation
A R T I C L E I N F O
A B S T R A C T
Article history:
This study describes a simple and efficient procedure to synthesize a series of benzene-fluorinated 2,2-
dimethyl-2,3-dihydro-1H-quinolin-4-ones by the PTSA-catalyzed cyclocondensation reaction of the
corresponding ortho-alkynylanilines prepared by the Sonogashira reaction of fluoro-substituted 2-
Received 21 May 2015
Received in revised form 2 July 2015
Accepted 8 July 2015
iodanilines with 2-methylbut-3-yn-2-ol. The photofluorescent properties (shape of bands, lex, lem,
Available online 19 July 2015
Stokes shift) of the new compounds were investigated. It has been revealed that the 2,3-
dihydroquinolinones with different number of fluoro-substituents have almost the same fluorescence
properties. The cytotoxicity evaluation of the 2,3-dihydroquinolinones against human myeloma, human
mammary adenocarcinoma, human hepatocellular carcinoma HepG2 epithelial tumor cells, normal
mouse fibroblasts and Chinese hamster Ag 17 cells was performed. It has been found that the benzo-
perfluorinated derivatives of 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-ones show enhanced cytotoxic
effect against the tumor RPMI (human myeloma) cells line compared with the normal cells. Mutagenic
and antioxidant properties of the compounds using Salmonella tester strain were studied. It has been
shown, that the compounds are well antioxidants.
Keywords:
Sonogashira coupling
PTSA-catalyzed cyclocondensation
Benzene-fluorinated 2,2-dimethyl-2,3-
dihydro-1H-quinolin-4-ones
Photophysical properties
Cytotoxicity against cancer cells
Mutagenic and antioxidant properties
ß 2015 Elsevier B.V. All rights reserved.
1. Introduction
are insufficiently studied. Nevertheless, since products containing
this scaffold have demonstrated interesting biological properties,
Quinolone-based compounds are considered as one of the highly
privileged building blocks in medicinal chemistry, thus widely
known fluorine-containing antibacterial drugs, including Ciproflox-
acin [1]. On the contrary, the bioactivity properties of some
quinolone derivatives, namely 2,3-dihydro-4(1H)-quinolinones,
this demanded developing new general methods of quinolinone
synthesis [2]. In our synthetic planning to generate diverse
quinolinone-based compounds, the objective was to synthesize
fluorinated 2,3-dihydro-4(1H)-quinolinones 1. From the one side,
compounds of such structural backbone are known to possess a
broad scope of pharmacological properties including anti-ulcer,
antiinflammatory and anticancer activity (A) [3–5], high binding
affinities for 5-HT6 receptor with good selectivity over other
serotonin and dopamine receptors (B) [6], and, as the last example,
pain-blocking properties (C) [7].
*
Corresponding authors.
E-mail addresses: plv@nioch.nsc.ru (L.V. Politanskaya), nevinsky@niboch.nsc.ru
(G.A. Nevinsky).
1
Deceased.
http://dx.doi.org/10.1016/j.jfluchem.2015.07.006
0022-1139/ß 2015 Elsevier B.V. All rights reserved.

L.V. Politanskaya et al. / Journal of Fluorine Chemistry 178 (2015) 142–153
143
From the other side, aromatic fluorine is a unique modulator of
the biological properties of organic compounds [8] that is directly
associated with the specific electronic and structural features of a
fluorine atom, such as a high electronegativity, relatively small
size, a low polarizability of the C–F-bond and, in many cases,
increased lipophilicity of fluorine containing organic molecules [9].
From synthetic point of view, the presence of several fluorine
atoms in the benzene moiety of benzoheterocycles opens ample
opportunities for a scaffold functionalization by the nucleophilic
substitution of fluorine atoms, as was shown in [6] by the synthesis
of piperazinyl derivatives of 1-(arylsulfonyl)-2,3-dihydro-1H-
quinolin-4-ones (B).
Herein, we wish to report a highly efficient synthesis of a broad
range of fluorinated derivatives of 2,2-dimethyl-2,3-dihydro-1H-
quinolin-4-ones, data about their cytotoxicity against cancer cells
and fluorescent properties as well, depending on the number and
the location of fluorine atoms in the benzene moiety.
2-methyl-3-butyn-2-ol in MeCN in the presence of Pd(PPh3)2Cl2
(4 mol %), CuI (9 mol%) and Et3N. Then, the prepared acetylene
derivatives 3(a–f) were cyclized in boiling AlkOH (Alk = Me, Et, n-
Bu) in the presence of PTSA as a catalyst to give 2,2-dimethyl-2,3-
dihydro-1H-quinolin-4-ones 1(a–f) with good and excellent yields
calculated for the two-step procedure (Scheme 1, Table 1). The
acid-mediated cyclization is generally accepted to proceed via
regioselective hydrative–dehydrative rearrangement of the alkyne
moiety through intermediate 1-(2-aminophenyl)-3-methylbut-2-
en-1-ones [10,11].
According to [13], aliphatic alcohols are preferable for using as
solvents in the acid-catalyzed hydration of arylalkynes. In case of
our fluoro-derivative to identify the optimal conditions, different
alcohols were screened. We have revealed that boiling of ethanolic
solution of 3c in the presence of PTSA during 8 h resulted in the
totally gumming of the reaction mixture, whereas using MeOH
gave 1c with acceptable yield (Table 1, entry 3). An attempt to
prepare 1e in boiling EtOH led mainly to earlier known [14] 2-
substituited-4,5,6,7-tetrafluoroindole (ꢀ90% according to 19F NMR
and GC–MS analysis data) as result of acid-catalyzed intramolecu-
lar cyclization of the starting 2-alkynylaniline 3e [15]. Using MeOH
suppressed the backside process and gave 3e with acceptable
yields (Table 1, entry 5). As to 3f, only using high-boiling n-BuOH
allowed us to convert 3f into the corresponding 2,3-dihydro-1H-
quinolin-4-ones (Table 1, entry 6).
2. Results and discussion
2.1. The synthesis of fluorinated 2,2-dimethyl-2,3-dihydro-1H-
quinolin-4-ones
The synthesis is outlined in Scheme 1. On the first step,
fluorinated o-iodoanilines 2(a–f) were cross-coupled with
OH
NH2
NH2
X6
X6
X5
I
C(CH3)2OH
H
PTSA
AlkOH
reflux
Pd(PPh3)2Cl2, CuI,
Et3N, MeCN
X5
X3
X3
X4
X4
3(a-f)
Alk = Me, Et, n-Bu
2(a-f)
X3
O
X3
O
NH2
O
OH
X4
X5
X4
X5
X6
X5
PTSA
PTSA
CH3
CH3
-
AlkOH
reflux
H2O
X3
+
N
H
NH2
X6
X4
X6
X4
1(a- f)
X3
X5 X6
a
b
c
d
e
f
H
H
H
F
F
F
H
F
F
H
H
F
H
H
F
F
F
F
F
F
F
F
CF3
F
Scheme 1. Synthesis of 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-ones 1(a–f).

144
L.V. Politanskaya et al. / Journal of Fluorine Chemistry 178 (2015) 142–153
Table 1
Synthesized 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-ones 1(a–f).
Entry
1
Substrate
PTSA (equiv)
1.5
Alk
Et
Time, h
10
Product
Yield, %
89
2
3
4
1
2
2
Et
8.5
70a
38a
43a
Me
15
Et
17
5
1
Me
40
57a
6
2
n-Bu
17.5
55a
Isolated yield of pure product based on 2 (Compounds 3(b–f) were used without purification, their 1H and 19F NMR spectra correspond to those reported previously [12]).
a
The special case was the hydration of 3g having two acetylenic
groups, which was prepared by iodination of 3-fluoroaniline 4
followed by the Sonogashira reaction of 5-fluoro-2,4-diiodoaniline
2g with 2-methylbut-3-yn-2-ol (Scheme 2). The reaction of 3g in
the presence of 4 equivalents of PTSA in boiling EtOH for 15 h gave
the substituted 2,3-dihydro-1H-quinolin-4-one 1g in 83% yield.
The increase of this reaction duration resulted in obtaining 6-
acetyl-7-fluoro-2,2-dimethyl-2,3-dihydroquinolin-4(1H)-one (1h)
as a single product in 67% yield (Scheme 2).
The fact that the formation of 2,3-dihydroquinolinone nucleus
in 1g is accompanied by rearrangement of the tertiary acetylenic
alcohol into the corresponding vinyl ketone proves the mecha-
nism of heterocyclisation depicted on the Scheme 1. When the
reaction time was prolonged, compound 3g completely trans-
formed into compound 1h, probably due to the acid catalyzed
retro-aldol cleavage (Scheme 3). The cleavage also proceeds on
silica during TLC that leads to complete conversion of 1g into
compound 1h.
2.2. UV–vis, absorption and fluorescence spectra for 2,3-
dihydroquinolinones 1(a–h)
In general 2,3-dihydro-1H-quinolin-4-one derivatives are of
special interest in terms of their fluorescent properties [16]. The
most of the fluorinated 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-
ones 1(a–h) show an intense green fluorescence in dichloro-
methane that is clearly visible by naked eye. The objective of this
story was to determine whether the fluoro atoms introduced into
the benzene ring can influence on photoluminescence of the 2,3-
dihydroquinolinone. In this regard it was
important to compare the photophysical
properties of compounds 1(a–h) with similar
data for their non-fluorinated analog. For this
purpose, we synthesized 2,2-dimethyl-2,3-
dihydro-1H-quinolin-4-ones (5) via the same
procedure (Scheme 1) in 90% yield based on o-
iodoaniline (see Section 4).

L.V. Politanskaya et al. / Journal of Fluorine Chemistry 178 (2015) 142–153
145
NH2
emission maxima and Stokes’s shift of compounds 1(a–h) and 5 are
summarized in Table 3. It can be seen that, compared to
acetonitrile solutions, alcohol solutions exhibit bathochromic shift
(red shift) both in absorption and fluorescence maxima. Of
particular notice is the Stokes shift in going from MeCN to EtOH,
which is clearly indicative of higher stabilization of the photo-
excited state of 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-ones
1(a–h) compared to their ground electronic state.
I
I
I2, NaHCO3
H2O
C(CH3)2OH
H
F
Pd(PPh3)2Cl2, CuI,
Et3N, MeCN
F
NH2
4
2g
55%
O
F
O
15 h
Now it is reasonable to compare the fluorescence properties of
fluorinated derivatives 1(a–h) with that of non-fluorinated 2,2-
dimethyl-2,3-dihydro-1H-quinolin-4-ones 5. The replacement of
OH
HO
N
H
1g
83%
PTSA
EtOH
the hydrogen atom in compounds 5 with a
p-electron donor
F
NH2
3g
fluorine atom in position 7 (compounds 1a) led to a blue shift of
fluorescence spectra. At the same time, the introduction of two
fluorine atoms at position 6 and 8 (compound 1c) resulted in a red
shift of the bands compared with that for the compound 5. It is
noteworthy that the fluorescence spectra of benzo-perfluorinated
compound 1e and unsubstituted 2,2-dimethyl-2,3-dihydro-1H-
quinolin-4-ones 5 were similar. Therefore, the fluorination of the
benzene ring in 5 has a relatively weak effect on the fluorescence
properties that can be explained by un-co-operation of the
substituents on the transfer of electron density from the nitrogen
atom to the carbonyl group in the excited state of the molecule.
O
F
O
86%
25 h
N
H
67%
1h
Scheme 2. Synthesis of 2,3-dihydroquinolinones 1(g, h).
The UV–vis absorption spectra for the fluorinated derivative
1(a–h) and 5 were measured in MeCN and EtOH. One can see that
for the given compounds the line pattern and absorption maxima
were almost similar in both solvents (Table 2, Figs. 1 and 2 and SI).
All compounds are characterized by an intense band with a
maximum at 220–236 nm and two less intense bands between 241
and 386 nm, whose positions varied only slightly and non-
systematically. The UV–vis spectra of the 2,3-dihydroquinolinones
1g and 1h with the extended conjugated systems exhibit an
additional intense absorption band with a maximum at 302–
314 nm and an increased intensity of the second short-wavelength
band as compared with the band for the compounds 1(a–g) and 5.
The observed appearance of the additional intense absorption band
is related with the light-induced intramolecular charge transfer
from the amino-group to the benzene carbonyl substituent.
The fluorescence properties of 1(a–h) and 5 were studied in
MeCN and EtOH (Figs. 3 and 4 and SI). The absorption maxima,
2.3. The cytotoxicity of 2,3-dihydroquinolinones 1(a–h), 5
The benzene-fluorinated 2,2-dimethyl-2,3-dihydro-1H-quino-
lin-4-ones 1(a–h) as well as non-fluorinated analog 5 were
examined for their ability to inhibit the growth of three
mammalian cell lines: tumor cell lines from human mammary
adenocarcinoma (MCF-7), human hepatocellular carcinoma
HepG2 epithelial tumor cells (HEP), human myeloma (RPMI
8226) as well as normal mouse fibroblasts (LMTK) and normal
Chinese hamster Ag 17 cells (AG). Fig. 5 shows schematically the
effect (relative activity, RA) of 2,2-dimethyl-2,3-dihydro-1H-
quinolin-4-ones 1(a–h) and 5 at max concentration of 300
on the viability of all types of cells (%).
It can be seen, the non-fluorinated 5 did not suppress the
growth of cells at all. Compounds 1(b, g, h), containing substituents
at the 6 and 7 positions of the aromatic ring and the hydrogen
mM
Scheme 3. Proposed mechanism for the acid promoted formation of 2,3-dihydroquinolinones 1(g, h).

146
L.V. Politanskaya et al. / Journal of Fluorine Chemistry 178 (2015) 142–153
Table 2
UV–vis absorption spectra for 1.0 ꢁ 10ꢂ4 mol/L solutions of 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-ones 1(a–h) and 5 in MeCN and EtOH.a
Compd
1lex, nm (1I, u.e.)
2lex, nm (2I, u.e.)
3lex, nm (2I, u.e.)
4lex, nm (3I, u.e.)
MeCN
EtOH
236 (2.06)
MeCN
EtOH
MeCN
EtOH
MeCN
EtOH
5
233 (2.21)
228 (2.19)
229 (1.50)
225 (2.02)
222 (1.78)
225 (2.44)
230 (2.65)
231 (0.97)
ꢀ226 (0.63) (sh)
258 (0.72)
259 (0.75)
258 (0.56)
250 (0.54)
251 (0.51)
244 (0.59)
241 (0.35)
252 (2.21)
244 (0.96)
260 (0.67)
262 (0.75)
260 (0.59)
250 (0.56)
254 (0.50)
247 (0.94)
263 (1.11)
255 (1.66)
245 (0.78)
372 (0.41)
356 (0.41)
369 (0.42)
377 (0.39)
374 (0.38)
360 (0.38)
341 (0.35)
356 (0.38)
352 (0.19)
383 (0.39)
368 (0.42)
381 (0.44)
386 (0.41)
384 (0.38)
368 (0.61)
347 (0.37)
374 (0.60)
355 (0.19)
1a
1b
1c
1d
1e
1f
231 (2.01)
233 (1.46)
225 (2.16)
220 (2.03)
222 (3.19)
233 (2.60)
233 (1.30)
ꢀ230 (0.53) (sh)
1g
1h
314 (1.18)
302 (1.11)
325 (2.02)
308 (0.94)
a
lex – max excitation band wavelength, I–max absorption band intensity.
atoms at 5 and 8 positions, showed partially selective cytotoxic
activity toward RPMI cells, which being more profound in the case
of the compounds 1g. Compound 1g exhibited also the high
cytotoxic activity toward HEP tumor cells. Benzene-perfluorinated
derivatives of 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-ones 1e
and 1f demonstrated the best cytotoxicity in all tested cell lines.
The results (IC50) obtained for 2,3-dihydro-1H-quinolin-4-ones
1(e, f) with all types of cells are summarized in Table 4. IC50 values
for these compounds were comparable.
3,0
800
Absorption Spectra
5
Excitation Spectra
2,5
700
600
500
400
300
200
100
0
5
MeCN
MeCN
1a
1b
1c
1d
1e
1f
1a
1b
1c
1d
1e
1f
2,0
1,5
1,0
0,5
0,0
275
300
325
350
375
400
425
450
Wavelength (nm)
200
250
300
350
400
450
Wavelength (nm)
Fig. 3. Fluorescence excitation spectra of 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-
ones 5 and 1(a–f) in MeCN.
Fig. 1. UV–vis spectra for 1.0 ꢁ 10ꢂ4 mol/L solutions of 2,2-dimethyl-2,3-dihydro-
1H-quinolin-4-ones 5, 1(a–f) in MeCN.
800
1,8
Emission Spectra
MeCN
5
700
600
500
400
300
200
100
0
1a
1b
1c
1d
1e
1f
Absorption Spectra
MeCN
1,6
1,4
1,2
1,0
0,8
0,6
0,4
0,2
0,0
1g
1h
1g
1h
350
400
450
500
550
600
200
250
300
350
400
450
Wavelength (nm)
Wavelength (nm)
Fig. 2. UV–vis spectra for 1.0 ꢁ 10ꢂ4 mol/L solutions of 2,2-dimethyl-2,3-dihydro-
1H-quinolin-4-ones 1(g, h) in MeCN.
Fig. 4. Fluorescence emission spectra of 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-
ones 5 and 1(a–h) in MeCN.

L.V. Politanskaya et al. / Journal of Fluorine Chemistry 178 (2015) 142–153
147
Table 3
Table 4
Solvent shift data for excitation and emission fluorescence spectra for
1.0 ꢁ 10ꢂ4 mol/L solutions of 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-ones 5 and
1(a–h) in MeCN and EtOH.a
Cytotoxicity (IC50) of the benzo-perfluorinated derivatives of 2,2-dimethyl-2,3-
dihydro-1H-quinolin-4-ones 1(e, f).
Compd
IC50 (m
M) for different cell linesa
Compd
l
ex, nm
l
em, nm
Stokes shift, nm
Tumor cellsb
Control cells
LMTK
MeCN
EtOH
MeCN
EtOH
MeCN
EtOH
MCF-7
HEP
RPMI
AG
5
364
379
439
421
435
455
459
449
419
422
483
461
472
492
499
479
453
459
75
65
71
77
81
87
74
70
104
97
1e
1f
59.5 ꢃ 2.8
60.9 ꢃ 2.1
41.9 ꢃ 8.1
18.7 ꢃ 9.4
17.5 ꢃ 7.6
13.0 ꢃ 6.7
51.0 ꢃ 8.2
53.0 ꢃ 3.9
95.0 ꢃ 2.9
73.0 ꢃ 2.3
1a
1b
1c
1d
1e
1f
356
364
364
379
93
a
378
386
106
119
115
106
97
Mean ꢃ standard deviation from three independent experiments.
b
378
380
MCF-7, human mammary adenocarcinoma; HEP, human hepatocellular
362
364
carcinoma HepG2 epithelial tumor cells; RPMI, human myeloma; LMTK, normal
mouse fibroblasts; AG, Chinese hamster Ag 17 cells.
345
347
1g
302, 352
311,
362 (sh)
301,
1h
310,
417
457
67
109
2.4. Antioxidant properties of 2,3-dihydroquinolinones
350 (sh)
348 (sh)
a
l
ex – position of the maximum of the long-wavelength excitation band, lem
ex).
–
It is known that some compounds interacting with many cell
targets at the same time may be polyfunctional and possess
cytoprotective properties, or, on the contrary, may be mutagenic or
carcinogenic. Obviously, drugs are more successful when they are
not mutagenic at least at the therapeutic concentrations. The
Salmonella typhimurium TA102 strain is often used both for
evaluation of mutagenicity of different compounds and for
detection of antioxidant properties, as judged from suppression
of spontaneous mutagenesis in this strain and from a decrease in
mutagenicity of oxidants, usually H2O2 [17]. The mutagenic
activity of several compounds was estimated in the Ames test
[17] using S. typhimurium TA102 as reported by Kemeleva et al.
[18]. The mutation induction in the Ames assay is estimated by
calculating the frequency of reversion from histidine auxotrophy
to prototrophy in response to the substance under testing [17,18].
Some antioxidant compounds are known to efficiently decrease
the mutagenic effect of H2O2 [17,18]. In the Ames test, H2O2 was
position of the maxima of the emission band, Stokes shift (lem l
ꢂ
One can see that compounds 1e and 1f exhibited the highest
cytotoxic activity toward human myeloma cell line, demonstrating
the lowest IC50 values. Fig. 6 shows the change of the viability of
RPMI cells (%) depending on the concentration (mM) of compounds
1e and 1f.
Antitumor drugs can be considered as useful when they are
better suppressors of tumor than normal mammalian cells.
Therefore, we further compared the effects of these compounds
on three tumor cell lines and normal mouse fibroblasts LMTK and
AG cells. Overall, the compounds 1e and 1f demonstrated various
toxicity ratios in the suppression of tumor vs. normal cells. For the
best inhibitor containing four fluorine atoms on the benzene
fragment (5,6,7,8-tetrafluoro-2,2-dimethyl-2,3-dihydroquinolin-
4-one 1e), the average IC50 value toward tumor cell lines is
approximately 2-fold lower than that toward normal cells. The best
differences are observed in inhibition of human myeloma cell line
(RPMI) and normal cells (LMTK, AG) (Fig. 7).
added to TA102 cells at the optimal concentration, 3
mM [17]. Fig. 8
shows the representative data for compounds 5 and 1e in the
suppression of spontaneous and the H2O2-dependent formation of
mutants. At low concentrations compounds 5 and 1e efficiently
MCF-7
HEP
RPMI
LMTK
AG
120
100
80
60
40
20
0
5
1a
1b
1f
1g
1h
1c
1d
1e
Fig. 5. Living cell count (%) by action of 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-ones 5, 1(a–h) in the concentration of 300
mM.

148
L.V. Politanskaya et al. / Journal of Fluorine Chemistry 178 (2015) 142–153
140
100
80
60
40
20
0
5 in the absence (1) and
in the presence (2) of H O
120
2
2
1e
1f
1e in the absence (3) and
in the presence (4) of H O
100
2
2
80
2
1
60
4
40
3
20
0
0
1
2
3
4
5
Concentration,μM
0
10
20
30
40
50
60
70
80
Fig. 8. Analysis of the mutagenic and antioxidant activity of compounds 5 (curves 1
and 2) and 1e (curves 3 and 4) by a standard Ames test using the S. typhimurium
strain TA102 in the absence (curves 1 and 3) and in the presence (curves 2 and 4) of
Concentration, µM
Fig. 6. The effect of the benzo-perfluorinated derivatives of 2,2-dimethyl-2,3-
dihydro-1H-quinolin-4-ones 1(e,f) on the growth of RPMI cells (%).
3
mM H2O2. The number of revertants in the absence of H2O2 was taken for 100%.
The average error in three experiments for any compound concentration did not
exceed 7–12%.
suppressed the H2O2-dependent formation of mutants from 130 to
100% and at higher concentration from 100 to 50% of revertants
(the number of revertants observed in controls without H2O2 was
taken for 100%). The data for six analyzed compounds are
summarized in Table 5.
Table 5
IC50 values characterizing suppression of spontaneous and H2O2-induced
mutagenesis by derivatives of benzene-fluorinated 2,2-dimethyl-2,3-dihydro-1H-
quinolin-4-ones.
Compd
IC50, m
Ma
Minimal effect of spontaneous mutagenesis suppression was
Suppression of spontaneous
mutagenesis (from 100 to
50%)
Suppression of H2O2-induced
and spontaneous
observed for non-fluorinated compound 5 (IC50 = 1.40
this effect was increased for fluorinated ones in the following
order: 1d (1.10 M) ꢅ 1c (1.00 M) < 1 h
M) ꢄ 1b (1.00
(0.60 M) < 1e (0.23 M) (Table 5). The Compound 5 (IC50
1.40 M) was also the worst suppressor of H2O2-induced
mutagenesis from 130 to 100%, while other compound inhibited
effect of H2O2 in an order: 1c (0.55 M) < 1b (0.37 M) < 1d
(0.21 M) < 1e (0.16 M) < 1 h (0.06 M). The suppression of
mM) and
mutagenesis
m
m
m
From 130
to 100%
From 100
to 50%
m
m
m
=
Control 5
1.40 ꢃ 0.07a
1.00 ꢃ 0.08
1.00 ꢃ 0.07
1.10 ꢃ 0.07
0.23 ꢃ 0.02
0.60 ꢃ 0.04
0.73 ꢃ 0.05
0.37 ꢃ 0.03
0.55 ꢃ 0.04
0.21 ꢃ 0.02
0.16 ꢃ 0.01
0.06 ꢃ 0.0004
1.80 ꢃ 0.08
1.30 ꢃ 0.08
1.40 ꢃ 0.07
1.10 ꢃ 0.07
0.97 ꢃ 0.07
0.81 ꢃ 0.06
1b
1c
m
m
m
m
m
1d
1e
1 h
H2O2-induced mutagenesis from 100 to 50% was observed at
higher concentrations and the effect was increased in the
following order: 5 (1.80
(1.10 M) < 1e (0.97
m
M) < 1c (1.40 M) ꢄ 1b (1.30
m
m
M) ꢅ 1d
a
Mean ꢃ standard deviation from three independent experiments.
m
m
M) < 1 h (0.81 mM) (Table 5). These data
indicate that all analyzed compounds are not mutagenic them-
selves and efficiently decrease the level of spontaneous mutagen-
esis as well as the mutagenic effect of H2O2.
Interestingly, when non-fluorinated 5 is a relatively effective
antioxidant it is not suppressing the growth of any tumor cells at
all (Fig. 5). Compound 1e, which is one of the best suppressors of all
tumor cells, efficiently inhibits spontaneous and H2O2-induced
mutagenesis. At the same time, 1h also demonstrating high
activity in the suppression spontaneous and H2O2-induced
mutagenesis, but it possesses relatively low and selective effect
on different tumor cells (Fig. 5). It is possible that all new
compounds can play a double role, acting both as inhibitors of cell
growth and as antioxidants and these functions probably only
partially overlap.
MCF-7
HEP
RPMI
LMTK
AG
120
110
100
90
80
70
60
50
40
30
20
10
0
3. Conclusion
In summary, we have developed the two-step procedure for
preparation of fluorinated 2,2-dimethyl-2,3-dihydro-1H-quinolin-
4-ones including the Sonogashira cross-coupling of fluorinated
ortho-iodanilines with 2-methylbut-3-yn-2-ol and the following
PTSA-catalyzed hydration-cyclization of prepared ortho-alkynyla-
nilines. A wide range of the fluoro-substituted ortho-iodanilines
effectively participated in the reactions to give access to a variety of
unknown fluorinated 2,2-dimethyl-2,3-dihydro-1H-quinolin-4-
ones. The photophysical data indicated that fluorinated 2,2-
dimethyl-2,3-dihydro-1H-quinolin-4-ones are the intramolecular
charge transfer fluorescent compounds and can have potential
1e
1f
Fig. 7. IC50 values (mM) of the benzo-perfluorinated derivatives of 2,2-dimethyl-
2,3-dihydro-1H-quinolin-4-ones 1(e, f).

L.V. Politanskaya et al. / Journal of Fluorine Chemistry 178 (2015) 142–153
149
application as novel electroluminescent materials. It has been
revealed that the polyfluorinated compounds 1(e, f) inhibit the
growth of three tumor mammalian cell lines, the average IC50 value
toward tumor cell lines being approximately 2-fold lower than that
toward normal cells. In addition all fluorinated compounds
efficiently suppress spontaneous and H2O2-induced mutagenesis
of bacterial cells.
JH4,H6 = 2.8 Hz, H4), 4.17 (br s, 2H, NH2); 13C NMR (100.62 MHz,
CDCl3):
d
= 164.0 (d, JC5,F = 244.7 Hz, C5), 148.1 (d, JC1,F = 11.0 Hz,
C1), 139.7 (d, JC3,F = 9.5 Hz, C3), 107.2 (d, JC4,F = 22.6 Hz, C4), 101.5
(d, JC6,F = 25.6 Hz, E6), 77.0 (d, JC2,F = 2.5 Hz, C2); 19F NMR
(282.37 MHz, CDCl3):
d
= ꢂ114.7 (ddd, 1F, JF,H6 = 10.5;
JF,H4 = 8.2; JF,H3 = 6.2 Hz, F5); HRMS (EI) calcd. for C6H5IFN (M+)
236.9445, found 236.9452.
From the second fraction 0.20 g (6%) of 2g (Rf 0.55, hexane/ethyl
acetate, 5:1) was isolated, colorless crystals, m.p. 94.6 8C with
4. Experimental
decomposition from hexane. IR (KBr):
1607, 1557, 1460, 1396, 1294, 1267, 1248, 1175, 1032, 872, 831, 737,
621, 575, 444 cmꢂ1; 1H NMR (400.13 MHz, CDCl3):
= 7.87 (d, 1H,
JH3,F = 6.8 Hz, H3), 6.48(d,1H, JH6,F = 9.5 Hz,H6), 4.23(br s, 2H, NH2);
n 3445, 3354, 2926, 2853,
4.1. General methods
d
All the cross-coupling reactions were carried out in oven-dried
glassware under an argon atmosphere. All solvents were purified
using the standard procedures and dried before use. Et3N, MeCN
were distilled and kept over CaH2 before to use. 2-Iodo-4,5-
difluoroaniline (2b) [19], 2-iodo-4,6-difluoroaniline (2c) [12], 2-
iodo-3,4,6-trifluoroaniline (2d) [12], 2-iodo-3,4,5,6-tetrafluoroani-
line (2e) [12], 2-iodo-3,5,6-trifluoro-4-(trifluoromethyl)aniline
(2f) [12], Pd(PPh3)2Cl2 [20] were prepared according to known
procedures. Other starting materials were obtained from commer-
cial supplies and used without purification.
Silica gel (100–300 mesh) was used for column chromatogra-
phy and analytical thin-layer chromatography was performed on
Merck precoated silica gel 60 PF254 containing gypsum or on Sorbfil
plates (UV 254). The visualization of the developed chromato-
grams was performed by UV light. To obtain analytically pure
samples, the synthesized compounds were crystallized from
hexane or sublimed at 100–150 8C under vacuum (ꢀ15 Torr).
The NMR spectra were recorded on a Bruker Avance-300
(300.13 MHz for 1H and 282.37 MHz for 19F), Avance-400
(400.13 MHz for 1H and 100.62 MHz for 13C) and DRX-500
(125.76 MHz for 13C) spectrometers. Deuterochloroform (CDCl3)
13C NMR (125.76 MHz, CDCl3):
d
= 162.4 (d, JC5,F = 244.0 Hz, C5),
148.2 (d, JC1,F = 10.2 Hz, C1), 146.5 (d, JC3,F = 3.0 Hz, C3), 101.2 (d,
JC6,F = 28.2 Hz, C6), 77.9 (d, JC2,F = 2.8 Hz, C2), 66.1 (d, JC4,F = 27.0 Hz,
C4); 19F NMR (282.37 MHz, CDCl3):
d
= ꢂ96.2 (dd, 1F, JF,H6 = 9.5;
JF,H3 = 6.8 Hz, F5); Anal. calcd. for C6H4I2FN: C, 19.86; H, 1.11; N 3.86.
Found: C, 19.90; H, 1.25; N, 3.86; HRMS (EI) calcd. for C6H4I2FN (M+)
362.8412, found 362.9441. (Compound 2g was also prepared in 55%
isolated yield (1.8 g) via the same procedure by action on 4 (1.0 g,
9 mmol) in H2O (50 mL) of fine-ground I2 (5.1 g, 20 mmol) and
NaHCO3 (3.3 g, 32 mmol) at room temperature for 1 h.)
From the third fraction 1.4 g (74%) of 6 (Rf 0.23, hexane/ethyl
acetate, 5:1) was isolated, colorless solid material, m.p. 67.3–
67.7 8C (67.0–68.5 8C [21]) from hexane. IR (KBr):
n 3427, 3319,
3209, 2955, 2855, 1634, 1597, 1578, 1483, 1439, 1313, 1240, 1173,
1142, 1069, 1022, 959, 845, 797, 741, 588, 548, 444 cmꢂ1; 1H NMR
(400.13 MHz, CDCl3):
d = 7.38 (dd, 1H, JH3,H2 = 8.5; JH3,F = 7.2 Hz,
H3), 6.40 (dd, 1H, JH6,F = 9.9; JH6,H2 = 2.6 Hz, H6), 6.25 (dd, 1H,
JH2,H3 = 8.5; JH2,H6 = 2.6 Hz, H2), 3.80 (br s, 2H, NH2); 13C NMR
(100.62 MHz, CDCl3):
d
= 162.2 (d, JC5,F = 242.8 Hz, C5), 148.5 (d,
JC1,F = 10.1 Hz, C1), 139.0 (d, JC3,F = 3.4 Hz, C3), 112.8 (d,
JC2,F = 2.5 Hz, C2), 102.4 (d, JC6,F = 27.1 Hz, C6), 65.5 (d,
was used as the solvent, with residual CHCl3
(dH = 7.26 ppm) or
CDCl3 ( C = 77.0 ppm) being employed as an internal standard. The
d
JC4,F = 25.9 Hz, C4); 19F NMR (282.37 MHz, CDCl3):
d
= ꢂ95.5 (dd,
13C NMR spectra were registered with C–H spin decoupling. The
masses of molecular ions were determined by HRMS on a DFS
Thermo scientific instrument (EI, 70 eV). The melting points were
registered on a Mettler-Toledo FP81 Thermosystem apparatus. The
IR spectra were recorded on a Bruker Vector 22 spectrometer (KBr).
The elemental analyses were performed on a Euro EA-3000 CHNS
analyzer, or on Carlo Erba 1106 CHN elemental analyzer. The UV–
vis absorption spectra were taken on a spectrophotometer Hewlett
Packard 4853. The fluorescence spectra were recorded on a Cary
Eclipse Varian spectrofluorimeter equipped with a pulse xenon
lamp and a scheme of the luminescence registration at an angle of
908 with the excitation and emission slits of 5 nm, quartz cells
10 mm thick, at room temperature.
1F, JF,H6 = 9.9; JF,H3 = 7.2 Hz, F5); Anal. calcd. for C6H5IFN: C, 5.91;
H, 2.13; N 5.91. Found: C, 30.39; H, 2.25; N, 5.90. HRMS (EI) calcd.
for C6H5IFN (M+) 236.9445, found 236.9451.
4.1.2. 4-(2-Amino-4-fluorophenyl)-2-methylbut-3-yn-2-ol (3a)
Pd(PPh3)2Cl2 (28 mg, 0.04 mmol), CuI (17 mg, 0.09 mmol) and
Et3N (3 mL) were added to a stirred solution of iodoaniline 2a
(237 mg, 1 mmol) and 2-methylbut-3-yn-2-ol (168 mg, 2 mmol) in
dry MeCN (10 mL) at room temperature under an argon atmo-
sphere. The mixture was heated at 50 8C for 1.5 h with stirring. The
reaction mixture was allowed to cool down to room temperature,
and CH2Cl2 (10 mL) was added. The mixture was poured into H2O
(20 mL) and extracted with CH2Cl2 (3ꢁ 50 mL). The combined
organic layers were washed with H2O (20 mL) and dried (MgSO4).
After the evaporation of the solvent in vacuo, the crude product 3a
was purified by TLC (Merck precoated plates, Rf 0.29, hexane/ethyl
acetate, 5:1, three times) to afford the title compound (133 mg,
4.1.1. 5-Ffluoro-2-iodoaniline (2a), 5-fluoro-2,4-diiodoaniline (2g)
and 3-fluoro-4-iodoaniline(6)
NaHCO3 (1.4 g, 13 mmol) and fine-ground I2 (2.0 g, 8 mmol)
were added to a stirred emulsion of 3-fluoroaniline (4) (1.0 g,
9 mmol) in H2O (50 mL) at room temperature. The reaction
mixture was maintained for 0.5 h with stirring. After the mixture
was extracted with CH2Cl2 (3ꢁ 50 mL), the combined organic
layers were washed with sat. aq. solutions of Na2S2O3 (2ꢁ 30 mL),
H2O (50 mL) and dried (MgSO4). After the evaporation of the
solvent in vacuo, the crude products were separated by column
chromatography (hexane/ethyl acetate, 10:1). The first fraction
was evaporated to give 0.085 g (4%) of 2a (Rf 0.71, hexane/ethyl
69%) as an oil. IR (liquid film):
1622, 1589, 1503, 1443, 1364, 1281, 1254, 1207, 1167, 978, 961,
899, 843, 793, 554, 513, 495 cmꢂ1 1H NMR (500.13 MHz, CDCl3):
= 7.15 (m*, 1H, JH3,H4 = 8.6; JH3,F = 6.3; JH3, H6 = 0.3 Hz, H3), 6.34
n 3360, 2982, 2934, 2870, 2222,
;
d
(m*, 1H, JH6,F = 10.6; JH6,H4 = 2.5 Hz, H6), 6.32 (m*, 1H, JH4,H3 = 8.6;
JH4,F = 8.5; JH4,H6 = 2.5 Hz, H4), 4.27 (br s, 2H, NH2), 2.20 (br s, 1H,
C(CH3)2OH), 1.61 (s, 6H, C(CH3)2OH); 13C NMR (125.76 MHz,
CDCl3):
d
= 163.5 (d, JC5,F = 247.0 Hz, C5), 149.2 (d, JC1,F = 11.7 Hz,
C1), 133.5 (d, JC3,F = 10.4 Hz, C3), 103.1 (d, JC2,F = 2.5 Hz, C2), 104.9
(d, JC4,F = 22.6 Hz, C4), 100.8 (d, JC6,F = 25.4 Hz, C6), 99.8 (s, CjC–
C(CH3)2OH), 77.6 (s, CjC–C(CH3)2OH), 65.6 (s, CjC–C(CH3)2OH),
acetate, 5:1) as an oil material. IR (liquid film):
n 3470, 3375, 3204,
3078, 2926, 1614, 1574, 1481, 1429, 1283, 1253, 1173, 1119, 1013,
970, 839, 783, 573; 1H NMR (400.13 MHz, CDCl3):
d = 7.52 (dd, 1H,
JH3,H4 = 8.6; JH3,F = 6.2 Hz, H3), 6.45 (dd, 1H, JH6,F = 10.5;
JH6,H4 = 2.8 Hz, H6), 6.24 (ddd, 1H, JH4,H3 = 8.6; JH4,F = 8.2;
*
XSIM.LINUX software (version 93.02.01) was used to modeling of these signals
to determine the coupling constants.

150
L.V. Politanskaya et al. / Journal of Fluorine Chemistry 178 (2015) 142–153
31.4 (s, CjC–C(CH3)2OH); 19F NMR (282.37 MHz, CDCl3):
d
= ꢂ108.4
with stirring for 15 h. The mixture was cooled to room tempera-
ture, diluted with CH2Cl2 (10 mL), poured into H2O (20 mL) and
extracted with CH2Cl2 (2ꢁ 50 mL). The combined organic layers
were washed with H2O (20 mL) and dried (MgSO4). The solvent
was evaporated in vacuo. The crude product 1g was purified by
crystallization from hexane to afford the title compound (22 mg,
83%) as a colorless solid, m.p. 148.7–150.5 8C from hexane. IR
(m*, 1F, JF,H6 = 10.6; JF,H4 = 8.5; JF,H3 = 6.3 Hz, F5); HRMS (EI) calcd.
for C11H12FNO (M+) 193.0897, found 193.0903.
4.1.3. 4,40-(4-Amino-6-fluoro-1,3-phenylene)bis(2-methylbut-3-yn-
2-ol) (3g)
Pd(PPh3)2Cl2 (77 mg, 0.11 mmol), CuI (47 mg, 0.25 mmol) and
Et3N (3 mL) were added to a stirred solution of 2,4-diiodoaniline 2g
(500 mg, 1.4 mmol) and 2-methylbut-3-yn-2-ol (350 mg,
4.1 mmol) in dry MeCN (10 mL) at room temperature under an
argon atmosphere. The mixture was heated at 70 8C for 3 h with
stirring. The reaction mixture was allowed to cool down to room
temperature, and CH2Cl2 (10 mL) was added. The mixture was
poured into H2O (20 mL) and extracted with CH2Cl2 (3ꢁ 50 mL).
The combined organic layers were washed with H2O (20 mL) and
dried (MgSO4). After the evaporation of the solvent in vacuo, the
crude product 3g was purified by column chromatography
(hexane/EtOH, 1:1). The fractions containing 3g (Rf 0.35, hex-
ane/ethyl acetate, 1:1) were combined and evaporated to give the
title compound as yellow viscous oil, yield 331 mg (86%). IR (liquid
(KBr):
1517, 1429, 1360, 1321, 1236, 1171, 1151, 1043, 1020, 847, 708,
646, 617, 548, 440 cmꢂ1; 1H NMR (400.13 MHz, CDCl3):
= 8.31 (d,
n 3449, 3277, 3146, 2968, 2939, 1688, 1649, 1616, 1572,
d
1H, JH5,F7 = 8.5 Hz, H5), 6.53 (m, 1H, COCH = C(CH3)2), 6.25 (d, 1H,
JH8,F7 = 12.5 Hz, H8), 4.68 (br s, 1H, NH), 2.58 (s, 2H, CH2), 2.16 (d,
3H, JH,H ꢅ 1.0 Hz, COCH = C(CH3)2), 1.95 (d, 3H, JH,H ꢅ 1.0 Hz,
COCH = C(CH3)2), 1.33 (s, 6H, CH3); 13C NMR (400.13 MHz, CDCl3):
d
= 191.7 (s, COCH2), 187.4 (d, JC,F = 3.2 Hz, COCH = C(CH3)2), 165.9
(d, JC7,F7 = 262.0 Hz, C7), 156.0 (s, COCH = C(CH3)2), 153.1 (d,
JC8a,F7 = 13.5 Hz, C8a), 132.5 (d, JC5,F7 = 5.9 Hz, C5), 123.7 (d,
JC,F = 4.7 Hz, COCH = C(CH3)2), 119.0 (d, JC6,F7 = 13.4 Hz, C6), 114.1
(s, C4a), 101.5 (d, JC8,F7 = 27.0 Hz, C8), 53.8 (s, C(CH3)2), 50.0 (s,
CH2), 27.8 (s, COCH = C(CH3)2), 27.6 (s, CH3), 21.1 (s,
film):
1429, 1364, 1308, 1261, 1238, 1161, 1119, 961, 910, 843, 735, 554,
449 cmꢂ1 1H NMR (400.13 MHz, CDCl3):
= 7.19 (d, 1H,
n
3356, 2982, 2934, 2872, 2224, 1705, 1626, 1570, 1506,
COCH = C(CH3)2); 19F NMR (282.37 MHz, CDCl3):
d
= ꢂ103.8
(ddd, 1F, JF7,H8 = 12.5; JF7,H5 = 8.5; JF7,H = 3.0 Hz, F7); HRMS (EI)
calcd. for C16H17FNO2 ([M–H+]–): 274.1238, found 274.1236. Anal.
calcd. for C16H18FNO2: C, 69.80; H, 6.59; N 5.09. Found: C, 69.40; H,
6.57; N, 5.33.
;
d
JH3,F = 7.8 Hz, H3), 6.31 (d, 1H, JH6,F = 11.0 Hz, H6), 4.56 (br s, 2H,
NH2), 3.32 (br s, 1H, C(CH3)2OH), 3.08 (br s, 1H, C(CH3)2OH), 1.56 (s,
6H, C(CH3)2OH), 1.54 (s, 6H, C(CH3)2OH); 13C NMR (100.62 MHz,
CDCl3):
d
= 163.3 (d, JC5,F = 251.3 Hz, C5), 149.6 (d, JC1,F = 11.4 Hz,
4.2. 6-Acetyl-7-fluoro-2,2-dimethyl-2,3-dihydroquinolin-4(1H)-one
C1), 137.1 (s, C3), 103.7 (s, C2), 100.9 (d, JC6,F = 25.4 Hz, C6), 100.3 (d,
JC4,F = 17.1 Hz, C4), 99.3 (s, CjC–C(CH3)2OH), 96.7 (s, CjC–
C(CH3)2OH), 77.0 (s, CjC–C(CH3)2OH), 75.4 (s, CjC–C(CH3)2OH),
65.7 (s, CjC–C(CH3)2OH), 31.6 (s, CjC–C(CH3)2OH), 31.4 (s, CjC–
(1h)
PTSA (608 mg, 3.2 mmol) was added to the solution of 3g
(220 mg, 0.8 mmol) in 15 mL EtOH. The mixture was heated under
reflux with stirring for 25 h, cooled to room temperature, diluted
with CH2Cl2 (10 mL), poured into H2O (30 mL) and extracted with
CH2Cl2 (2ꢁ 50 mL). The combined organic layers were washed
with H2O (50 mL) and dried (MgSO4). The solvent was evaporated
in vacuo to give the crude product, which was purified by TLC
(Sorbfil plates, Rf 0.31, hexane/ethyl acetate, 2:1, six times) to
afford the title compound (126 mg, 67%) as a colorless solid, m.p.
C(CH3)2OH); 19F NMR (282.37 MHz, CDCl3):
d
= ꢂ105.9 (dd, 1F,
JF,H6 = 11.0; JF,H3 = 7.8 Hz, F5); HRMS (EI) calcd. for C16H18FNO2
(M+) 275.1316, found 275.1321; Anal. calcd. for C16H18FNO2: C,
69.80; H, 6.59; N 5.09. Found: C, 70.18; H, 6.41; N, 5.12.
4.1.4. 7-Fluoro-2,2-dimethyl-2,3-dihydroquinolin-4(1H)-one (1a)
PTSA (142 mg, 0.7 mmol) was added to the solution of 3a
(73 mg, 0.5 mmol) in 10 mL EtOH. The mixture was heated under
reflux with stirring for 10 h, cooled to room temperature, diluted
with CH2Cl2 (10 mL), poured into H2O (20 mL) and extracted with
CH2Cl2 (2ꢁ 50 mL). The combined organic layers were washed
with H2O (20 mL) and dried (MgSO4). The solvent was evaporated
in vacuo to give the crude product, which was purified by TLC
(Merck precoated plates, Rf 0.21, hexane/ethyl acetate, 10:1) to
afford the title compound 1a (86 mg, 89%) as a yellow solid, m.p.
182.7–183.2 8C from hexane. IR (KBr):
n 3344, 2976, 1680, 1603,
1516, 1418, 1362, 1319, 1294, 1256, 1223, 1171, 1151, 982, 939,
847, 577, 546, 438 cmꢂ1; 1H NMR (400.13 MHz, CDCl3):
d = 8.42 (d,
1H, JH5,F7 = 8.6 Hz, H5), 6.26 (d, 1H, JH8,F7 = 12.8 Hz, H8), 4.83 (br s,
1H, NH), 2.59 (s, 2H, CH2), 2.52 (d, 3H, JH,F7 = 4.3 Hz, COCH3), 1.33
(s, 6H, CH3); 13C NMR (100.62 MHz, CDCl3):
d = 193.8 (d,
JC,F = 3.4 Hz, COCH3), 191.7 (s, CO), 166.7 (d, JC7,F7 = 262.0 Hz,
C7), 153.8 (d, JC8a,F7 = 13.7 Hz, C8a), 132.9 (d, JC5,F7 = 5.8 Hz, C5),
116.6 (d, JC6,F7 = 13.9 Hz, C6), 114.4 (s, C4a), 101.4 (d,
JC8,F7 = 27.4 Hz, C8), 53.9 (s, C(CH3)2), 50.1 (s, CH2), 30.5 (d,
JC,F = 6.2 Hz, COCH3), 27.8 (s, CH3); 19F NMR (282.37 MHz, CDCl3):
135.0–135.5 8C from hexane. IR (KBr):
2932, 1657, 1626, 1585, 1522, 1464, 1366, 1310, 1273, 1231, 1161,
1101, 1003, 851, 791, 702, 646, 563, 474 cmꢂ1 1H NMR
(300.13 MHz, CDCl3): = 7.80 (dd, 1H, JH5,H6 = 8.8; JH5,F7 = 6.6 Hz,
n 3426, 3317, 3069, 2965,
;
d
d
= ꢂ102.6 (m, 1F, JF7,H8 = 12.8; JF7,H5 = 8.6; JF7,H = 4.3 Hz, F7);
H5), 6.37 (ddd, 1H, JH6,H5 = 8.8; JH6,F7 = 8.4; JH6,H8 = 2.3 Hz, H6),
6.24 (dd, 1H, JH8,F7 = 10.5; JH8,H6 = 2.3 Hz, H8), 4.24 (br s, 1H, NH),
2.55 (s, 2H, CH2), 1.30 (s, 6H, CH3); 13C NMR (100.62 MHz, CDCl3):
HRMS (EI) calcd. for C13H14FNO2 (M+): 235.1003, found 235.1007.
Anal. calcd. for C13H14FNO2: C, 66.37; H, 6.00; N 5.95. Found: C,
66.28; H, 5.89; N, 5.94.
d
= 192.4 (s, COCH2), 167.5 (d, JC7,F7 = 253.2 Hz, C7), 151.5 (d,
JC8a,F7 = 12.5 Hz, C8a), 130.1 (d, JC5,F7 = 11.8 Hz, C5), 114.8 (s, C4a),
105.7 (d, JC6,F7 = 23.1 Hz, C6), 101.1 (d, JC8,F7 = 24.8 Hz, C8), 53.7 (s,
C(CH3)2), 50.2 (s, CH2), 27.6 (s, CH3); 19F NMR (282.37 MHz, CDCl3):
4.3. General procedure for synthesis of 2,2-dimethyl-2,3-dihydro-1H-
quinolin-4-ones 1(b–f), 5
d
= ꢂ101.5 (ddd, 1F, JF7,H8 = 10.5; JF7,H6 = 8.4; JF7,H5 = 6.6 Hz, F7);
Pd(PPh3)2Cl2 (28 mg, 0.04 mmol), CuI (17 mg, 0.09 mmol)
and Et3N (3 mL) were added to a stirred solution of iodoaniline
2(b–f) or 2-iodoaniline (7) (1 mmol), 2-methylbut-3-yn-2-ol
(126 mg, 1.5 mmol) in dry MeCN (10 mL) at room temperature
under an argon atmosphere. The mixture was heated at 50 8C for
2 h with stirring. The reaction mixture was allowed to cool down
to room temperature, and CH2Cl2 (10 mL) was added. The
mixture was poured into H2O (40 mL) and extracted with CH2Cl2
(3ꢁ 50 mL). The combined organic layers were washed with H2O
HRMS (EI) calcd. for C11H12FON (M+): 193.0897, found 193.0898.
Anal. calcd. for C11H12FON: C, 68.38; H, 6.26; N 7.25. Found: C,
68.52; H, 6.20; N, 7.28.
4.1.5. 7-Fluoro-2,2-dimethyl-6-(3-methylbut-2-enoyl)-2,3-
dihydroquinolin-4(1H)-one (1g)
PTSA (76 mg, 0.4 mmol) was added to the solution of 3g (27 mg,
0.1 mmol) in 10 mL EtOH and the mixture was heated under reflux

L.V. Politanskaya et al. / Journal of Fluorine Chemistry 178 (2015) 142–153
151
(40 mL) and dried (MgSO4). The evaporation of the solvent in
4.3.3. 5,6,8-Trifluoro-2,2-dimethyl-2,3-dihydroquinolin-4(1H)-one
(1d)
The reaction of 2d (273 mg, 1 mmol) and 2-methylbut-3-yn-2-
ol (126 mg, 1.5 mmol) gave the crude compound 3d (the 1H and 19
NMR spectra agreed with the data reported [12]). Then PTSA
(380 mg, 2 mmol) was added to the solution of crude 3d in EtOH
(25 mL) and the mixture was heated under reflux for 17 h with
stirring. The crude product 1d was purified by TLC (Sorbfil plates, Rf
0.27 hexane/ethyl acetate, 7:1, twice) to afford the title compound
(98 mg, 43%) as a yellow solid, m.p. 161.1–161.6 8C from hexane. IR
vacuo gave the crude product 3(b–f) or 4-(2-aminophenyl)-2-
methylbut-3-yn-2-ol (8) that was used without further purifi-
cation (the 1H and 19F NMR spectra agreed with the literature
data [11,12]). PTSA was added to the solution of crude 3(b–f) or
8 in AlkOH (25 mL), and the mixture was heated under reflux
with stirring. The mixture was cooled to room temperature,
diluted with CH2Cl2 (10 mL), poured into H2O (20 mL) and
extracted with CH2Cl2 (3ꢁ 50 mL). The combined organic layers
were washed with H2O (40 mL) and dried (MgSO4). The solvent
was evaporated in vacuo and the residue was purified by the TL
or column chromatography.
F
(KBr):
n 3335, 3088, 2972, 2934, 1668, 1524, 1474, 1393, 1310,
1269, 1227, 1190, 1155, 1109, 1020, 999, 957, 905, 878, 743, 679,
629, 582, 447 cmꢂ1 1H NMR (300.13 MHz, CDCl3):
; d = 7.02 (ddd,
4.3.1. 6,7-Difluoro-2,2-dimethyl-2,3-dihydroquinolin-4(1H)-one(1b)
The reaction of 2b (255 mg, 1 mmol) and 2-methylbut-3-yn-2-
ol (126 mg, 1.5 mmol), carried out according to the above general
procedure, afforded the crude compound 3b (the 1H and 19F NMR
spectra agreed with the literature data [12]). Then PTSA (190 mg,
1 mmol) was added to the solution of crude 3b in EtOH (25 mL) and
the reaction mixture was heated under reflux for 8.5 h with
stirring. The crude product 1b was purified by TLC (Sorbfil plates, Rf
0.45, hexane/ethyl acetate, 7:1) to afford the title compound
(148 mg, 70%) as a yellow solid, m.p. 134.8–135.0 8C from hexane.
1H, JH7,F8 = 10.4; JH7,F6 = 9.7; JH7,F5 = 6.8 Hz, H7), 4.29 (br s, 1H,
NH), 2.60 (s, 2H, CH2), 1.33 (s, 6H, CH3); 13C NMR (125.76 MHz,
CDCl3):
d = 190.3 (s, CO), 145.4 (ddd, JC5,F5 = 260.5; JC5,F6 = 13.0;
JC5,F8 = 4.0 Hz, C5), 144.9 (ddd, JC8,F8 = 240.8; JC8,F6 = 9.1; JC8,F5 =
4.5 Hz, C8), 140.0 (ddd, JC6,F6 = 240.5; JC6,F5 = 14.1; JC6,F8 = 10.5 Hz
C6), 135.3 (ddd, JC8a,F8 = 13.9; JC8a,F5 = JC8a,F6 = 2.5 Hz, C8a), 109.6
(ddd, JC7,F6 = JC7,F8 = 23.3; JC7,F5 = 1.8 Hz, C7), 108.5 (dd,
JC4a,F5 = 8.2; JC4a,F = 2.8 Hz, C4a), 53.5 (s, C(CH3)2), 51.2 (s, CH2),
27.2 (s, CH3); 19F NMR (282.37 MHz, CDCl3):
d
= ꢂ139.2 (dddd, 1F,
JF8,F5 = 17.0; JF8,H7 = 10.4; JF8,F6 = 3.0; JF8,H1 = 3.0 Hz, F8), ꢂ146.5
(dddd, 1F, JF5,F6 = 20.2; JF5,F8 = 17.0; JF5,H7 = 6.8; JF5,H1 = 1.6 Hz,
F5), ꢂ152.9 (ddd, 1F, JF6,F5 = 20.2; JF6,H7 = 9.7; JF6,F8 = 3.0 Hz, F6);
HRMS (EI) calcd. for C11H10F3NO (M+): 229.0709, found 229.0705.
Anal. calcd. for C11H10F3NO: C, 57.64; H, 4.40; N 6.11. Found: C,
57.86; H, 4.36; N, 6.15.
IR (KBr):
1462, 1369, 1310, 1285, 1256, 1163, 1119, 1032, 945, 885, 841,
770, 663, 625, 548, 500, 457, 436 cmꢂ1 1H NMR (400.13 MHz,
CDCl3):
= 7.54 (dd, 1H, JH5,F6 = 10.5; JH5,F7 = 9.0 Hz, H5), 6.38 (dd,
1H, JH8,F7 = 11.4; JH8,F6 = 6.2 Hz, H8), 4.30 (br s, 1H, NH), 2.53 (s,
2H, CH2), 1.28 (s, 6H, CH3); 13C NMR (100.62 MHz, CDCl3):
= 192.4
n 3337, 2984, 2966, 2932, 2878, 1657, 1639, 1593, 1510,
;
d
d
(s, CO), 155.8 (dd, JC7,F7 = 256.0; JC7,F6 = 15.0 Hz, C7), 147.6 (d,
JC8a,F7 = 10.4 Hz, C8a), 143.8 (dd, JC6,F6 = 240.5; JC6,F7 = 14.0 Hz,
C6), 115.0 (dd, JC5,F6 = 17.7; JC5,F7 = 3.2 Hz, C5), 113.8 (dd,
JC4a,F6 = 3.7; JC4a,F7 = 1.9 Hz, C4a), 103.7 (d, JC8,F7 = 20.6 Hz, C8),
54.1 (s, C(CH3)2), 50.1 (s, CH2), 27.7 (s, CH3); 19F NMR (282.37 MHz,
4.3.4. 5,6,7,8-Tetrafluoro-2,2-dimethyl-2,3-dihydroquinolin-4(1H)-
one (1e)
The reaction of 2e (291 mg, 1 mmol) and 2-methylbut-3-yn-2-
ol (126 mg, 1.5 mmol) gave the crude compound 3e [12]. Then
PTSA (190 mg, 1 mmol) was added to the solution of crude 3e in
MeOH (25 mL) and the mixture was heated under reflux for 40 h
with stirring. The crude product 1e was purified by TLC (Merck
precoated plates, Rf 0.50, hexane/ethyl acetate, 10:1) to afford the
title compound (141 mg, 57%) as a yellow solid, m.p. 128.3–
CDCl3):
d
= ꢂ124.8 (ddd, 1F, JF7,H6 = 22.2; JF7,H8 = 11.4;
JF7,H5 = 9.0 Hz, F7), ꢂ149.5 (ddd, 1F, JF6,F7 = 22.2; JF6,H5 = 10.5;
JF6,H8 = 6.2 Hz, F6); HRMS (EI) calcd. for C11H11F2NO (M+):
211.0803, found 211.0800. Anal. calcd. for C11H11F2NO: C, 62.55;
H, 5.25; N 6.63. Found: C, 62.62; H, 5.00; N, 6.89.
128.5 8C from hexane. IR (KBr):
n 3337, 2974, 2938, 2895, 1676,
1659, 1531, 1504, 1474, 1416, 1373, 1310, 1283, 1234, 1205, 1165,
1119, 1088, 1026, 961, 922, 868, 758, 667, 598, 450, 438 cmꢂ1; 1H
4.3.2. 6,8-Difluoro-2,2-dimethyl-2,3-dihydroquinolin-4(1H)-one (1c)
The reaction of 2c (255 mg, 1 mmol) and 2-methylbut-3-yn-2-
ol (126 mg, 1.5 mmol) according to the general procedure gave the
crude compound 3c (the 1H and 19F NMR spectra agreed with the
literature data [12]). PTSA (380 mg, 2 mmol) was added to the
solution of crude 3c in MeOH (25 mL) and the mixture was heated
under reflux for 15 h with stirring. The crude product 1c was
purified by TLC (Merck precoated plates, Rf 0.65 hexane/ethyl
acetate, 10:1, twice) to afford the title compound (80 mg, 38%) as a
NMR (400.13 MHz, CDCl3):
d
= 4.29 (br s, 1H, NH), 2.60 (s, 2H, CH2),
= 189.6 (s, CO),
1.33 (s, 6H, CH3); 13C NMR (100.62 MHz, CDCl3):
d
147.0 (dm, JC5,F5 = 262.5; JC5,F6 = 10.5; JC5,F7 ꢅ JC5,F8 ꢅ 4.3 Hz,
C5), 144.5 (dm, JC7,F7 = 257.5; JC7,F6 ꢅ JC7,F8 ꢅ 13.8; JC7,F5 =
5.2 Hz, C7), 135.5 (ddd, JC8,F8 = 241.0; JC8,F7 = 12.4; JC8,F5 = 1.6 Hz,
C8), 135.5 (m, JC8a,F8 = 10.5; JC8a,F5 ꢅ JC8a,F7 ꢅ 4.2; JC8a,F6 =
2.1 Hz, C8a), 132.2 (dm, JC6,F6 = 244.0; JC6,F5, JC6,F7 = 16.3, 13.1;
JC6,F8 = 2.1 Hz, C6), 103.8 (d, JC4a,F5 = 7.5 Hz, C4a), 53.9 (s, C(CH3)2),
51.3 (s, CH2), 27.4 (s, CH3); 19F NMR (282.37 MHz, CDCl3):
yellow solid, m.p. 75–81 8C after sublimation. IR (KBr):
n 3325,
3325, 3080, 2972, 2932, 1661, 1591, 1518, 1476, 1373, 1310, 1290,
1263, 1177, 1146, 1113, 1092, 997, 922, 864, 827, 731, 669, 579,
d
= ꢂ143.5 (dddd, 1F, JF5,F6 = 20.8; JF5,F8 = 12.6; JF5,F7 = 9.4;
JF5,H1 = 1.6 Hz, F5), ꢂ149.6 (ddd, 1F, JF7,F6 = 21.1; JF7,F8 = 20.4;
JF7,F5 = 9.4 Hz, F7), ꢂ164.5 (dddd, 1F, JF8,F7 = 20.4; JF8,F5 = 12.6;
JF8,F6 = 6.1; JF8,H1 = 2.8 Hz, F8), ꢂ175.5 (ddd, 1F, JF6,F7 = 21.1;
JF6,F5 = 20.8; JF6,F8 = 6.1 Hz, F6); HRMS (EI) calcd. for C11H9F4NO
(M+): 247.0615, found 247.0614. Anal. calcd. for C11H9F4NO: C,
53.45; H, 3.67; N 5.67. Found: C, 53.79; H, 3.85; N, 5.68.
461, 430 cmꢂ1 1H NMR (400.13 MHz, CDCl3):
; d = 7.26 (ddd, 1H,
JH5,F6 = 8.8; JH5,H7 = 2.9; JH5,F8 = 1.7 Hz, H5), 6.91 (ddd, 1H,
JH7,F8 = 10.7; JH7,F6 = 8.0; JH7,H5 = 2.9 Hz, H7), 4.21 (br s, 1H,
NH), 2.58 (s, 2H, CH2), 1.30 (s, 6H, CH3); 13C NMR (100.62 MHz,
CDCl3):
d = 192.2 (s, CO), 153.3 (dd, JC6,F6 = 240.0; JC6,F8 = 10.4 Hz,
C6), 150.8 (dd, JC8,F8 = 245.0; JC8,F6 = 10.7 Hz, C8), 135.9 (d,
JC8a,F8 = 12.9 Hz, C8a), 119.1 (s, C4a), 109.4 (dd, JC7,F6,
JC7,F8 = 28.0, 22.0 Hz, C7), 107.3 (dd, JC5,F6 = 22.0; JC5,F8 = 3.0 Hz,
C5), 53.9 (s, C(CH3)2), 50.5 (s, CH2), 27.5 (s, CH3); 19F NMR
4.3.5. 5,7,8-Trifluoro-2,2-dimethyl-6-(trifluoromethyl)-2,3-
dihydroquinolin-4(1H)-one (1f)
The reaction of 2f (341 mg, 1 mmol) and 2-methylbut-3-yn-2-
ol (126 mg, 1.5 mmol) gave the crude compound 3f [12]. Then
PTSA (380 mg, 2 mmol) was added to the solution of crude 3f in n-
BuOH (25 mL) and the reaction mixture was heated under reflux
for 17.5 h with stirring. The crude product 1f was purified by
column chromatography (hexane/ethyl acetate, 10:1). After the
(282.37 MHz, CDCl3):
d
= ꢂ126.4 (ddd, 1F, JF6,H5 = 8.6; JF6,H7 = 8.0;
JF6,F8 = 1.3 Hz, F6), ꢂ133.3 (ddd, 1F, JF8,H7 = 10.7; JF8,H5 = 1.7;
JF8,F6 = 1.3 Hz, F8); HRMS (EI) calcd. for C11H11F2NO (M+):
211.0803, found 211.0806. Anal. calcd. for C11H11F2NO: C, 62.55;
H, 5.25; N 6.63. Found: C, 62.57; H, 5.20; N, 6.32.

152
L.V. Politanskaya et al. / Journal of Fluorine Chemistry 178 (2015) 142–153
evaporation of the fractions that contained the pure title
compound 1f (Rf 0.25, hexane/ethyl acetate, 7:1), 163 mg (55%)
of colorless solid material was obtained, m.p. 152–156 8C after
analyzed by the standard method without metabolic activation
[17]. A liquid culture of TA102 was obtained by 16-h growth of cells
from a frozen stock at 37 8C in LB medium with penicillin. Then
cells were plated on minimal glucose agar, antibiotics and histidine
at the density sufficient to obtain isolated colonies. A separate
bacterial colony was inoculated into LB medium (5 mL) containing
sublimation. IR (KBr):
1477, 1346, 1319, 1263, 1250, 1221, 1175, 1117, 1074, 957, 945,
910, 843, 826, 762, 704, 609, 563, 532, 467, 413 cmꢂ1 1H NMR
(400.13 MHz, CDCl3): = 5.00 (br s, 1H, NH), 2.61 (s, 2H, CH2), 1.38
(s, 6H, CH3); 13C NMR (125.76 MHz, CDCl3):
= 188.4 (s, CO), 156.0
n 3327, 2974, 2934, 1683, 1655, 1599, 1538,
;
d
ampicillin (50
shaking (130 rpm) for 15 h at 37 8C.
The Ames test was carried out using the double-layer method as
described in [17]. The overnight culture of bacteria (100 l)
mg/mL) and tetracycline (2 mg/mL), and grown with
d
(d, JC5,F5 = 273.0 Hz, C5), 150.5 (ddd, JC7,F7 = 263.5; JC7,F8 =
13.4, JC7,F5 = 8.5 Hz, C7), 142.0 (m, JC8a,F8 = 10.0; JC8a,F5 ꢅ J-
C8a,F7 ꢅ 6.7 Hz, C8a), 134.9 (ddd, JC8,F8 = 240.0; JC8,F7 = 14.8;
JC8,F5 = 4.5 Hz, C8), 121.5 (q, JC,F = 273.0 Hz, CF3), 104.0 (d,
JC4a,F5 = 11.2 Hz, C4a), 96.2 (m, JC6,CF3 = 34.4; JC6,F5, JC6,F7 ꢅ 15.0,
13.0 Hz, C6), 53.7 (s, C(CH3)2), 50.6 (s, CH2), 27.3 (s, CH3); 19F NMR
m
containing one of the tested compounds in different concentra-
tions and, if required, 3 mM H2O2, were mixed at 42 8C with 2 mL of
liquid 0.6% top agar. The mixture was poured onto plates with a
minimal medium containing 0.2% glucose and 3% agar, taking care
to distribute the mixture uniformly on the surface of the solid agar.
The plates were incubated for 48 h at 37 8C, and the revertants
were counted. The cells incubated with H2O2 in the absence of
compounds analyzed were used as positive controls, and the cells
grown in the absence of H2O2 and antioxidants served as negative
controls for mutation induction. The results are expressed as
mean ꢃ standard deviation of at least 3 independent experiments.
(282.37 MHz, CDCl3):
d
= ꢂ56.2 (dd, 3F, JCF3,F5 = 23.0; JCF3,F7 =
21.2 Hz, CF3), ꢂ116.1 (qdd, 1F, JF5,CF3 = 23.0; JF5,F8 = 14.1;
JF5,F7 = 4.7 Hz, F5), ꢂ131.6 (qdd, 1F, JF7,CF3 = 21.2; JF7,F8 = 20.0;
JF7,F5 = 4.7 Hz, F7), ꢂ165.8 (ddd, 1F, JF8,F7 = 20.0; JF8,F5 = 14.1;
JF8,H1 = 3.0 Hz, F8); HRMS (EI) calcd. for C12H9F6NO (M+):
297.0583, found 297.0578. Anal. calcd. for C12H9F6NO: C, 48.50;
H, 3.05; N 4.71. Found: C, 48.84; H, 3.10; N, 4.71.
4.3.6. 2,2-Dimethyl-2,3-dihydroquinolin-4(1H)-one (5)
Acknowledgments
The reaction of 7 (219 mg, 1 mmol) and 2-methylbut-3-yn-2-ol
(126 mg, 1.5 mmol) afforded the crude compound 8 (the 1H NMR
spectra agreed with the literature data [11]). Then PTSA (285 mg,
1.5 mmol) was added to the solution of crude 8 in EtOH (25 mL)
and the mixture was heated under reflux for 8 h with stirring. The
crude product 5 was purified by column chromatography (eluant:
hexane/ethyl acetate, 8:1). The evaporation of the fractions
containing 5 (Rf 0.30, hexane/ethyl acetate, 7:1), gave 157 mg
(90%) of the title product as yellow solid material, m.p. 82.7–
The analytical and spectral measurements were performed by
the Collective Service Center of the Siberian Branch of the Russian
Academy of Science. The authors thank the Russian Foundation of
Basic Research for financial support (grant 14-03-00108). The
biological work was supported by the interdisciplinary grant 98
from the Siberian Branch of the Russian Academy of Science.
Appendix A. Supplementary data
82.9 8C from hexane (yellow oil [18]; 82–83 8C [22]). IR (KBr):
n
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.jfluchem.2015.07.
006.
3325, 3065, 2984, 2961, 2928, 1661, 1616, 1512, 1483, 1462, 1431,
1348, 1315, 1267, 1231, 1155, 1126, 1111, 1024, 758, 681, 631,
571, 528, 473 cmꢂ1; 1H NMR (400.13 MHz, CDCl3):
d = 7.78 (dd, 1H,
JH5, H6 = 7.9; JH5, H7 = 1.5 Hz, H5), 7.26 (ddd, 1H, JH7,H8 = 8.2;
JH7,H6 = 7.0; JH7,H5 = 1.5 Hz, H7), 7.67 (ddd, 1H, JH6,H5 = 7.9;
JH6,H7 = 7.0; JH6,H8 = 0.9 Hz, H6), 6.58 (dm, 1H, JH8,H7 = 8.2 Hz,
H8), 4.13 (br s, 1H, NH), 2.57 (s, 2H, CH2), 1.30 (s, 6H, CH3); 13C NMR
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d
= 194.0 (s, C4), 149.8 (s, C8a), 135.2 (s, C7),
127.1 (s, C5), 117.8 (s, C4a), 117.2 (s, C6), 115.6 (s, C8), 53.5 (s, C2),
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Tumor cell lines from human myeloma RPMI 8226, human
mammary adenocarcinoma MCF-7, mouse fibroblasts LMTK and
primary mouse fibroblast cell line (PMF) (ꢀ2000 cells per well)
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