Synthesis of 2-aminobenzophenone derivatives and their anticancer activity

Article abstract of DOI:10.1080/00397911.2010.521435

A number of 2-aminobenzophenones have been synthesized by acylation of para-chloroaniline with different 2-, 3-, 4-chloro-or fluorobenzoyl chloride in solid state via the Friedel-Crafts reaction. Synthesized compounds were characterized by ¹H and ¹³C NMR, Fourier transform-infrared, ultraviolet-visible spectroscopy, mass spectrometry, and elemental analysis. Evaluation of biological activity in vitro showed that the selected compounds 9, 10, and 13 have potential anticancer activity. The presence of one chlorine atom in the second aromatic ring of the benzophenone molecule makes it more active.

Full text of DOI:10.1080/00397911.2010.521435

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Synthesis of 2-Aminobenzophenone
Derivatives and Their Anticancer Activity
S. Cortez-Maya a , E. Cortes Cortes a , S. Hernández-Ortega a , T.
Ramirez Apan a & M. Martínez-García a
a Instituto de Química, Universidad Nacional Autónoma de México,
Coyoacán, México
Accepted author version posted online: 27 Jun 2011.Published
online: 14 Sep 2011.
To cite this article: S. Cortez-Maya , E. Cortes Cortes , S. Hernández-Ortega , T. Ramirez Apan & M.
Martínez-García (2012): Synthesis of 2-Aminobenzophenone Derivatives and Their Anticancer Activity,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:1, 46-54
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Synthetic Communications1, 42: 46–54, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.521435
SYNTHESIS OF 2-AMINOBENZOPHENONE
DERIVATIVES AND THEIR ANTICANCER ACTIVITY
´
S. Cortez-Maya, E. Cortes Cortes, S. Hernandez-Ortega,
´
T. Ramirez Apan, and M. Martınez-Garcıa
Instituto de Quımica, Universidad Nacional Autonoma de Mexico,
´
´
´
´
´
Coyoacan, Mexico
´
GRAPHICAL ABSTRACT
Abstract A number of 2-aminobenzophenones have been synthesized by acylation of para-
chloroaniline with different 2-, 3-, 4-chloro- or fluorobenzoyl chloride in solid state via the
1
Friedel–Crafts reaction. Synthesized compounds were characterized by H and 13C NMR,
Fourier transform–infrared, ultraviolet–visible spectroscopy, mass spectrometry, and
elemental analysis. Evaluation of biological activity in vitro showed that the selected
compounds 9, 10, and 13 have potential anticancer activity. The presence of one chlorine
atom in the second aromatic ring of the benzophenone molecule makes it more active.
Keywords Aminobenzophenones; anticancer activity; benzodiazepine intermediates;
biological activity; Friedel–Crafts acylation
INTRODUCTION
The development of resistance to current antibiotics continues to be an
important problem in the treatment of various diseases.[1–4] Therefore, the synthesis
of new drugs is a high-priority area of biochemical research. Aminobenzophenones
are a new class of biologically active compounds. A great variety of aminobenzophe-
nones and their derivatives have been synthesized. These compounds showed differ-
ent types of biological activity such as antitumoral and anticonvulsive activities[5]
and activity against the hepatitis C RNA virus.[6] Some aminobenzophenones
showed high activity against a panel of human cancer cell lines including multidrug-
resistant ones.[7,11] In addition, aminobenzophenones are intermediates in the
Received April 21, 2010.
Address correspondence to M. Martınez-Garcıa, Instituto de Quımica, Universidad Nacional
´
´
´
Autonoma de Mexico, Cd. Universitaria, Circuito Exterior, Coyoacan, C.P. 04510, Mexico D.F.,
´
Mexico. E-mail: margar@servidor.unam.mx
´
´
´
´
46

2-AMINOBENZOPHENONE DERIVATIVES
47
synthesis of benzodiazepine derivatives,[9] more than 10,000 of which were found to
have pharmacological properties. Several of them are commercially applied.
Recently, it has been shown that aminobenzophenones with an amino group in
the ortho position of the benzophenone ring show interesting biological activity char-
acteristics.[10,11] In the present work, we report the synthesis of a series of 2-amino-5-
chloro-benzophenones, chloro- or fluoro-substituted in ortho-, meta-, or para-positions,
and results of their biological activity against six human cancer cell lines.
RESULTS AND DISCUSSION
Synthesis and Characterization of Aminobenzophenones
The synthesis of 2-aminobenzophenones 9–15 was achieved starting from para-
chloroaniline and substituted benzoyl chlorides (Scheme 1) using freshly dried ZnCl2
as a catalyst.[12,13] The 2-aminobenzophenones were obtained in good yields (from 40
to 50%).
1
The structures of 2-aminobenzophenones 9–15 were determined by H and
13C NMR, Fourier transform–infrared (FTIR), ultraviolet–visible (UV-vis) spec-
troscopy, mass spectrometry, and elemental analysis.
When the same reaction was carried out using ZnCl2 that had not been dried
previously, only the amide products were obtained in most cases (Scheme 2). For
example, the reaction between para-chloroaniline and 4-fluorobenzoyl chloride in
the presence of untreated ZnCl2 catalyst resulted in N-(4-chlorophenyl)-4-fluoroben-
zamide with 80% yield.
1
The structure of compound 16 was determined by H and 13C NMR, FTIR,
UV-vis spectroscopy, mass spectrometry, and elemental analysis and was confirmed
by x-ray diffraction analysis of a single crystal prepared by crystallization from
CH2Cl2. The general view of the crystal structure of compound 16 is shown in Fig. 1.
Cytotoxic Activity
The cytotoxic activity of the synthesized 2-aminobenzophenones 9–15 was
tested in macrophages, and three compounds [free benzophenone 9 and benzophe-
nones with chloro- or fluoro-substituents in ortho-position (compounds 10 and 13,
respectively)] were chosen for the evaluation of their biological activity against
Scheme 1. Synthesis of 2-amino-5-chlorobenzophenone derivatives 9–15.

48
S. CORTEZ-MAYA ET AL.
Scheme 2. Synthesis of N-(4-chlorophenyl)benzamide derivative 16.
cancer. The rest of the compounds were discarded because of lower activity. The
selected compounds 9, 10, and 13 were screened in vitro against six human cancer
cell lines. K-562 (human chronic myelogenous leukemia), SKLU-1 (human lung
adenocarcinoma), and HCT-15 (human colorectal adenocarcinoma) cell lines were
supplied by the National Cancer Institute (NCI, USA). The human tumor cytotoxi-
city was determined using the protein-binding dye sulforhodamine B (SRB) in
microculture assay to measure cell growth, as described in the protocols established
by the NCI.[14] The cell lines were cultured in RPMI-1640 medium supplemented
with 10% fetal bovine serum, 2 mM L-glutamine, 10000 units=ml penicillin G sodium,
0
˚
Figure 1. Crystal structure and crystal packing of 16. Selected bond lengths (A): N(1)–C(1 ) ¼ 1.422(2),
N(1)–C(7) ¼ 1.343(2), O(1)–C(7) ¼ 1.226(2), F(1)–C(4) ¼ 1.366(2), Cl(1)–C(40) ¼ 1.739(2). Selected bond
angles (ꢀ): C(7)–N(1)–C(10) ¼ 126.39(16), C(7)–N(1)–H(1) ¼ 120.7(12), C(10)–N(1)–H(1) ¼ 112.8(12),
O(1)–C(7)–N(1) ¼ 122.24(19), O(1)–C(7)–C(1) ¼ 120.99(17), N(1)–C(7)–C(1) ¼ 116.76(17).

2-AMINOBENZOPHENONE DERIVATIVES
49
Table 1. Inhibition on the growth (%) of human tumor cell lines for 9, 10, and 13 at 50 mM in DMSO
Cell line
Compound
U-251
PC-3
K-562
HCT-15
MCF-7
SKLU
9
10
13
16.06
62.04
52.85
21.77
58.6
40.72
49.37
89.92
98.36
66.56
95.43
75.89
73.04
67.84
78.36
25.64
81.47
76.86
Table 2. Inhibitory concentration (IC50) (mM) values obtained in K-562,
HCT-15, and SKLU-1 cell lines for compounds 9, 10, and 13 in DMSO
Compounds
K-562
HCT-15
SKLU-1
9
10
58.54 ꢁ 4.6
25.48 ꢁ 2.3
40.86 ꢁ 1.6
15.20 ꢁ 1.4
45.43 ꢁ 2.5
18.87 ꢁ 0.75
33.62 ꢁ 1.9
13.83 ꢁ 0.7
59.71 ꢁ 2.3
15.59 ꢁ 0.24
32.64 ꢁ 1.0
7.13 ꢁ 0.2
13
Cis-platin
10000 mg=ml streptomycin sulfate, 25 mg=ml amphotericin B (Gibco), and 1% non-
essential amino acids (Gibco). They were maintained at 37 ꢀC in a humidified atmos-
phere with 5% CO2. The viability of the cells used in the experiments exceeds 95% as
determined with trypan blue. The initially obtained cytotoxic screening data (Table 1)
show that the selected compounds have good activities, especially halogen-substituted
ones, and that the activity depends on the nature of the halogen substituent.
The inhibitory concentration (IC50) values were only determined for those lines
(K-562, HCT-15, and SKLU-1), for which almost all of the IC50 values were lower
than 60 mM, and were compared to the results obtained with the cis-platin cytotoxic
agent (Table 2). For the three cell lines, compound 10 was found to be the most potent
among all 2-aminobenzophenones studied, exhibiting the lowest inhibitory concen-
trations (25.48 ꢁ 2.3, 18.87 ꢁ 0.75 and 15.59 ꢁ 0.24 mM, Table 2). The comparison
of the activity of chloro-derivative (compound 10) with that of the corresponding
fluoro-derivative (compound 13) indicates that the presence of a chlorine atom in
the second ring of the benzophenone gives better results for cancer inhibition.
In conclusion, in the present work it was observed that 2-aminobenzophenones
with chloro- or fluoro-substituents in the second ring can be obtained in good yields
from para-chloroaniline and benzoyl chloride using freshly dried ZnCl2 as a catalyst.
When untreated ZnCl2 catalyst is used, only amide compounds are obtained from the
same reactants. Biological activity tests showed that the synthesized 2-aminobenzo-
phenones compounds have potential activity against cancer, which was enhanced in
the presence of a chloro-substituent in the second ring of the 2-aminobenzophenones.
EXPERIMENTAL
Materials and Equipment
Solvents and chemicals were purchased from Aldrich as reagent grade and
used without further purification. Column chromatography was performed on silica

50
S. CORTEZ-MAYA ET AL.
1
gel 60 A, Merck (70–230 mesh). H and 13C NMR spectra were recorded on a
Varian-Unity 300-MHz instrument with tetramethylsilane (TMS) as an internal
reference. Infrared (IR) spectra were measured on a Nicolet FT-SSX spectro-
photometer. Elemental analyses were performed by Galbraith Laboratories, Inc.,
Knoxville. Electron impact (EI) mass spectra were taken on a Jeol JMS AX505
HA instrument.
˚
Cytotoxicity Assay
The cells were removed from the tissue culture flasks and diluted with fresh
media. Of these cell suspensions, 100 ml (containing 5000 or 10,000 cell per well) were
pipetted into 96-well microtiter plates (Costar), and the material was incubated at
37 ꢀC for 24 h in a 5% CO2 atmosphere. Subsequently, 100 ml of a solution of the test
compounds, obtained by diluting the stocks, were added to each well. The cultures
were exposed for 48 h to the drug at concentrations ranging from 10 to 100 mM.
After the incubation period, cells were fixed to the plastic substratum by the
addition of 50 ml of cold 50% aqueous trichloroacetic acid. The plates were incubated
at 4 ꢀC for 1 h, washed with tap H2O, and air dried. The trichloroacetic-acid-fixed
cells were stained by the addition of 0.4% SRB. Free SRB solution was removed
by washing with 1% aqueous acetic acid. The plates were air dried, and the bound
dye was solubilized by addition of 10 mM unbuffered Tris base (100 ml). The plates
were placed on a shaker for 5 min, and the absorption was determined at 515 nm using
an ELISA plates reader (Bio-Tex Instruments).
General Procedure for the Preparation of 2-Aminobenzophenones
To 21.0 mmol of the corresponding benzoyl chloride, 8.4 mmol of p-chloroaniline
were added. Then the mixture was heated to about 180–200ꢀC, 10.08 mmol of anhy-
drous ZnCl2 were added slowly, and the temperature was gradually increased to
220–230 ꢀC. The reaction mixture was maintained at reflux for 3 h. Then it was cooled
to 120 ꢀC, and hot water was added to remove the benzoic acid, giving a green-brown
product. The obtained green-brown product was added to a mixture of H2SO4,
CH3COOH, and H2O (5.0:3.5:3.0 mL) and refluxed for 40 min. Then, about 20–25 mL
of ice-water mixture was added, and the reaction mixture was subsequently extracted
using dichloromethane. The organic phase was washed three times using water and a
solution of 10% ammonium hydroxide to neutralize it. The organic phase was dried
with anhydrous sodium sulfate. Its vacuum evaporation yielded a brown-yellow solid,
which was purified by column chromatography (SiO2, 1:2 ethylacetate=hexanes
mixture as eluent).
Select Data
(2-Aminophenyl)-phenyl-methanone 9. Known compound, mp 86–88 ꢀC.[13]
(2-Amino-5-chlorophenyl)(2-chlorophenyl)methanone 10. Known com-
pound, mp 87–89 ꢀC.[13]

2-AMINOBENZOPHENONE DERIVATIVES
51
(2-Amino-5-chlorophenyl)(3-chlorophenyl)methanone 11. Yellow solid,
mp: 100–102 ꢀC; UV-vis (CH2Cl2, k nm): 394, 235, 204; FTIR (KBr, cmꢂ1): 3435,
3322, 1616, 1590, 1530, 1466, 1294, 1152, 940, 754, 633, 498; H NMR (CDCl3):
1
6.75 (d, 1H, Ar-3, J ¼ 8.8 Hz), 7.26 (dd, 1H, Ar-4, J ¼ 2.4 Hz), 7.41 (d, 1H, Ar-6,
J ¼ 2.4 Hz), 7.45–7.48 (m, 1H, Ar-50), 7.52–5.55 (m, 1H, Ar-40), 7.56 (br, 2H, NH2),
7.62 (d, 1H, Ar-20, J ¼ 2.0 Hz), 7.63–7.67 (m, 1H, Ar-60);13C NMR (CDCl3): 112.6
(Ar-1), 117.02 (Ar-3), 126.4 (Ar-5), 127.90 (Ar-6), 128.7 (Ar-30,50), 131.8 (Ar-20,60),
=
136.9 (Ar-1 ), 137.7 (Ar-4), 138.7 (Ar-4 ), 154.3 (Ar-2), 195.4 (C O); MS m=z:
266. Anal. calcd. for C13H9 Cl2NO: C, 58.67; H, 3.41; N, 5.26. Found: C, 58.68;
H, 3.41; N, 5.25.
(2-Amino-5-chlorophenyl)(4-chlorophenyl)methanone 12. Yellow solid,
mp: 100–102 ꢀC; UV-vis (CH2Cl2, k nm): 394, 235, 204; FTIR (KBr, cmꢂ1): 3435,
3322, 1616, 1590, 1530, 1466, 1294, 1152, 940, 754, 633, 498; H NMR (CDCl3):
1
6.77 (d, 1H, Ar-3, J ¼ 8.8 Hz), 7.26 (dd, 1H, Ar-4, J ¼ 2.6 Hz), 7.41 (d, 1H, Ar-6,
J ¼ 2.4 Hz), 7.45–7.48 (m, 1H, Ar-50), 7.52–5.55 (m, 1H, Ar-30), 7.56 (br, 2H,
NH2), 7.62 (d, 1H, Ar-20, J ¼ 2.0 Hz), 7.63–7.67(m, 1H, Ar-60); 13C NMR (CDCl3):
112.60 (Ar-1), 117.2 (Ar-3), 126.4 (Ar-5), 127.7 (Ar-6), 128.7 (Ar-30,50), 131.8
0
0
0
=
(Ar-2 ,6 ), 136.9 (Ar-1 ), 137.7 (Ar-4), 138.7 (Ar-4 ), 154.3 (Ar-2), 195.4 (C O);
MS m=z: 266. Anal. calcd. for C13H9 Cl2NO: C, 58.67; H, 3.41; N, 5.26. Found:
C, 58.68; H, 3.41; N, 5.25.
(2-Amino-5-chlorophenyl)(2-fluorophenyl)methanone 13. Yellow solid,
mp: 63–65 ꢀC; UV-vis (CH2Cl2, k nm): 392, 235, 205; FTIR (KBr, cmꢂ1): 3443,
3333, 1619, 1539, 1455, 1318, 1299, 1239, 1215, 1150, 947, 755, 645; 1H NMR
(CDCl3): 6.71 (d, 1H, Ar-3, J ¼ 9.0 Hz), 7.12 (d, 1H, Ar-30, J ¼ 0.8 Hz), 7.17 (t, 1H,
Ar-50, J ¼ 1.1 Hz), 7.22–7.29 (m, 1H, Ar-40), 7.39 (dd, 1H, Ar-4, J ¼ 2.0, 1.4 Hz),
7.44–7.49 (m, 1H, Ar-6); 7.51–7.56 (m, 1H, Ar-60); 13C NMR (CDCl3): 116.0, 116.4
(Ar-1), 118.7 (Ar-3), 119.0, 120.6 (Ar-30), 124.2, 124.3 (Ar-50), 127.6, 127.9 (Ar-10),
129.4 (Ar-5), 129.6, 129.7 (Ar-60), 132.1, 132.3 (Ar-6), 133.0 (Ar-40), 135.0 (Ar-4),
148.8 (Ar-20), 156.5 (Ar-2), 161.5 (Ar-20), 194.3 (C ¼ O); MS m=z: 249. Anal. calcd.
for C13H9ClFNO: C, 62.54; H, 3.63; N, 5.61. Found: C, 62.53; H, 3.63; N, 5.60.
(2-Amino-5-chlorophenyl)(3-fluorophenyl)methanone 14. Yellow solid,
mp: 106–108 ꢀC; UV-vis (CH2Cl2, k nm): 392, 235, 204; FTIR (KBr, cmꢂ1): 3462,
3348, 1630, 1580, 1540, 1471, 1436, 1243, 1162, 769, 523; H NMR (CDCl3): 6.00
1
(br, 2H, NH2), 6.70 (d, 1H, Ar-3, J ¼ 8.8 Hz), 7.12 (d, 1H, Ar-30, J ¼ 0.8 Hz), 7.18
(t, 1H, Ar-50, J ¼ 1.1 Hz), 7.26 (dd, 1H, Ar-4, J ¼ 2.0, 1.4 Hz), 7.37 (d, 1H, Ar-6),
13
7.66 (d, 2H, Ar-60), 7.68 (d, 1H, Ar-20); C NMR (CDCl3): 115.1, 115.7 (Ar-20,40),
118.5 (Ar-3), 120.0 (Ar-1), 121.6, 121.7 (Ar-60), 122.8 (Ar-6), 123.0 (Ar-5), 132.5,
132.8 (Ar-50), 134.2 (Ar-4), 135.4, 135.7 (Ar-10), 154.2 (Ar-2), 163.1, 166.4 (Ar-30),
=
196.3 (C O); MS m=z: 249. anal. calcd. for C13H9ClFNO: C, 62.54; H, 3.63; N,
5.61. Found: C, 62.53; H, 3.63; N, 5.60.
(2-Amino-5-chlorophenyl)(4-fluorophenyl)methanone 15. Yellow solid,
mp: 106–108 ꢀC; UV-vis (CH2Cl2, k nm): 392, 235, 204; FTIR (KBr, cmꢂ1): 3462,
3348, 1630, 1580, 1540, 1471, 1436, 1243, 1162, 769, 523; H NMR (CDCl3): 5.98
1
(br, 2H, NH2), 6.70 (d, 1H, Ar-3, J ¼ 9.0 Hz), 7.16 (m, 1H, Ar-30), 7.13–7.19 (m,
2H, Ar-30,50), 7.20–7.36 (m, 1H, Ar-6), 7.36 (d, 1H, Ar-4, J ¼ 2.4 Hz), 7.67 (dd, 2H,

52
S. CORTEZ-MAYA ET AL.
Ar-20,60); 13C NMR (CDCl3): 115.3, 115.6 (Ar-30,50), 118.4 (Ar-3), 118.7 (Ar-5), 120.0
(Ar-1), 131.6, 131.7 (Ar-20,60), 132.8 (Ar-6), 134.2 (Ar-4), 135.4 (Ar-10), 149.2 (Ar-2),
0
=
163.1, 166.4 (Ar-4 ), 196.3 (C O); MS m=z: 249. Anal. calcd. for C13H9ClFNO: C,
62.54; H, 3.63; N, 5.61. Found: C, 62.53; H, 3.63; N, 5.60.
Crystal Structure Determination
A suitable crystal of compound 16 (obtained by crystallization from CH2Cl2 at
room temperature) was rolled in epoxy resin and mounted on a glass fiber. Bruker
Apex AXS CCD area detector x-ray diffractometer was the instrument used for deter-
mination. The data were first reduced and corrected for absorption using psi scans
and then solved using the program SHELL-XS. All nonhydrogen atoms were refined
using the anisotropic thermal parameters, and the hydrogen atoms were refined at
calculated positions by applying thermal parameters constrained to the carbon atom
on which they were attached. A summary of the key crystallographic information is
given in Table 3. CCDC 778732 contains the supplementary crystallographic data for
this article. These data can be obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: þ44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk.
Table 3. Crystal data and structure refinement
Parameter
Value
Empirical formula
Formula weight
Temperature
C13 H9 Cl F N O
249.66
298(2) K
˚
Wavelength
0.71073 A
Monoclinic
P 21=c
Crystal system
Space group
Unit cell dimensions
ꢀ
˚
a ¼ 12.081(2) A, a ¼ 90
ꢀ
˚
b ¼ 9.7923(16) A, b ¼ 93.514(3)
ꢀ
˚
c ¼ 9.9142(16) A, c ¼ 90
3
˚
Volume
Z
1170.6(3) A
4
Density (calculated)
Absorption coefficient
F(000)
1.417 Mg=m3
0.320 mmꢂ1
512
Crystal size=shape=color
Theta range for data collection
Index ranges
0.40 ꢃ 0.10 ꢃ 0.10 mm=prism=colorless
1.69 to 25.30ꢀ
ꢂ14 < ¼ h < ¼ 14, ꢂ11 < ¼ k < ¼ 11, ꢂ11 < ¼ l < ¼ 11
Reflections collected
Independent reflections
Completeness to theta ¼
Absorption correction
Refinement method
Data=restraints=parameters
Goodness of fit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
Largest diff. peak and hole
9420
2135 [R(int) ¼ 0.0622]
25.30ꢀ 100.0%
None
Full-matrix least-squares on F2
2135=1=157
0.869
R1 ¼ 0.0386, wR2 ¼ 0.0773
R1 ¼ 0.0679, wR2 ¼ 0.0859
ꢂ3
˚
0.201 and ꢂ0.144 e.A

2-AMINOBENZOPHENONE DERIVATIVES
53
ACKNOWLEDGMENTS
This work was supported by DGAPA-UNAM Grant IN202010-3. We thank
O. H. Rios, L. Velasco, S. E. Huerta, M. M. R. Patin˜o, and M. A. Pen˜a Gonzalez
for technical assistance.
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