Synthesis and evaluation of the antitumor activity of polyhalo acridone derivatives

Article abstract of DOI:10.1039/c4ra12354a

A series of polyhalo acridone heterocyclic compounds were synthesized and evaluated for their in vitro antitumor activity. It was noteworthy that halogen atoms were present at the 1, 3 and 4 sites of the compounds, and an amide group or a cyano group was at the 2 site. The antitumor bioactivity screening revealed that all the compounds exhibited potent antitumor activity. In particular, compounds 4d, 4o, 5j and 5k showed good antineoplastic selectivity, with a survival rate above 50% in NIH3T3 mouse embryonic cells. The IC₅₀ values were 8.69-13.06 μM in A431 cells. A preliminary assessment of the structure-selectivity relationship of the compounds was also performed.

Full text of DOI:10.1039/c4ra12354a

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Synthesis and evaluation of the antitumor activity
of polyhalo acridone derivatives†
Cite this: RSC Adv., 2015, 5, 17444
a
a
c
c
Chao Huang,ab Sheng-Jiao Yan, Xiang-Hui Zeng, Bo Sun, Min-Bo Lan
*
*
a
*
and Jun Lin
A series of polyhalo acridone heterocyclic compounds were synthesized and evaluated for their in vitro
antitumor activity. It was noteworthy that halogen atoms were present at the 1, 3 and 4 sites of the
compounds, and an amide group or a cyano group was at the 2 site. The antitumor bioactivity screening
revealed that all the compounds exhibited potent antitumor activity. In particular, compounds 4d, 4o, 5j
and 5k showed good antineoplastic selectivity, with a survival rate above 50% in NIH3T3 mouse
embryonic cells. The IC50 values were 8.69–13.06 mM in A431 cells. A preliminary assessment of the
structure–selectivity relationship of the compounds was also performed.
Received 14th October 2014
Accepted 3rd February 2015
DOI: 10.1039/c4ra12354a
www.rsc.org/advances
Introduction
Acridone compounds exist extensively in natural products. As a
macro-cyclic conjugated system with a rigid planar structure on
the acridine ring, acridone can be embedded in biological
macromolecules (Fig. 1), such as DNA,1 and possess potent
antitumor,2 antiviral,3 antimalarial4 and antimicrobial5 bioac-
tivity. Owing to its strong uorescence emission, it has also
been applied to cell labeling and medical testing as a uores-
cent pH indicator.6
Fig. 1 The structure of acridone compounds.
aminals11 with antitumor activity and polyhalo iso-
phthalonitriles12 with antimicrobial activity. The synthesis of
acridone and the study of its application as a uorescent pH
indicator have also seen some progress.13 In this paper, we
present our work on the rational design and synthesis of novel
polyhalo acridone derivatives. We also evaluate their in vitro
antitumor activity with a view to obtaining acridone antineo-
plastic compounds.
The oxidation of acridines14 and intramolecular cyclization of
substituted diaryl amines15 are common methods of acridone
synthesis. Intramolecular cyclization is more generic. PPA16 and
phosphorus oxychloride17 are usually used as the reagents of ring
closure. Here, we used polyhalo isophthalonitriles as raw mate-
rials, affording intermediates by a substitution reaction of their
halogen atoms and anilines, to prepare different substituted
Recently, reports on halogen compounds, especially uori-
nated compounds, have gradually increased in medicinal
chemistry
research7
because
of
their
recognized
environmentally-friendly features and the improved bioactivity
of target compounds due to the introduction of uoride.8
Previous studies have revealed that organic halides show good
antitumor and antibacterial activity.9 Meanwhile, as imitative
halogens, cyano groups also play an important role in the
activity of drugs on account of their inherently strong electro-
negativity and coordination property with amino acids and
metal ions, cyanide-containing drugs are constantly emerging.10
Our team has committed to the research on halogen and cyano
compounds, and we discovered polyhalo heterocyclic ketene
aKey Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), polyhalo acridones with side chains containing amide or cyano
Ministry Education, School of Chemical Science and Technology, Yunnan University,
groups catalyzed by concentrated sulfuric acid (Scheme 1).
Kunming, 650091, P. R. China. E-mail: yanshengjiao@126.com; linjun@ynu.edu.cn;
Fax: +86 871 65033215
bKey Laboratory of Ethnic Medicine Resource Chemistry, State Ethnic Affairs
Results and discussion
Commission
& Ministry of Education, School of Chemistry and Biotechnology,
Yunnan Minzu University, Kunming 650050, P. R. China
In DMF solution, polyhalo isophthalonitriles 1 and substituted
anilines 2 can produce intermediates 3 with potassium
carbonate as the catalyst. The intramolecular cyclization of 3
runs easily in sulfuric acid heated for 45 min at 90 ꢀC, affording
polyhalo acridones 4 with side chains containing amide groups
cShanghai Key Laboratory of Functional Materials Chemistry and Research Centre of
Analysis and Test, East China University of Science and Technology, Shanghai
200237, P. R. China. E-mail: minbolan@ecust.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra12354a
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Scheme 1
Table 1 Cytotoxic activity of polyhalo acridones in vitroa (IC50, mMb)
Anti-cancer activity IC50 (mM)
Entry
Compound
Gibbs energyc [kJ molꢁ1
]
C log P
HL60
K562
A431
HepG-2
Skov-3
HT-29
A549
1
2
3
4
5
6
7
8
4a
4b
4c
4e
4f
5a
5b
5c
5e
5f
181.46
0.98
0.80
0.16
1.53
0.89
3.23
2.48
1.83
3.19
2.55
2.24
1.60
5.7
0.2
2.0
16.6
1.3
2.02
0.00711
12.31
0.58
20.46
20.77
5.47
3.1
7.7
0.2
4.5
3.0
2.7
5.70
2.50
19.25
2.55
1.52
0.37
1.59
8.5
1.2
0.08
0.05
0.3
1.9
0.2
6.5
3.4
4.3
—
—
—
—
—
28.0
4.0
4.5
5.3
3.9
—
—
—
—
—
—
—
—
—
—
—
—
—
—
ꢁ184.3
ꢁ367.18
ꢁ205.86
ꢁ388.74
377.11
0.3
—
3.41
6.97
21.07
2.99
23.99
2.44
2.83
2.3
6.45
10.57
0.0348
64.51
4.61
6.29
2.3
11.35
0.0334
33.26
16.31
30.26
10.30
29.84
ꢁ171.53
ꢁ10.21
ꢁ193.09
9
10
11
12
5h
5i
DDP
ADM
—
—
8.2
—
—
10.7
4.98
2.02
0.11
0.12
0.053
0.44
a
Cytotoxicity as IC50 for each cell line, refers to the concentration of compound which reduced by 50% the optical density of treated cells with
b
c
respect to untreated cells using the MTT assay. Data represent the mean values of three independent determinations. Gibbs energy and
C log P values of the compounds were calculated by ChemDraw Ultra 11.0.
in high yields. Then, polyhalo acridones 5 with side chains amide or cyano groups on the side chain of polyhalo acridones
containing cyano groups can be generated by the phosphorus exhibited weak cytotoxic effects (4a vs. 5a, 4b vs. 5b, 4c vs. 5c).
oxychloride catalyzed reduction of the amide group of 4. All the
Next, the antitumor selectivity against the mouse embryonic
cell NIH3T3 of polyhalo acridones 4 and 5 was analyzed by the
MTT assay to perform a safety evaluation of the prepared
target compounds have been well characterized by 1H NMR, 13
NMR, 19F NMR and HRMS (Table 1).
C
Firstly, the in vitro antitumor activity of representative poly- compounds using normal cells. Survival rates were obtained
halo acridones 4a–f with side chains containing amide group aer 72 h of treatment at the concentration of 10 mM, as shown
and polyhalo acridones 5a–i with side chains containing cyano in Table 2. The survival rates for compounds 4a, 4d, 4m, 5j and
groups were evaluated by MTT assay against the human myeloid 5k were found to be higher than 50%, while those of
leukemia cell lines HL-60 and K562,18 epidermoid carcinoma cell compounds 4c, 4i, 4j, 4l, 4n and 4o were found to be in the range
line A431, ovarian cancer cell line Skov-3, laryngeal carcinoma of 11.47% to 41.63%; the rest was in the range of 0.66–8.52%
cell line Hep-2, adenomatous tumor cell line HT-29 and lung under similar conditions. The results illustrate that although
cancer cell line A549, using ADM and DDP as the positive the compounds in this paper showed cytotoxicity against
controls. As the results show in Table 1 (4a–f, 5a–i), all the tested normal cells, some of them were weakly toxic and relatively safe.
compounds displayed good antitumor activity with IC50 values in
Among those compounds with a survival rate above 50%,
the range of 0.00711–64.51 mM. Therefore, it is reasonable to compounds 4a, 4d, 4m and 5j contain uorine atoms, indi-
believe that polyhalo acridones in this paper indicated favorable cating that uorine atoms may have a positive inuence on
in vitro cytotoxicity. It is worth noting that all the compounds 4 antitumor activity against cancer cell lines, as well as cytotox-
were sensitive against A431 with IC50 values in the range of 0.05– icity in normal cells. It is important to point out that amide
1.2 mM, and exhibited better inhabitation than DDP. Among groups in the halogen-containing benzene ring of 4a, 4d and 4m
them, 4b, with IC50 values in the range of 0.08–4.0 mM and 5b, were relatively safe for normal cells, while the reduction of
with IC50 values in the range of 0.00711–6.97 mM, show cyano groups of 5a and 5d from amide groups increased cyto-
outstanding activity. Based on the cytotoxic inhibition screening, toxicity against normal cells. Moreover, 5j and 5k, compounds
the introduction of uorine atoms improved the antitumor containing methyl and cyano groups at the ortho-position in the
activity against cancer cell lines (4b, 4c vs. 4a, 5b vs. 5a), while benzene ring, and the corresponding amide acridones 4j and 4k
also exhibited strong cytotoxic activity. Then, antitumor activity
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Table 2 Cytotoxic activity of polyhalo acridones in vitro (IC50, mMa)
Entry
Compound
Gibbs energyb [kJ molꢁ1
]
C log P
X
Y
R
Yieldc (%)
Survival rate (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
181.46
3.26
2.46
2.06
3.81
3.01
2.61
2.87
1.91
1.42
3.74
2.94
2.54
2.87
2.07
1.67
4.38
3.58
3.18
4.94
4.14
3.74
3.66
2.70
2.21
4.87
4.07
3.67
Cl
F
F
Cl
F
F
Cl
F
F
Cl
F
F
Cl
F
F
Cl
F
F
Cl
F
F
Cl
F
F
Cl
Cl
F
Cl
Cl
F
Cl
Cl
F
Cl
Cl
F
Cl
Cl
F
Cl
Cl
F
Cl
Cl
F
Cl
Cl
F
H
H
H
Cl
Cl
Cl
NO2
NO2
NO2
Me
Me
Me
OH
OH
OH
H
84
76
86
80
85
81
78
83
82
82
85
83
83
86
87
73
72
77
76
75
78
75
72
70
80
83
83
>50
ꢁ184.3
ꢁ367.18
159.9
2.60
17.16
>50
ꢁ205.86
7.90
8.52
5.70
1.46
15.54
11.47
1.52
21.13
>50
20.69
41.63
0.96
1.87
1.36
1.31
3.29
0.66
2.44
1.54
2.31
>50
ꢁ388.74
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
4j
4k
4l
180.25
ꢁ185.51
ꢁ368.39
26.84
ꢁ338.92
ꢁ521.8
377.11
11.35
ꢁ171.53
355.55
ꢁ10.21
ꢁ193.09
4m
4n
4o
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
H
H
Cl
Cl
Cl
NO2
NO2
NO2
Me
Me
Me
375.9
10.14
ꢁ172.74
Cl
F
F
Cl
Cl
F
>50
1.31
a
Cytotoxicity as IC50 for each cell line, refers to the concentration of compound which reduced by 50% the optical density of treated cells with
b
respect to untreated cells using the MTT assay. Gibbs energy and C log P values of the compounds were calculated by ChemDraw Ultra 11.0.
c
Isolated yield by silica gel column chromatography.
of relatively safer compounds with survival rates above 50% lines (NIH3T3) and cancer cell lines (A431), such as the
against cell line NIH3T3, was evaluated to nd novel antitumor randomly selected compounds 4k and 5a (shown in Table 3),
leads with high selectivities. The apoptosis ratios in the characterized by poor antitumor selectivity. The IC50 values
epidermoid carcinoma cell line A431 treated with 4a, 4d, 4m, showed the same trend by the SRB method in vitro against
4o, 5j and 5k for 72 h, respectively, are shown in Table 3. As human lung cancer (A549) and human liver cancer (HepG2).
suggested by the results, all the tested compounds showed
Based on the above observations, the preliminary structure–
potent in vitro antitumor activity. Especially, 4d, 4o, 5j and 5k selectivity relationship of polyhalo acridones was determined
exhibited excellent antitumor selectivity as inhibition in A431 and shown in Scheme 2. The uorine atoms of the compounds
was more signicant, but weaker in normal cells. These described in this study, which reduced the Gibbs energy and
compounds also showed good inhibition both in normal cell C log P values of molecules, may result in an enhancement in
cytotoxic activity. As the antitumor activity results of these
compounds were in a relatively narrow range, the basic struc-
ture of the polyhalo acridones appeared to have the greatest
Table 3 Cytotoxic activity of polyhalo acridones in vitroa
inuence, while the cyano and amide groups on the side chain
IC50 (mM)
Compounds
A431
A549
HepG2
4a
4d
4k
4m
4o
5a
5j
25.3 ꢂ 0.41
8.69 ꢂ 3.52
1.78 ꢂ 0.08
26.45 ꢂ 0.13
10.71 ꢂ 0.19
5.97 ꢂ 0.1
1.32
1.75
0.23
7.16
—
0.90
1.05
0.97
1.75
1.45
0.25
7.16
—
4.74
3.80
3.23
12.1 ꢂ 0.34
13.06 ꢂ 0.47
5k
a
The IC50 value of A431 was determined using the MTT assay. IC50 value
of A549 and HepG2 were determined using the SRB assay.
Scheme 2 The preliminary structure–selectivity relationship of poly-
halo acridones.
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had little effect on activity, as well as the substitution position in
the aromatic ring. The in vitro evaluation of antitumor activity
and cytotoxicity against normal cell lines and cancer cell lines
found that compounds 4d, 4o, 5j and 5k possessed antitumor
selectivity. The above results have laid the foundation for
further research on the antitumor activity of polyhalo acridones.
General procedure for the synthesis of polyhalo acridone with
side chains containing amide group 4
Polyhalo isophthalonitrile 3 (2 mmol) was dissolved in 6 mL 95–
98% sulfuric acid, and the solution was stirred for 1 h at 90 ꢀC.
The mixture was cooled to room temperature, and then was
poured into a 100 mL beaker, then 50 mL of water was added
under stirring. The pH of the mixture was adjusted to 9–10
using solid potassium carbonate. The mixture was ltered off
and the residue was washed with water to give a crude product
that was puried by ash column chromatography. The desired
compounds 4 were formed in good yields: 76–86%.
Conclusions
In summary, the evaluation of the in vitro antitumor activity of 27
polyhalo acridone compounds revealed that representative
compounds had potent cytotoxicity. By conducting the in vitro
safety evaluation against the normal mouse embryo cell line
NIH3T3 and further screening of the inhibitory effect of the
compounds on the A431 tumor cell line, where the results showed
a survival rate of more than 50%, it is suggested that compounds
4d, 4o, 5j and 5k showed good anticancer selectivity. The above
screening results provide not only a reference to developing
antitumor drugs with high selectivity, but also a basis for further
research into polyhalo acridones in medicinal chemistry.
1,3,4-Trichloro-9-oxo-9,10-dihydroacridine-2-carboxamide (4a).
Yellow solid; mp: 251–252 C; IR (KBr) (nmax, cmꢁ1) 3478, 3416,
ꢀ
1665, 1568, 1398, 1326, 1164, 755, 612; 1H NMR (500 MHz, DMSO-
d6): d 8.48–8.18 (m, 3H, PhH), 7.95–7.80 (m, 3H, NH2, PhH), 7.48
(br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): d 162.7, 152.5, 148.5,
145.5, 132.2, 131.9, 130.7, 130.0, 129.2, 125.4, 124.4, 123.4, 115.1,
+
108.4; HRMS (TOF ES+): m/z calcd for C14H8Cl3N2O2 [(M + H)+],
340.9646; found, 340.9644.
4-Chloro-1,3-diuoro-9-oxo-9,10-dihydroacridine-2-carbo
xamide (4b). Yellow solid; mp: >300 ꢀC; IR (KBr) (nmax, cmꢁ1
)
3486, 3371, 3246, 1679, 1559, 1382, 1260, 834, 759, 601 cmꢁ1; 1H
NMR (500 MHz, DMSO-d6): d 8.52–7.77 (m, 6H, PhH, NH2),
7.46–7.43 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6): d 161.3,
156.2 (d, J ¼ 267.5 Hz), 154.8 (d, J ¼ 258.8 Hz), 151.8, 149.5,
145.2, 132.5, 129.1, 123.8, 123.4, 114.1, 111.6, 109.1 (t, J ¼ 27.5
Hz), 101.2 (d, J ¼ 32.5 Hz); 19F NMR (470 MHz, DMSO-d6): d
Experimental section
General information
All compounds were fully characterized by spectroscopic tech-
niques. The NMR spectra were recorded on a Bruker-Avance 500 ꢁ111.3 (d, J ¼ 4.7 Hz, 1F), ꢁ111.7 (d, J ¼ 4.7 Hz, 1F); HRMS (TOF
MHz spectrometer (1H: 500 MHz, 13C: 125 MHz) with tetrame- ES+): m/z calcd for C14H8ClF2N2O2+ [(M + H)+], 309.0237; found,
thylsilane (TMS) as the internal standard (d 0.0 ppm). Chemical 309.0233.
shis (d) are expressed in ppm and J values are given in Hz.
Deuterated DMSO and DMF were used as the solvents. IR
spectra were recorded on an FT-IR Thermo Nicolet Avatar 360
using a KBr pellet. The reactions were monitored by thin layer
chromatography (TLC) using neutral alumina. The melting
1,3,4-Triuoro-9-oxo-9,10-dihydroacridine-2-carboxamide (4c).
Yellow solid; mp: >300 ꢀC; IR (KBr) (nmax, cmꢁ1) 3526, 3421, 3151,
1
1685, 1557, 1388, 1265, 967, 758, 602 cmꢁ1; H NMR (500 MHz,
DMSO-d6): d 8.53–7.78 (m, 6H, PhH, NH2), 7.44 (br, 1H, NH); 13
C
NMR (125 MHz, DMSO-d6): d 161.0, 152.6 (d, J ¼ 261.3 Hz), 151.2,
points were determined on an XT-4A melting point apparatus 149.4, 145.3 (d, J ¼ 252.5 Hz), 140.5 (d, J ¼ 248.8 Hz), 140.4, 132.4,
and are uncorrected. HRMS was performed on an Agilent LC- 129.1, 123.7, 123.5, 114.1, 108.4 (t, J ¼ 25.0 Hz), 101.2; HRMS (TOF
ES+): m/z calcd for C14H8F3N2O2 [(M + H)+], 293.0532; found,
+
MSD TOF instrument.
1a, 1c and 2 were purchased from Aldrich Corporation 293.0529.
1,3,4,7-Tetrachloro-9-oxo-9,10-dihydroacridine-2-carboxamide
Limited. All chemicals and solvents were used as received
without further purication unless otherwise stated. Column
chromatography was performed on silica gel (200–300 mesh).
(4d). Yellow solid; mp: >300 ꢀC; IR (KBr) (nmax, cmꢁ1) 3297, 1637,
1553, 1437, 1234, 1094, 824, 637, 508 cmꢁ1; HRMS (TOF ESꢁ) m/z
2ꢁ
calcd for C14H4Cl4N2O2
371.9045.
[(M ꢁ 2H)2ꢁ], 371.9038; found,
4,7-Dichloro-1,3-diuoro-9-oxo-9,10-dihydroacridine-2-carbo
xamide (4e). Yellow solid; mp: >300 ꢀC; IR (KBr) (nmax, cmꢁ1
3433, 3353, 3245, 1650, 1554, 1376, 1251, 1102, 834, 630 cmꢁ1
General procedure for the synthesis of polyhalo
isophthalonitrile 3
)
;
A
50 mL round-bottom ask was charged with poly-
1H NMR (500 MHz, DMSO-d6): d 8.67 (br, 1H, NH), 8.28–7.74 (m,
5H, PhH, NH2); 13C NMR (125 MHz, DMSO-d6): d 161.0, 156.0 (d,
J ¼ 255.0 Hz), 155.0 (d, J ¼ 247.5 Hz), 151.2, 147.9, 145.4, 132.9,
131.3, 128.2, 122.4, 114.6, 111.8, 109.9 (t, J ¼ 26.3 Hz), 101.2;
HRMS (TOF ES+): m/z calcd for C14H7Cl2F2N2O2 [(M + H)+],
342.9847; found, 342.9845.
haloisophthalonitrile 1 (5 mmol), DMF (30 mL), aniline deriv-
atives 2 (6.0 mmol) and potassium carbonate 1.4 g (10 mmol),
and the solution was stirred for 0.5–18 h at room temperature
until the polyhaloisophthalonitrile 1 was completely consumed.
The mixture was dumped into a beaker (100 mL) and quenched
by the addition of water (30 mL). The mixture was ltered off
and the residue was washed with water to give a crude product
that was puried by ash column chromatography. The desired
compounds 3 were formed in excellent yields: 84–96%.
7-Chloro-1,3,4-triuoro-9-oxo-9,10-dihydroacridine-2-carbo
xamide (4f). Yellow solid; mp: 181–185 ꢀC; IR (KBr) (nmax, cmꢁ1
)
3494, 3347, 3181, 1661, 1558, 1376, 1117, 976, 829, 654 cmꢁ1; 1H
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NMR (500 MHz, DMSO-d6): d 8.64 (br, 1H, NH), 8.29–7.73 (m, 109.2 (t, J ¼ 26.3 Hz), 101.9 (d, J ¼ 10.0 Hz), 21.5; 19F NMR (467
5H, PhH, NH2); 13C NMR (125 MHz, DMSO-d6): d 160.8, 152.5 (d, MHz, DMF-d6): d ꢁ117.5 (d, J ¼ 18.7 Hz, 1F), ꢁ142.5 (d, J ¼ 18.7
J ¼ 257.5 Hz), 150.7, 147.6, 145.6 (d, J ¼ 247.5 Hz), 140.4 (d, J ¼ Hz, 1F), ꢁ157.7 (t, J ¼ 14.0 Hz, 1F); HRMS (TOF ESꢁ) m/z calcd
2ꢁ
247.5 Hz), 140.3, 132.9, 131.0, 128.2, 122.4, 114.5, 109.1 (t, J ¼ for C15H7F3N2O2 [(M ꢁ 2H)2ꢁ], 304.0471; found, 304.0480.
25.0 Hz), 101.4; 19F NMR (467 MHz, DMSO-d6): d ꢁ115.4 (d, J ¼
1,3,4-Trichloro-7-hydroxy-9-oxo-9,10-dihydroacridine-2-car
14.1 Hz, 1F), ꢁ139.3 (s, 1F), ꢁ155.9 (d, J ¼ 14.1 Hz, 1F); HRMS boxamide (4m). Yellow solid; mp: >300 ꢀC; IR (KBr) (nmax, cmꢁ1
)
(TOF ES+): m/z calcd for C14H7ClF3N2O2 [(M + H)+], 327.0143; 3399, 1634, 1502, 1455, 1407, 1332, 1244, 837, 602; 1H NMR (500
+
found, 327.0140.
MHz, DMF-d6): d 10.29 (br, 1H, NH), 8.43–7.55 (m, 5H, PhH,
1,3,4-Trichloro-7-nitro-9-oxo-9,10-dihydroacridine-2-carbo NH2), 3.08–2.74 (m, 1H, OH); 13C NMR (125 MHz, DMF-d6): d
xamide (4g). Yellow solid; mp: >300 ꢀC; IR (KBr) (nmax, cmꢁ1
)
166.1, 155.2, 150.3, 144.3, 143.8, 132.2, 131.1, 128.7, 125.5,
3369, 1567, 1498, 1329, 1182, 849, 748 cmꢁ1; 1H NMR (500 MHz, 125.2, 116.6, 108.2, 103.2, 88.9; HRMS (TOF ESꢁ) m/z calcd for
2ꢁ
DMF-d6): d 9.21 (br, 1H, NH), 8.48–7.84 (m, 5H, PhH, NH2);
C
14H5Cl3N2O3 [(M ꢁ 2H)2ꢁ], 353.9377; found, 353.9385.
HRMS (TOF ESꢁ) m/z calcd for C14H4Cl3N3O4 [(M ꢁ 2H)2ꢁ],
4-Chloro-1,3-diuoro-7-hydroxy-9-oxo-9,10-dihydroacridine-
2-carboxamide (4n). Yellow solid; mp: >300 C; IR (KBr) (nmax
2ꢁ
ꢀ
382.9278; found, 382.9278.
,
4-Chloro-1,3-diuoro-7-nitro-9-oxo-9,10-dihydroacridine-2- cmꢁ1) 3398, 1641, 1463, 1366, 1243, 1067, 835, 630; 1H NMR
carboxamide (4h). Yellow solid; mp: 219–221 ꢀC; IR (KBr) (nmax
,
(500 MHz, DMF-d6): 10.34 (br, 1H, NH), 8.36–6.82 (m, 5H, PhH,
cmꢁ1) 3375, 1676, 1541, 1500, 1331, 1244, 1128, 914, 837, 745 NH2), 2.99–2.73 (m, 1H, OH); 13C NMR (125 MHz, DMF-d6): d
cmꢁ1; 1H NMR (500 MHz, DMSO-d6): d 9.60 (br, 1H, NH), 8.36– 161.3, 156.3 (d, J ¼ 250.0 Hz), 154.8, 152.3 (d, J ¼ 317.5 Hz),
7.86 (m, 5H, PhH, NH2); 13C NMR (125 MHz, DMSO-d6): d 160.8, 150.0, 147.0, 144.6, 143.1, 125.8, 115.4, 114.7, 109.7, 103.4,
157.0, 155.1, 154.5, 151.5, 147.0, 142.4, 130.5, 125.3, 122.5, 101.0; 19F NMR (467 MHz, DMF-d6): d ꢁ112.5 (s, 1F), ꢁ113.2 (s,
112.4, 112.1, 110.3 (t, J ¼ 27.5 Hz), 101.7; HRMS (TOF ESꢁ) m/z 1F); HRMS (TOF ESꢁ) m/z calcd for C14H5ClF2N2O3 [(M ꢁ
2ꢁ
[(M ꢁ 2H)2ꢁ], 350.9869; found, 2H)2ꢁ], 321.9968; found, 321.9975.
2ꢁ
calcd for C14H4ClF2N3O4
350.9878.
1,3,4-Triuoro-7-hydroxy-9-oxo-9,10-dihydroacridine-2-carbo
1,3,4-Triuoro-7-nitro-9-oxo-9,10-dihydroacridine-2-carbo xamide (4o). Yellow solid; mp: 197–198 ꢀC; IR (KBr) (nmax, cmꢁ1
)
xamide (4i). Yellow solid; mp: >300 ꢀC; IR (KBr) (nmax, cmꢁ1
)
3379, 1657, 1465, 1369, 1259, 1129, 977; 1H NMR (500 MHz,
3409, 3233, 1656, 1501, 1332, 1252, 1127, 978, 616 cmꢁ1 1H DMF-d6): d 10.19 (br, 1H, NH), 8.36–7.54 (m, 5H, PhH, NH2),
;
NMR (500 MHz, DMF-d6): d 10.15 (br, 1H, NH), 9.74–8.17 (m, 3.09–2.57 (m, 1H, OH); 13C NMR (125 MHz, DMF-d6): d 161.7,
5H, PhH, NH2); 13C NMR (125 MHz, DMF-d6): d 159.8, 159.0, 155.1, 154.0, 152.0, 149.5, 145.6, 144.1, 139.2, 131.3, 126.1,
154.3 (d, J ¼ 252.5 Hz), 150.1 (d, J ¼ 251.3 Hz), 144.1, 143.1, 115.9, 109.2, 103.7, 101.6; 19F NMR (467 MHz, DMF-d6):
136.8 (d, J ¼ 250.0 Hz), 132.6, 130.3, 122.8, 121.3, 112.7, 111.8 d ꢁ117.9 (d, J ¼ 14.1 Hz, 1F), ꢁ143.7 (d, J ¼ 14.0 Hz, 1F), ꢁ157.7
(d, J ¼ 20.0 Hz), 101.5; 19F NMR (467 MHz, DMF-d6): d ꢁ116.8 (s, (t,
J
¼
14.02ꢁ Hz, 1F); HRMS (TOF ESꢁ) m/z calcd for
1F), ꢁ131.5 (d, J ¼ 14.0 Hz, 1F), ꢁ159.4 (s, 1F); HRMS (TOF ESꢁ)
C
14H5F3N2O3 [(M ꢁ 2H)2ꢁ], 306.0263; found, 320.0272.
2ꢁ
m/z calcd for C14H4F3N3O4 [(M ꢁ 2H)2ꢁ], 335.0165; found,
335.0176.
General procedure for the synthesis of polyhalo acridone with
side chains containing cyano group 5
1,3,4-Trichloro-7-methyl-9-oxo-9,10-dihydroacridine-2-carbo
xamide (4j). Yellow solid; mp: >300 ꢀC; IR (KBr) (nmax, cmꢁ1
)
3389, 1682, 1631, 1456, 1329, 1258, 826, 648 cmꢁ1 1H NMR Polyhalo acridone with side chains containing an amide group 4
;
(500 MHz, DMSO-d6): d 10.48 (br, 1H, NH), 8.30–7.65 (m, 5H, (2 mmol) was dissolved in 8 mL of dry pyridine, the phosphorus
PhH, NH2), 2.51–2.48 (m, 3H, CH3); HRMS (TOF ESꢁ) m/z calcd oxychloride (0.5 mL) was added in an ice bath, and the solution
2ꢁ
for C15H7Cl3N2O2 [(M ꢁ 2H)2ꢁ], 351.9584; found, 351.9596.
was stirred for 1 h until the polyhalo acridone with side chains
4-Chloro-1,3-diuoro-7-methyl-9-oxo-9,10-dihydroacridine- containing an amide group 4 was completely consumed. The
2-carboxamide (4k). Yellow solid; mp: >300 C; IR (KBr) (nmax
ꢀ
,
reaction mixture was added to a beaker lled with crushed ice,
cmꢁ1) 3358, 1634, 1556, 1372, 1258, 1047, 828, 630 cmꢁ1; H and neutralized by Na2CO3 under stirring. The mixture was
NMR (500 MHz, DMF-d6): 7.65–6.88 (m, 6H, PhH, NH, NH2), ltered off and the residue was washed with water to give a
2.33–2.12 (m, 3H, CH3). 13C NMR (125 MHz, DMF-d6): d 160.8, crude product that was puried by ash column chromatog-
155.9 (d, J ¼ 267.5 Hz), 154.3 (d, J ¼ 260.0 Hz), 150.5, 147.6, raphy. The desired compounds 5 were formed in good yields:
144.3, 133.9, 133.0, 128.3, 120.8, 113.5, 111.3, 108.7 (t, J ¼ 26.3 70–83%.
1
Hz), 100.6, 20.5; 19F NMR (467 MHz, DMF-d6): d ꢁ112.9 (s, 1F),
1,3,4-Trichloro-9-oxo-9,10-dihydroacridine-2-carbonitrile (5a).
ꢁ113.4 (s, 1F); HRMS (TOF ESꢁ) m/z calcd for C15H7ClF2N2O2
Yellow solid; mp: 242–243 C; IR (KBr) (nmax, cmꢁ1) 3394, 2229,
2ꢁ
ꢀ
[(M ꢁ 2H)2ꢁ], 320.0175; found, 320.0183.
1633, 1563, 1335, 1167, 756, 599 cmꢁ1 1H NMR (500 MHz,
;
1,3,4-Triuoro-7-methyl-9-oxo-9,10-dihydroacridine-2-carbo DMSO-d6): d 8.60–7.49 (m, 5H, PhH, NH); 13C NMR (125 MHz,
xamide (4l). Yellow solid; mp: 177–178 ꢀC; IR (KBr) (nmax, cmꢁ1
3394, 1658, 1562, 1467, 1375, 1268, 1134, 972, 628 cmꢁ1
)
DMSO-d6): d 154.3, 149.2, 146.6, 137.4, 133.9, 131.4, 131.2, 129.6,
;
1H 125.5, 124.2, 115.8, 115.6, 108.8, 106.6; HRMS (TOF ESꢁ) m/z
NMR (500 MHz, DMF-d6): d 8.39–7.65 (m, 6H, PhH, NH, NH2), calcd for C14H3Cl3N2O2ꢁ [(M ꢁ 2H)2ꢁ], 319.9322; found,
2.95–2.74 (m, 3H, CH3); 13C NMR (125 MHz, DMF-d6): d 161.7, 321.9456.
153.4 (d, J ¼ 252.5 Hz), 150.9, 148.9, 145.8 (d, J ¼ 247.5 Hz),
4-Chloro-1,3-diuoro-9-oxo-9,10-dihydroacridine-2-carbo
141.4 (d, J ¼ 248.8 Hz), 140.7, 134.9, 134.0, 129.5, 121.9, 114.6, nitrile (5b). Yellow solid; mp: >300 ꢀC; IR (KBr) (nmax, cmꢁ1
)
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3394, 2237, 1634, 1559, 1382, 1262, 1078, 760 cmꢁ1; H NMR
(500 MHz, DMF-d6): d 8.60–7.50 (m, 5H, PhH, NH); 13C NMR
(125 MHz, DMF-d6): d 161.6, 154.8 (d, J ¼ 260.0 Hz), 153.0, 150.1,
146.6, 133.5, 129.3, 124.7, 123.3, 114.6, 112.4, 110.1, 100.5, 83.4
(t, J ¼ 21.3 Hz); 19F NMR (467 MHz, DMF-d6): d ꢁ100.5 (s, 1F),
ꢁ110.3 (s, 1F); HRMS (TOF ESꢁ) m/z calcd for C14H4ClF2N2Oꢁ
[(M ꢁ H)ꢁ], 288.9986; found, 288.9998.
1
1,3,4-Triuoro-7-nitro-9-oxo-9,10-dihydroacridine-2-carbo
nitrile (5i). Yellow solid; mp: 255–256 C; IR (KBr) (nmax, cmꢁ1
)
ꢀ
3443, 3369, 3268, 2241, 1655, 1500, 1335, 1254, 1142, 982, 609
1
cmꢁ1; H NMR (500 MHz, DMF-d6): d 9.78 (br, 1H, NH), 8.75–
7.98 (m, 3H, PhH); 13C NMR (125 MHz, DMF-d6): d 159.2, 144.5
(d, J ¼ 166.3 Hz), 144.4, 143.6, 136.3, 131.2, 129.2, 123.3, 122.8,
122.1, 120.7, 113.9, 108.7, 102.3; 19F NMR (467 MHz, DMF-d6): d
ꢁ103.6 (s, 1F), ꢁ130.3 (s, 1F), ꢁ164.7 (s, 1F); HRMS (TOF ESꢁ)
1,3,4-Triuoro-9-oxo-9,10-dihydroacridine-2-carbonitrile (5c).
Yellow solid; mp: 196–197 ꢀC; IR (KBr) (nmax, cmꢁ1) 3369, 3232,
2237, 1660, 1563, 1499, 1273, 1144, 981, 763, 598 cmꢁ1; 1H NMR
(500 MHz, DMSO-d6): d 8.57–7.51 (m, 5H, PhH, NH); 13C NMR
(125 MHz, DMSO-d6): d 162.0, 159.9, 152.2, 149.8, 146.3, 142.1,
133.7, 129.1, 124.7, 123.8, 114.5, 110.5, 100.9, 82.4 (d, J ¼ 32.5
Hz); 19F NMR (467 MHz, DMSO-d6): d ꢁ102.6 (d, J ¼ 14.0 Hz, 1F),
ꢁ138.1 (s, 1F), ꢁ154.5 (t, J ¼ 18.7 Hz, 1F); HRMS (TOF ESꢁ) m/z
m/z calcd for C14H2F3N3O3 [(M ꢁ 2H)2ꢁ], 317.0059; found,
2ꢁ
317.0068.
1,3,4-Trichloro-7-methyl-9-oxo-9,10-dihydroacridine-2-
ꢀ
carbonitrile (5j). Yellow solid; mp: 197–198 C; IR (KBr) (nmax
,
cmꢁ1) 3391, 2925, 2230, 1640, 1563, 1496, 1085, 831, 723, 553
cmꢁ1; 1H NMR (500 MHz, DMF-d6): d 10.83–10.09 (m, 1H, NH),
8.35–7.43 (m, 3H, PhH), 2.48–2.32 (m, 3H, CH3); 13C NMR (125
MHz, DMF-d6): d 159.1, 140.3, 139.4, 138.4, 137.7, 137.1, 134.5,
123.7, 122.1, 119.7, 114.6, 113.5, 110.5, 109.1, 20.8; HRMS (TOF
ESꢁ) m/z calcd for C15H5Cl3N2O2ꢁ [(M ꢁ 2H)2ꢁ], 333.9478;
found, 333.9486.
calcd for C14H3F3N2O2ꢁ [(M
272.0216.
ꢁ
2H)2ꢁ], 272.0208; found,
1,3,4,7-Tetrachloro-9-oxo-9,10-dihydroacridine-2-carbo
nitrile (5d). Yellow solid; mp: 240–241 ꢀC; IR (KBr) (nmax, cmꢁ1
)
3403, 2235, 1636, 1555, 1312, 1253, 1085, 870, 610 cmꢁ1 1H
;
4-Chloro-1,3-diuoro-7-methyl-9-oxo-9,10-dihydroacridine-
NMR (500 MHz, DMF-d6): d 8.77–7.97 (m, 4H, PhH, NH); 13C
NMR (125 MHz, DMF-d6): d 162.8, 159.5, 142.6, 138.4, 137.7,
135.0, 128.9, 125.2, 124.4, 122.2, 121.4, 116.6, 114.1, 109.5;
HRMS (TOF ESꢁ) m/z calcd for C14H5Cl3N2Oꢁ [(M ꢁ Cl)ꢁ],
321.9473; found, 321.9483.
2-carbonitrile (5k). Yellow solid; mp: 237–238 ꢀC; IR (KBr) (nmax
,
cmꢁ1) 3344, 2924, 2235, 1639, 1548, 1391, 1296, 1083, 866, 619
1
cmꢁ1; H NMR (500 MHz, DMF-d6): d 8.29–7.65 (m, 4H, PhH,
NH), 2.54–2.46 (m, 3H, CH3); 13C NMR (125 MHz, DMF-d6): d
155.7, 149.9, 142.7, 136.4, 136.2, 129.2, 125.7, 124.5, 122.6,
122.6, 119.3, 110.6, 108.6, 88.7, 21.6; 19F NMR (467 MHz, DMF-
d6): d ꢁ102.9 (s, 1F), ꢁ104.0 (s, 1F); HRMS (TOF ESꢁ) m/z calcd
for C15H6ClF2N2Oꢁ [(M ꢁ H)ꢁ], 303.0142; found, 303.0153.
1,3,4-Triuoro-7-methyl-9-oxo-9,10-dihydroacridine-2-carbo
4,7-Dichloro-1,3-diuoro-9-oxo-9,10-dihydroacridine-2-
carbonitrile (5e). Yellow solid; mp: >300 ꢀC; IR (KBr) (nmax
,
;
cmꢁ1) 3446, 2239, 1622, 1543, 1333, 1245, 1140, 841, 596 cmꢁ1
1H NMR (500 MHz, DMSO-d6): d 8.61–7.75 (m, 4H, PhH, NH);
13C NMR (125 MHz, DMSO-d6): d 163.7 (dd, J1 ¼ 270.0 Hz, J2 ¼
8.8 Hz), 154.7 (d, J ¼ 243.8 Hz), 152.0, 148.2, 146.5, 133.9, 131.2,
129.2, 122.7, 114.9, 112.2 (d, J ¼ 13.8 Hz), 110.3, 100.6 (d, J ¼ 6.3
Hz), 83.9 (t, J ¼ 22.5 Hz); 19F NMR (467 MHz, DMSO-d6): d ꢁ98.7
(s, 1F), ꢁ108.7 (s, 1F); HRMS (TOF ESꢁ) m/z calcd for C14H2-
Cl2F2N2O2ꢁ [(M ꢁ 2H)2ꢁ], 321.9523; found, 321.9532.
nitrile (5l). Yellow solid; mp: 213–214 ꢀC; IR (KBr) (nmax, cmꢁ1
)
3387, 2925, 2235, 1658, 1562, 1388, 1266, 1047, 609 cmꢁ1; H
NMR (500 MHz, DMF-d6): d 9.02–7.72 (m, 4H, PhH, NH), 2.53 (s,
3H, CH3); 13C NMR (125 MHz, DMF-d6): d 160.6, 152.0, 149.2,
142.2, 142.1, 140.1, 136.1, 135.1, 129.6, 122.4, 114.9, 110.6,
101.5, 82.9, 21.5; 19F NMR (467 MHz, DMF-d6): d ꢁ104.6 (d, J ¼
14.0 Hz, 1F), ꢁ140.3 (d, J ¼ 18.7 Hz, 1F), ꢁ155.5 (t, J ¼ 14.0 Hz,
1F); HRMS (TOF ESꢁ) m/z calcd for C15H5F3N2O2ꢁ [(M ꢁ 2H)2ꢁ],
286.0365; found, 286.0378.
1
7-Chloro-1,3,4-triuoro-9-oxo-9,10-dihydroacridine-2-carbo
nitrile (5f). Yellow solid; mp: 240–241 C; IR (KBr) (nmax, cmꢁ1
)
ꢀ
3452, 3216, 2923, 2234, 1663, 1559, 1500, 1248, 985, 833, 594
cmꢁ1; 1H NMR (500 MHz, DMSO-d6): d 8.60–7.77 (m, 4H, PhH,
NH); 13C NMR (125 MHz, DMSO-d6): d 160.6 (d, J ¼ 267.5 Hz),
151.4, 148.1, 145.2 (dt, J1 ¼ 253.8 Hz, J2 ¼ 8.8 Hz), 142.1, 140.1
(d, J ¼ 241.3 Hz), 133.9, 131.2, 129.1, 122.7, 114.9, 110.3, 100.9
(d, J ¼ 6.3 Hz), 83.0 (t, J ¼ 21.3 Hz); 19F NMR (467 MHz, DMSO-
d6): d ꢁ102.6 (d, J ¼ 14.0 Hz, 1F), ꢁ137.4 (d, J ¼ 18.7 Hz, 1F),
ꢁ154.0 (t, J ¼ 18.7 Hz, 1F); HRMS (TOF ESꢁ) m/z calcd for C14-
H2ClF3N2O2ꢁ [(M ꢁ 2H)2ꢁ], 305.9819; found, 305.9830.
Acknowledgements
This work was supported by the Program for Changjiang
Scholars and Innovative Research Team in University (no.
IRT13095), the National Natural Science Foundation of China
(nos U1202221, 21162037, 21202142, 21262042, 21362042 and
81160384), and the Key Project of Chinese Ministry of Education
(no. 212161), Start-up funds of Yunnan Minzu University.
1,3,4-Trichloro-7-nitro-9-oxo-9,10-dihydroacridine-2-carbo
nitrile (5g). Yellow solid; mp: 201–203 ꢀC; IR (KBr) (nmax, cmꢁ1
)
;
3426, 3175, 2238, 1681, 1608, 1555, 1335, 1251, 743, 614 cmꢁ1
2ꢁ
HRMS (TOF ESꢁ) m/z calcd for C14H2Cl3N3O3 [(M ꢁ 2H)2ꢁ],
References
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4-Chloro-1,3-diuoro-7-nitro-9-oxo-9,10-dihydroacridine-2-
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carbonitrile (5h). Yellow solid; mp: 251–252 C; IR (KBr) (nmax
,
cmꢁ1) 3445, 2925, 2243, 1625, 1334, 1245, 742, 610 cmꢁ1; HRMS
(TOF ESꢁ) m/z calcd for C14H2ClF2N3O3
[(M ꢁ 2H)2ꢁ],
2ꢁ
332.9764; found, 332.9775.
This journal is © The Royal Society of Chemistry 2015
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17450 | RSC Adv., 2015, 5, 17444–17450
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