Iodine-catalyzed three-component one-pot synthesis of novel 1,8-dioxo-decahydroacridines derivatives bearing benzene sulfonamide moiety

Article abstract of DOI:10.1007/s11164-013-1105-4

An efficient synthetic method for 1,8-dioxo-decahydroacridines derivatives bearing the biologically active sulfonamide moiety is described. Aromatic aldehyde reacted with 5,5-dimethyl-1,3-cyclohexanedione and sulfanilamide, with molecular iodine as cataly

Full text of DOI:10.1007/s11164-013-1105-4

Res Chem Intermed
DOI 10.1007/s11164-013-1105-4
Iodine-catalyzed three-component one-pot synthesis
of novel 1,8-dioxo-decahydroacridines derivatives
bearing benzene sulfonamide moiety
•
Shenghui Li Shan Ding Shengjie Xu
•
•
•
•
•
Jinchao Zhang Shuxiang Wang Chuanqi Zhou
Xiaoliu Li
Received: 1 January 2013 / Accepted: 6 February 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract An efficient synthetic method for 1,8-dioxo-decahydroacridines deriv-
atives bearing the biologically active sulfonamide moiety is described. Aromatic
aldehyde reacted with 5,5-dimethyl-1,3-cyclohexanedione and sulfanilamide, with
molecular iodine as catalyst, to give 1,8-dioxo-decahydroacridines derivatives in
high to excellent yield. The structures of these compounds were established on the
basis of elemental (C, H and N) and spectral analysis (1H NMR, 13C NMR, MS and
FTIR). All the compounds were tested for their cytotoxic activity in vitro against
three human tumor cell lines: human mammary cancer cells (MCF-7), human
cervical carcinoma cells (Hela), and human lung cancer cells (A549) by the 3-(4,
5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Most of
them showed moderate to potent cytotoxic activity against the tested cell lines.
Among them, the most active compound 4e exhibited more efficient activity
(10.92 lM) against MCF-7 cells than cisplatin (11.06 lM).
Keywords 1,8-Dioxo-decahydroacridines ꢀ Sulfanilamide ꢀ Cytotoxicity ꢀ
Molecular iodine
S. Li (&) ꢀ S. Ding ꢀ S. Xu ꢀ J. Zhang (&) ꢀ S. Wang ꢀ C. Zhou ꢀ X. Li
Key Laboratory of Chemical Biology of Hebei Province, Hebei University, Baoding 071002,
People’s Republic of China
e-mail: lish@hbu.edu.cn
J. Zhang
e-mail: jczhang6970@yahoo.com.cn
S. Li ꢀ S. Ding ꢀ S. Xu ꢀ J. Zhang ꢀ S. Wang ꢀ C. Zhou ꢀ X. Li
Key Laboratory of Medicinal Chemistry and Molecular Diagnosis, Ministry of Education, Hebei
University, Baoding 071002, People’s Republic of China
S. Li ꢀ S. Ding ꢀ S. Xu ꢀ J. Zhang ꢀ S. Wang ꢀ C. Zhou ꢀ X. Li
College of Chemistry & Environmental Science, Hebei University, Baoding 071002, People’s
Republic of China
123

S. Li et al.
Introduction
1,8-Dioxo-9-aryl decahydroacridines and their derivatives are well-known poly-
functionalized 1,4-dihydropyridine derivatives, which have been widely explored as
calcium channel blockers and used for the treatment of hypertension and
defibrillation [1]. In addition, acridine derivatives have also been used to synthesize
labeled conjugates with medicinals, peptides, proteins, and nucleic acids [2–4] that
exhibit antitumor and DNA-binding properties. The remarkable drug activity of
these compounds not only attracted many chemists to synthesize this heterocyclic
nucleus but also became an active research area of continuing interest.
Consequently, there have been some reports in the literature on the synthesis of
acridine derivatives containing 1,4-dihydropyridines. For example, preparation from
dimedone, aldehyde and different nitrogen sources like urea [5], methyl amine [6],
and different anilines or ammonium acetate [7] via traditional heating in organic
solvents, promoted by triethylbenzylammonium chloride (TEBAC) [8], p-dodecyl-
benzenesulfonic acid (DBSA) [9], Proline [10], Amberlyst-15 [11], tris(pentaflu-
orophenyl)borane [12], ammonium chloride or Zn(OAc)2ꢀ2H2O or L-proline [13],
silica-bonded S-sulfonic acid (SBSSA) [14], sulfonic acid functionalized silica
(SiO2–Pr–SO3H) [15] and MCM-41–SO3H [16], under microwave irradiation [17–
20], and using ionic liquids such as 1-methylimidazolium trifluoroacetate
([Hmim]TFA) [21] or bronsted acidic imidazolium salts containing perfluoroalkyl
tails [22]. Each of these methods have their own advantages, but some of them often
suffer from one or more disadvantages, such as poor yields, prolonged reaction time,
harsh reaction conditions, tedious work-up processes, and expensive catalyst. Thus,
the development of a simple, efficient and versatile method for the preparation of
these compounds is an active area of research, and there is scope for further
improvement towards milder reaction conditions and higher product yields.
Recently, molecular iodine has received considerable attention as an inexpensive,
nontoxic, readily available reagent for various organic transformations, affording
the corresponding products with high selectivity in excellent yields [23–25]. The
mild Lewis acidity associated with iodine has led to its use in organic synthesis
using catalytic to stoichiometric amounts. Owing to numerous advantages
correlative with this eco-friendly element, iodine has been explored as a powerful
catalyst for various organic transformations [26, 27].
r
A
O
O
NH2
O
lodine
N
+
+
ArCHO
2
i-propanol,reflux
O
NH2
SO2
NH2
SO2
1
2
3
4
Scheme 1 Preparation of 1,8-dioxo-decahydroacridines derivatives 4a–4l
123

Synthesis of novel 1,8-dioxo-decahydroacridines derivatives
Table 1 Optimizing the
reaction conditions
Entry
Iodine (mol%)
Time (min)
Yield (%)
1
2
3
4
0
5
120
70
0
82
95
90
10
20
10
10
The sulfonamide is an important functional group. Compounds bearing
sulfonamide group have been extensively used as pharmaceutical and agricultural
agents because of their diverse biological properties. Representatives of this class of
pharmacological agents are widely used in clinic as antibacterial, hypoglycemic,
diuretic, anti-hypertensive, and antiviral drugs [28, 29]. Recently, enormous interest
has also been directed toward a host of structurally novel sulfonamide derivatives
which have shown promising bioactivities, such as antiviral, anti-inflammatory, and
anti-cancer properties [30–32].
Keeping in mind the various biomedical applications of 1,8-dioxo-9-aryl
decahydroacridines and sulfonamide derivatives, it was thought worthwhile to
incorporate both these scaffolds in a single molecular framework to further assess
the biological profile. To achieve this, novel 1,8-dioxo-decahydroacridines deriv-
atives bearing benzene sulfonamide moiety were designed and synthesized by
reaction of aromatic aldehyde with 5,5-dimethyl-1,3-cyclohexanedione and sulfa-
nilamide in the presence of molecular iodine (Scheme 1). The cytotoxic activity of
the obtained compounds 4a–4l was evaluated in vitro against MCF-7, Hela, and
A549 cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
assay and found to possess moderate activity.
Table 2 Iodine catalyzed the
synthesis of 1,8-dioxo-
decahydroacridines derivatives
Entry
Ar-
Product
(4)
Time
(min)
Yields
(%)a
1
4-ClC6H4
4a
4b
4c
4d
4e
4f
10
12
11
28
12
10
15
12
25
15
20
13
95
92
93
89
90
96
92
90
92
91
88
93
2
2-ClC6H4
3
2,4-Cl2C6H3
4-HOC6H4
4
5
3-NO2C6H4
4-NO2C6H4
4-CH3OC6H4
3,4,5-(CH3O)3C6H2
C6H5
6
7
4g
4h
4i
8
9
10
11
12
4-CH3C6H4
4-OH-3-CH3OC6H3
3,4-OCH2OC6H3
4j
4k
4l
a
Pure isolated yields
123

S. Li et al.
O
O
Ar
O
O
O
Ar
H
CH
- H2O
H
O
O
H
O
O
(I)
Ar
O
O
Ar
O
O
sulfanilamide
- H2O
Micheal reaction
:
O
N
H
OH
O
(III)
(II)
SO2NH2
Ar
Ar
N
O
O
O
O
- H
O
H+
N
HO
SO2NH2
(IV)
SO2NH2
4
Scheme 2 The proposed mechanism
Results and discussion
In search of the best experimental conditions, 5,5-dimethyl-1,3-cyclohexanedione,
p-chlorobenzaldehyde, and sulfanilamide were chosen as the three reactants, and
iodine as well as various Lewis acids as the catalyst. In each case, two equivalents
of 5,5-dimethyl-1,3-cyclohexanedione were added to the mixture of one equivalent
of p-chlorobenzaldehyde and one equivalent of sulfanilamide and the catalyst. The
progress of the reactions was monitored at an interval of 5 min by TLC.
In an initial endeavor, the condensation of 5,5-dimethyl-1,3-cyclohexanedione,
p-chlorobenzaldehyde, and sulfanilamide was carried out in the absence of any
catalyst, and after 2 h, the target product was not detected (Table 1, entry 1).
Among various Lewis acids used, we initiated the study with molecular iodine. The
reaction was monitored by TLC, and a clear spot of the product was obtained within
5 min, which indicated that the reaction is exceedingly fast. In order to improve the
product yields and to optimize the reaction condition, the reaction was also
performed using various amounts of iodine to determine the appropriate quantity of
catalyst used, and it was found that the increase in the quantity of iodine from 5 to
123

Synthesis of novel 1,8-dioxo-decahydroacridines derivatives
10 mol% not only lessens the reaction time from 70 to 10 min, but also enhanced
the product yield from 82 to 95 %. However, using 20 mol% of iodine as catalyst
did not reduce the reaction time and increase the yield of the product 4a (90 %).
Thus, the use of 10 mol% iodine is ideal to achieve the desired product in good
yields (Table 1).
To demonstrate the generality of this method, we next investigated the scope of
this reaction under the optimized conditions (i-PrOH, 20 mol% of I2, air, reflux) and
the results are summarized in Table 2. As shown in Table 2, this methodology is
equally effective irrespective of the nature and positions (o-, m-, p-) of the
substituents attached to the phenyl ring of the aromatic aldehyde. Strongly
activating (4, 7, 8, 11, and 12), weakly activating (10), weakly deactivating (1–3),
and strongly deactivating (5 and 6) systems all give products with nearly equal ease.
The versatility of the method has also been demonstrated by the tolerance of a
number of functional groups such as –NO2 (5 and 6), –OMe (7, 8, and 11) and –OH
(4 and 11).
On the basis of the reported literature, a possible reaction mechanism for the
conversion of 5,5-dimethyl-1,3-cyclohexanedione, aromatic aldehyde, and sulfanil-
amide into corresponding 1,8-dioxo-decahydroacridines derivatives, with molecular
iodine in isopropanol, is shown in Scheme 2. Initially, molecular iodine can serve as
a Lewis acid catalyst for the reaction of 5,5-dimethyl-1,3-cyclohexanedione and
aromatic aldehyde to give the intermediate (I) via Knoevenagel condensation. Then,
the active methylene group of the second molecule of 5,5-dimethyl-1,3-cyclohex-
anedione reacts with (I) to give intermediate (II). Nucleophilic attack of amine
group of sulfanilamide to carbonyl group creates intermediate (III). In the next step,
cyclization will occur by the nucleophilic attack of amine group to carbonyl group
to obtain intermediate (IV). Finally, by the removal of one molecule of water, the
acridine derivatives 4 will be generated. It is worthy of mention that possible
Table 3 The cytotoxicity of the
compounds (4a–4l) against
MCF-7, Hela, and A549
Compounds
IC50 (lL)
MCF-7
Hela
A549
4a
16.90
14.40
13.78
11.20
10.92
23.59
21.15
18.65
15.13
17.36
17.35
21.08
11.06
22.55
18.28
19.36
15.90
14.88
21.13
19.50
12.80
20.81
21.32
19.82
31.02
8.61
24.41
28.42
26.56
27.53
23.26
29.40
28.46
21.63
23.47
24.72
22.68
22.75
8.25
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
Cisplatin
123

S. Li et al.
interaction of molecular iodine with carbonyl oxygen has been previously indicated
in the literature [33, 34].
Almost all the compounds showed moderate cytotoxic activity against MCF-7,
Hela, and A549 cells. The cytotoxic activity data generated are tabulated in Table 3.
Conclusion
In conclusion, we have developed a convenient and efficient method for the
synthesis of 1,8-dioxo-decahydroacridines derivatives bearing benzene sulfonamide
moiety utilizing molecular iodine as a novel catalyst. The advantages of this method
are short reaction times, operational simplicity, excellent product yields, and
functional group tolerability. All the synthesized compounds were tested for their
in vitro cytotoxic activity against MCF-7, Hela, and A549 cell lines, the obtained
results revealing that most of the studied compounds exhibited moderate to potent
cytotoxic activity. Among them, the most active compound, 4e, exhibited more
efficient activity (10.92 lM) against MCF-7 cells than cisplatin (11.06 lM).
Experimental
Materials and methods
RPMI-1640 medium, trypsin, and fetal bovine serum were purchased from Gibco.
MTT, benzylpenicillin, and streptomycin were from Sigma. Three different human
carcinoma cell lines: MCF-7 (human mammary cancer cells), Hela (human cervical
carcinoma), and A549 (human lung cancer cells) were obtained from the American
Type Culture Collection. Melting points were measured on an XT-4 microscopic
melting-point spectrometer and are uncorrected. The 1H NMR and 13C NMR spectra
were obtained from solution in DMSO-d6 with tetramethylsilane (TMS) as internal
standard using a Bruker AVIII 600 NMR spectrometer. IR spectra were recorded
using KBr pellets and a Perkin-Elmer Model-683 spectrophotometer. Mass spectra
were measured by LC–MS apparatus Agilent 1200-6310. Elemental analysis was
determined on an Elementar Vario EL III elemental analyzer.
General procedure for the synthesis of 1,8-dioxo-decahydroacridines derivatives
A mixture of 5,5-dimethyl-1,3-cyclohexanedione (2 mmol), aromatic aldehyde
(1 mmol), sulfanilamide (1 mmol), and iodine (10 mol%) was refluxed in
isopropanol (3 mL) for the appropriate time (Table 2). After completion of the
reaction as indicated by thin layer chromatography (TLC), the reaction mixture was
cooled to room temperature and poured into 30 mL of sodium thiosulfate solution
[34], and then the solid was precipitated, filtered, and recrystallized in EtOH to
afford the title compound.
123

Synthesis of novel 1,8-dioxo-decahydroacridines derivatives
4-(9-(4-Chlorophenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacri-
din-10(9H)-yl)benzenesulfonamide (4a) Pale yellow solid; m.p. [250 °C; IR
(cm-1): 3,297 (NH2), 3,292 (NH2), 2,964 (CH3), 1,640 (CO), 1371 (SO2); 1H NMR
(600 MHz, DMSO-d6): d 8.03 (d, J = 8.4 Hz, 2H, Ar–H), 7.67 (d, J = 8.4 Hz, 2H,
Ar–H), 7.63 (s, 2H, –NH2), 7.34–7.30 (m, 4H, Ar–H), 5 0.03 (s, 1H, –CH), 2.19 (d,
J = 16.2 Hz, 4H, –CH2), 2.02 (d, J = 15.6 Hz, 2H, –CH2), 1.74 (d,
J = 17.4 Hz,2H, –CH2), 0.89 (s, 6H, –CH3), 0.73 (s, 6H, –CH3); 13C NMR
(DMSO-d6, 150 MHz) d: 195.54, 150.40, 145.48, 145.24, 141.51, 130.80, 130.39,
129.96, 128.36, 128.30, 113.27, 49.93, 41.44, 32.53, 32.33, 29.63, 26.63; ESI–MS:
m/z 562.5 [M ? Na]?; Anal. Calcd. for C29H31N2O4SCl.H2O: C 62.52, H 5.97, N
5.03. Found: C 62.81, H 5.35, N 5.07.
4-(9-(2-Chlorophenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacri-
din-10(9H)-yl)benzenesulfonamide (4b) Pale yellow solid; m.p. [250 °C; IR
(cm-1): 3,355 (NH2), 3,376 (NH2), 2,957 (CH3), 1,642 (CO), 1,371 (SO2); 1H NMR
(600 MHz, DMSO-d6): d 8.04 (d, J = 7.8 Hz, 2H), 7.66 (d, J = 7.2 Hz, 2H, Ar–H),
7.61 (s, 2H, –NH2), 7.51 (d, J = 7.8 Hz, 1H, Ar–H), 7.26 (t, J = 7.8 Hz, 2H,
Ar–H), 7.11 (t, J = 7.8 Hz, 1H, Ar–H), 5.30 (s, 1H, –CH), 2.16 (d, J = 15.6 Hz,
2H, –CH2), 2.15 (d, J = 17.4 Hz, 2H, –CH2), 1.96 (d, J = 16.2 Hz, 2H, –CH2),
1.73 (d, J = 17.4 Hz, 2H, –CH2), 0.87 (s, 6H, –CH3), 0.75 (s, 6H, –CH3); 13C NMR
(DMSO-d6, 150 MHz) d: 195.31, 150.65, 145.19, 143.37, 141.73, 133.07, 129.90,
127.87, 126.85, 112.50, 49.93, 41.70, 32.34, 29.70, 26.50; ESI–MS: m/z 561.8
[M ? Na]?; Anal. Calcd. for C29H31N2O4SCl: C 64.61, H 5.80, N 5.20. Found: C
64.40, H 5.72, N 5.05.
4-(9-(2,4-Dichlorophenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydro-
acridin-10(9H)-yl)benzenesulfonamide (4c) Pale yellow solid; m.p. [250 °C; IR
(cm-1): 3,350 (NH2), 3,199 (NH2), 2,964 (CH3), 1,657 (CO), 1,364 (SO2); 1H NMR
(600 MHz, DMSO-d6): d 8.03 (s, 2H, Ar–H), 7.67 (d, J = 9.0 Hz, 2H, Ar–H), 7.63
(s, 2H, –NH2), 7.52 (d, J = 8.4 Hz, 1H, Ar–H), 7.41 (s, 1H, Ar–H), 7.32(dd,
J1 = 8.4, J2 = 2.4 Hz, 1H, Ar–H), 5.23 (s, 1H, –CH), 2.16 (d, J = 16.2 Hz, 2H,
–CH2), 2.13 (d, J = 17.4 Hz,2H, –CH2), 1.96 (d, J = 16.2 Hz, 2H, –CH2), 1.73 (d,
J = 17.4 Hz, 2H, –CH2), 0.87 (s, 6H, –CH3), 0.75 (s, 6H, –CH3); 13C NMR
(DMSO-d6, 150 MHz) d: 195.39, 150.95, 145.24, 141.60, 133.98, 131.41, 129.12,
127.00, 112.07, 49.85, 41.67, 32.35, 32.18, 29.65, 26.53; ESI–MS: m/z 596.8
[M ? Na]?; Anal. Calcd. for C29H30N2O4SCl2. 0.5H2O: C 59.79, H 5.36, N 4.81.
Found: C 60.01, H 5.21, N 4.62.
4-(9-(4-Hydroxyphenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroac-
ridin-10(9H)-yl)benzenesulfonamide (4d) Pale yellow solid; m.p. [250 °C; IR
(cm-1): 3,292 (NH2), 3,231 (NH2), 2,962 (CH3), 1,645 (CO), 1,376 (SO2); 1H NMR
(600 MHz, DMSO-d6): d 9.11 (s, 1H, –OH), 8.02 (d, J = 8.4 Hz, 2H, Ar–H),
7.64–7.62 (m, 4H, –NH2, Ar–H), 7.09 (d, J = 8.4 Hz, 2H, Ar–H), 6.62 (d,
J = 9.0 Hz, 2H, Ar–H), 4.94 (s, 1H, –CH), 2.20 (d, J = 16.8 Hz, 2H, –CH2), 2.17
(d, J = 15.6 Hz, 2H, –CH2), 2.01 (d, J = 15.6 Hz, 2H, –CH2), 1.71 (d,
123

S. Li et al.
J = 16.8 Hz, 2H, –CH2), 0.88 (s, 6H, –CH3), 0.74 (s, 6H, –CH3); 13C NMR
(DMSO-d6, 150 MHz) d: 195.57, 149.74, 145.12, 141.74, 137.24, 135.25, 129.37,
128.90, 115.26, 115.06, 114.11, 50.07, 41.43, 32.53, 31.26, 29.72, 26.60; ESI–MS:
m/z 543.7 [M ? Na]?; Anal. Calcd. for C29H32N2O5S.H2O: C 62.66, H 6.36, N
5.20. Found: C 64.68, H 6.22, N 5.30.
4-(3,3,6,6-Tetramethyl-9-(3-nitrophenyl)-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-
10(9H)-yl)benzenesulfonamide (4e) Pale yellow solid; m.p. [250 °C; IR (cm-1):
3,311 (NH2), 3,228 (NH2), 2,959 (CH3), 1,639 (CO), 1,347 (SO2); 1H NMR
(600 MHz, DMSO-d6): d 8.15 (s, 1H, Ar–H), 8.07 (d, J = 8.4 Hz, 2H, Ar–H), 8.02
(d, J = 7.8 Hz, 1H, Ar–H), 7.79 (d, J = 7.8 Hz, 1H, Ar–H), 7.70–7.69 (m, 2H),
7.63 (s, 2H, –NH2), 7.60 (t, J = 7.8 Hz, 1H, Ar–H), 5.15 (s, 1H, –CH), 2.40 (d,
J = 16.2 Hz, 2H, –CH2), 2.32 (d, J = 16.2 Hz, 2H, –CH2), 2.03 (d, J = 16.2 Hz,
2H, –CH2), 1.79 (d, J = 16.8 Hz, 2H, –CH2), 0.90 (s, 6H, –CH3), 0.73 (s, 6H,
–CH3); 13C NMR (DMSO-d6, 150 MHz) d: 195.63, 151.00, 148.52, 147.88, 145.34,
141.34, 134.74, 130.25, 122.67, 121.54, 112.84, 49.81, 41.42, 32.98, 32.60, 29.57,
26.57; ESI–MS: m/z 572.8 [M ? Na]?; Anal. Calcd. for C29H31N3O6S.H2O: C
61.36, H 5.86, N 7.40. Found: C 61.84, H 5.69, N 7.22.
4-(3,3,6,6-Tetramethyl-9-(4-nitrophenyl)-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-
10(9H)-yl)benzenesulfonamide (4f) Pale yellow solid; m.p. [250 °C; IR (cm-1):
3,304 (NH2), 3,211 (NH2), 2,964 (CH3), 1,642 (CO), 1,347 (SO2); 1H NMR
(600 MHz, DMSO-d6): d 8.15 (d, J = 8.4 Hz, 2H, Ar–H), 8.05 (d, J = 8.4 Hz, 2H,
Ar–H), 7.74 (d, J = 8.4 Hz, 2H, Ar–H), 7.64 (s, 2H, –NH2), 7.61 (d, J = 9.0 Hz,
2H, Ar–H), 5.14 (s, 1H, –CH), 2.23 (d, J = 16.8 Hz, 2H, –CH2), 2.21 (d,
J = 15.6 Hz, 2H, –CH2), 2.02 (d, J = 15.6 Hz, 2H, –CH2), 1.77 (d, J = 16.8 Hz,
2H, –CH2), 0.89 (s, 6H, –CH3), 0.72 (s, 6H, –CH3); 13C NMR (DMSO-d6,
150 MHz) d: 195.52, 153.92, 150.93, 146.19, 145.33, 141.37, 129.47, 123.77,
112.64, 49.83, 41.45, 33.38, 32.55, 29.57, 26.64; ESI–MS: m/z 573.4 [M ? Na]?;
Anal. Calcd. for C29H31N3O6S.H2O: C 61.36, H 5.86, N 7.40. Found: C 61.90, H
5.83, N 7.23.
4-(9-(4-Methoxyphenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroac-
ridin-10(9H)-yl)benzenesulfonamide (4g) Pale yellow solid; m.p. 235–236 °C; IR
(cm-1): 3,306 (NH2), 3,223 (NH2), 2,959 (CH3), 1,642 (CO), 1,371 (SO2); 1H NMR
(600 MHz, DMSO-d6): d 8.03 (d, J = 8.4 Hz, 2H, Ar–H), 7.64 (d, J = 7.8 Hz, 2H,
Ar–H), 7.63 (s, 2H, –NH2), 7.22 (d, J = 8.4 Hz, 2H, Ar–H), 6.81 (d, J = 8.4 Hz,
2H, Ar–H), 4.99 (s, 1H, –CH), 3.69 (s, 3H, –OCH3), 2.20 (d, J = 17.4 Hz, 2H,
–CH2), 2.18 (d, J = 15.6 Hz, 2H, –CH2), 2.01 (d, J = 15.6 Hz, 2H, –CH2), 1.73 (d,
J = 17.4 Hz, 2H, –CH2), 0.89 (s, 6H, –CH3), 0.74 (s, 6H, –CH3); 13C NMR
(DMSO-d6, 150 MHz) d: 195.55, 157.79, 149.88, 145.16, 141.70, 138.87, 129.46,
129.01, 113.95, 113.74, 55.32, 50.03, 41.44, 32.52, 32.31, 29.70, 26.63; ESI–MS:
m/z 557.5 [M ? Na]?; Anal. Calcd. for C30H34N2O5S: C 67.39, H 6.41, N 5.24.
Found: C 67.09, H 6.59, N 5.25.
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Synthesis of novel 1,8-dioxo-decahydroacridines derivatives
4-(3,3,6,6-Tetramethyl-1,8-dioxo-9-(3,4,5-trimethoxyphenyl)-1,2,3,4,5,6,7,8-octahy-
droacridin-10(9H)-yl)benzenesulfonamide (4h) Pale yellow solid; m.p.
191–192 °C; IR (cm-1): 3,389 (NH2), 3,267 (NH2), 2,962 (CH3), 1,645 (CO),
1
1,364 (SO2); H NMR (600 MHz, DMSO-d6): d 8.04 (d, J = 9.0 Hz, 2H, Ar–H),
7.62 (s, 2H, –NH2), 7.57 (d, J = 9.0 Hz, 2H, Ar–H), 6.55 (s, 2H, Ar–H), 5.05 (s,
1H, –CH), 3.74 (s, 6H, –OCH3), 3.61 (s, 3H, –OCH3), 2.23 (d, J = 17.4 Hz, 2H,
–CH2), 2.21 (d, J = 16.2 Hz, 2H, –CH2), 2.07 (d, J = 16.2 Hz, 2H, –CH2), 1.77 (d,
J = 17.4 Hz, 2H, –CH2), 0.90 (s, 6H, –CH3), 0.79 (s, 6H, –CH3); 13C NMR
(DMSO-d6, 150 MHz) d: 195.73, 152.88, 150.30, 145.15, 142.04, 141.51, 136.08,
113.45, 104.91, 60.38, 56.11, 50.02, 41.49, 32.55, 32.06, 29.71, 26.56; ESI–MS:
m/z 617.4 [M ? Na]?; Anal. Calcd. for C32H38N2O7S.1.5H2O: C 61.82, H 6.65, N
4.51. Found: C 61.84, H 6.14, N 4.58.
4-(3,3,6,6-Tetramethyl-1,8-dioxo-9-phenyl-1,2,3,4,5,6,7,8-octahydroacridin-10(9)-
yl)benzenesulfonamide (4i) Pale yellow solid; m.p. 197–198 °C; IR (cm-1): 3,284
(NH2), 3,062 (NH2), 2,954 (CH3), 1,640 (CO), 1,364 (SO2); H NMR (600 MHz,
1
DMSO-d6): d 8.04 (d, J = 8.4 Hz, 2H, Ar–H), 7.65 (d, J = 7.8 Hz, 2H, Ar–H),
7.61 (s, 2H, –NH2), 7.33 (d, J = 7.2 Hz, 2H, Ar–H), 7.25 (t, J = 7.8 Hz, 2H,
Ar–H), 7.11 (t, J = 7.2 Hz, 1H, Ar–H), 5.06 (s, 1H, –CH), 2.22 (d, J = 17.4 Hz,
2H, –CH2), 2.20 (d, J = 16.2 Hz, 2H, –CH2), 2.02 (d, J = 16.2 Hz, 2H, –CH2),
1.75 (d, J = 17.4 Hz, 2H, –CH2), 0.89 (s, 6H, –CH3), 0.73 (s, 6H, –CH3); ESI–MS:
m/z 527.5 [M ? Na]?; 13C NMR (DMSO-d6, 150 MHz) d: 195.55, 150.18, 146.53,
145.18, 141.63, 128.41, 128.06, 127.88, 126.31, 113.67, 50.00, 41.45, 32.53, 32.43,
29.69, 26.58. Anal. Calcd. for C29H32N2O4S.H2O: C 66.64, H 6.56, N 5.36. Found:
C 66.06, H 6.21, N 5.34.
4-(3,3,6,6-Tetramethyl-1,8-dioxo-9-p-tolyl-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)
benzenesulfonamide (4j) Pale yellow solid; m.p.[250 °C; IR (cm-1): 3,299 (NH2),
3,040 (NH2), 2,952 (CH3), 1,642 (CO), 1,366 (SO2); H NMR (600 MHz, DMSO-
1
d6) : d 8.03 (d, J = 8.4 Hz, 2H, Ar–H), 7.64 (d, J = 8.4 Hz, 2H, Ar–H), 7.62 (s, 2H,
–NH2), 7.20 (d, J = 7.8 Hz, 2H, Ar–H), 7.05 (d, J = 7.8 Hz, 2H, Ar–H), 5.01(s,
1H, –CH), 2.23 (s, 3H, –CH3), 2.21 (d, J = 17.4 Hz, 2H, –CH2), 2.18 (d,
J = 16.8 Hz, 2H, –CH2), 2.01 (d, J = 16.8 Hz, 2H, –CH2), 1.73 (d, J = 17.4 Hz,
2H, –CH2), 0.89 (s, 6H, –CH3), 0.73 (s, 6H, –CH3); 13C NMR (DMSO-d6,
150 MHz) d: 195.53, 150.02, 145.16, 143.65, 141.68, 135.14, 128.99, 127.95,
113.81, 50.03, 41.44, 32.52, 31.93, 29.71, 26.61, 21.09; ESI–MS: m/z 541.6
[M ? Na]?; Anal. Calcd. for C30H34N2O4S.H2O: C 67.14, H 6.46, N 5.22. Found: C
67.09 H 6.56, N 5.20.
4-(9-(4-Hydroxy-3-methoxyphenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-
octahydroacridin-10(9H)-yl)benzenesulfonamide (4k) Pale yellow solid; m.p.
[250 °C; IR (cm-1): 3,279 (NH2), 3,084 (NH2), 2,952 (CH3), 1,642 (CO), 1,366
1
(SO2); H NMR (600 MHz, DMSO-d6): d 8.66 (s, 1H, –OH), 8.03 (d, J = 8.4 Hz,
2H, Ar–H), 7.60 (s, 2H, –NH2), 7.57 (d, J = 8.4 Hz, 2H, Ar–H), 6.81 (s, 1H, Ar–H),
6.70 (dd, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H, Ar–H), 6.65 (d, J = 8.4 Hz, 1H, Ar–H),
123

S. Li et al.
4.98 (s, 1H, –CH), 3.73 (s, 3H, –OCH3), 2.22 (d, J = 17.4 Hz, 2H, –CH2), 2.19 (d,
J = 15.6 Hz, 2H, –CH2), 2.04 (d, J = 15.6 Hz, 2H, –CH2), 1.74 (d, J = 17.4 Hz,
2H, –CH2), 0.90 (s, 6H, –CH3), 0.77 (s, 6H, –CH3); 13C NMR (DMSO-d6,
150 MHz) d: 195.66, 149.85, 147.41, 145.12, 145.03, 141.68, 137.74, 120.11,
115.57, 113.98, 112.09, 55.90, 50.07, 41.46, 32.53, 31.37, 29.75, 26.55; ESI–MS:
m/z 573.3 [M ? Na]?; Anal. Calcd. for C30H34N2O6S.0.5H2O: C 64.38, H 6.30, N
5.01. Found: C 64.11 H 6.44, N 4.86.
4-(9-(Benzo[d][1,3]dioxol-5-yl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-
decahydroanthracen-10-yl)benzenesulfonamide (4l) Pale yellow solid; m.p.
227–228 °C; IR (cm-1): 3,365 (NH2), 3,231 (NH2), 2,962 (CH3), 1,645 (CO),
1
1,366 (SO2); H NMR (600 MHz, DMSO-d6): d 8.03 (d, J = 8.4 Hz, 2H, Ar–H),
7.63 (d, J = 8.4 Hz, 2H, Ar–H), 7.61 (s, 2H, –CH2), 6.81–6.78 (m, 3H, Ar–H), 4.97
(s, 1H, –CH), 2.26 (d, J = 16.2 Hz, 1H, –CH2), 2.20 (d, J = 16.8 Hz, 2H, –CH2),
2.18 (d, J = 16.2 Hz, 2H, –CH2), 2.11 (d, J = 16.2 Hz, 1H, –CH2), 2.04 (d,
J = 16.2 Hz, 2H, –CH2), 1.75 (d, J = 16.8 Hz, 2H, –CH2), 0.89 (s, 6H, –CH3),
0.76 (s, 6H, –CH3);, 13C NMR (DMSO-d6, 150 MHz) d: 195.61, 150.00, 147.18,
145.64, 145.17, 141.60, 140.80, 120.86, 113.74, 108.78, 108.28, 101.06, 50.00,
41.44, 32.54, 32.33, 29.63, 26.69; ESI–MS: m/z 571.5 [M ? Na]?; Anal. Calcd. for
C30H34N2O6S.H2O: C 65.82, H 6.24, N 2.48. Found: C 65.31 H 5.94, N 2.27.
Cell culture
Three different human carcinoma cell lines: MCF-7, Hela, and A549 were cultured
in RPMI-1640 medium supplemented with 10 % fetal bovine serum, 100 U/mL of
penicillin, and 100 mg/mL of streptomycin. Cells were maintained at 37 °C in a
humidified atmosphere of 5 % CO2 in air.
Solutions
The obtained 1,8-dioxo-decahydroacridines derivatives, 4a–4l, were dissolved in
DMSO at a concentration of 5 mM as stock solution, and diluted in culture medium
at concentrations of 1.0, 10, 100, and 500 mM as working solution. To avoid DMSO
toxicity, the concentration of DMSO was less than 0.1 % (v/v) in all experiments.
Cytotoxicity analysis
The cells harvested from the exponential phase were seeded equivalently into a
96-well plate, and then the compounds were added to the wells to achieve final
concentrations. Control wells were prepared by addition of culture medium. Wells
containing culture medium without cells were used as blanks. All experiments were
performed in quintuplicate. The MTT assay was performed as described by
123

Synthesis of novel 1,8-dioxo-decahydroacridines derivatives
Mosmann [35]. Upon completion of the incubation for 44 h, stock MTT dye
solution (20 mL, 5 mg/mL) was added to each well. After 4 h incubation,
2-propanol (100 mL) was added to solubilize the MTT formazan. The optical
density (OD) of each well was measured on a microplate spectrophotometer at a
wavelength of 570 nm. The IC50 value was determined from plot of % viability
against dose of compounds added.
Acknowledgments We are grateful to the National Basic Research 973 Program (Grant No.
2010CB534913), Hebei Provincial Natural Science Foundation of China-Shijiazhuang Pharmaceutical
Group (CSPC) Foundation (B2011201174), Hebei Province Nature Science Fund for Distinguished
Young Scholars (B2011201164), the Nature Science Fund of Hebei Province (B2011201135), the Key
Basic Research Special Foundation of Science Technology Ministry of Hebei Province (11966412D,
12966418D) and Open Fund of Key Laboratory of Chemical Biology of Hebei Province (No.
09265631D-7).
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