Design, synthesis, in vitro cytotoxic activity evaluation, and apoptosis-induction study of new 9(10H-acridinone-1,2,3-triazoles

Article abstract of DOI:10.1007/s11030-015-9616-0

A new series of 9(10H-acridinone-1,2,3-triazole derivatives were designed, synthesized and evaluated for their cytotoxic activity against human breast cancer cell lines. The acridone skeleton was prepared through the Ullman condensation of 2-bromobenzoic acid and anilines. Subsequently, it was functionalized with propargyl bromide. Then, a click reaction of the latter compound and in situ prepared 1-(azidomethyl)-4-methoxybenzene derivatives led to the formation of the desired triazole products. Finally, all products were investigated for their capability to cause cytotoxicity against MCF-7, T-47D, and MDA-MB-231 cell lines. Among them, 2-methoxy-10-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)acridin-9(10H-one 8c exhibited the most potency (hbox {IC}_{50},{=},11.0,{pm }, 4.8, upmu hbox {M})(IC50=11.0±4.8μM) against MCF-7 cells, being more potent than etoposide (hbox {IC}_{50},{=}, 12.4,{pm }, 4.7 upmu hbox {M})(IC50=12.4±4.7μM). Also, apoptosis induced by compound 8c was confirmed via acridine orange/ethidium bromide and Annexin V-FITC/propidium iodide (PI) double staining.

Full text of DOI:10.1007/s11030-015-9616-0

Mol Divers
DOI 10.1007/s11030-015-9616-0
FULL-LENGTH PAPER
Design, synthesis, in vitro cytotoxic activity evaluation,
and apoptosis-induction study of new
9(10H)-acridinone-1,2,3-triazoles
Maryam Mohammadi-Khanaposhtani1 · Maliheh Safavi2 · Reyhaneh Sabourian3 ·
Mohammad Mahdavi4 · Mahboobeh Pordeli5 · Mina Saeedi6 ·
Sussan Kabudanian Ardestani5 · Alireza Foroumadi4 · Abbas Shafiee4 ·
Tahmineh Akbarzadeh1,3
Received: 12 March 2015 / Accepted: 1 July 2015
© Springer International Publishing Switzerland 2015
Abstract A new series of 9(10H)-acridinone-1,2,3-
triazole derivatives were designed, synthesized and evalu-
ated for their cytotoxic activity against human breast cancer
cell lines. The acridone skeleton was prepared through the
Ullman condensation of 2-bromobenzoic acid and anilines.
Subsequently, it was functionalized with propargyl bromide.
Then, a click reaction of the latter compound and in situ
prepared 1-(azidomethyl)-4-methoxybenzene derivatives led
to the formation of the desired triazole products. Finally,
all products were investigated for their capability to cause
cytotoxicity against MCF-7, T-47D, and MDA-MB-231 cell
lines. Among them, 2-methoxy-10-((1-(4-methoxybenzyl)-
1H-1,2,3-triazol-4-yl)methyl)acridin-9(10H)-one 8c exhib-
ited the most potency (IC50 = 11.0 4.8 µM) against MCF-
7 cells, being more potent than etoposide (IC50 = 12.4 4.7
µM). Also, apoptosis induced by compound 8c was con-
firmed via acridine orange/ethidium bromide and Annexin
V-FITC/propidium iodide (PI) double staining.
Keywords Acridone-1,2,3-triazoles · Cytotoxic activity ·
Click chemistry · Breast cancer
Introduction
Cancer is characterized by uncontrolled cell growth leading
to 15 % of human deaths worldwide [1]. Apoptosis is a pro-
grammed cell death process by which the body eliminates
damaged or unnecessary cells. This is a biologically impor-
tant phenomenon playing a vital role in cancer development
and tumor cell survival [2]. It has been proven that dysregula-
tion of apoptosis leads to cancer and tumor progression [3,4].
Killing tumor cells using chemotherapeutic methods is usu-
ally accomplished through the induction of apoptosis which
does not destroy the organism. Hence, apoptosis inducers
have been widely studied as a versatile platform for cancer
therapy in medicinal chemistry [5–9].
Electronic supplementary material The online version of this
article (doi:10.1007/s11030-015-9616-0) contains supplementary
material, which is available to authorized users.
Tahmineh Akbarzadeh
akbarzad@tums.ac.ir
B
Acridone is an important heterocyclic scaffold and both
synthetic and naturally occurring derivatives have shown var-
ious valuable biological properties [10]. Acridones can be
considered as 10-aza-analogs of anthrones [11] or xanthones
[12] from a structural point of view. A wide range of acridone
derivatives has been evaluated in vitro and in vivo to explore
novel anticancer agents [13–16]. Recently, acridone-based
anticancer agents that target DNA [17], topoisomerases [18],
telomerase [19], multidrug resistance [13], and apoptotic
inducer [20] have been reported in the literature. Further-
more, the 1,2,3-triazole ring has received much attention in
both chemistry and biology due to its high dipole moment
[21], metabolic stability, and capability to form hydrogen
bonds [22]. Also, it can be considered an amide bioisos-
1
Department of Medicinal Chemistry, Faculty of Pharmacy,
Tehran University of Medical Sciences, Tehran, Iran
2
Department of Biotechnology, Iranian Research Organization
for Science and Technology, Tehran, Iran
3
Persian Medicine and Pharmacy Research Center, Tehran
University of Medical Sciences, Tehran, Iran
4
Department of Medicinal Chemistry, Faculty of Pharmacy
and Pharmaceutical Sciences Research Center, Tehran
University of Medical Sciences, Tehran, Iran
5
Institute of Biochemistry and Biophysics, Department of
Biochemistry, University of Tehran, Tehran, Iran
6
Medicinal Plants Research Center, Faculty of Pharmacy,
Tehran University of Medical Sciences, Tehran, Iran
123

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[36], we designed, synthesized, and evaluated novel 9(10H)-
acridinone-1,2,3-triazole hybrids (A, Fig. 1) against human
breast cancer cell lines.
Results and discussion
Chemistry
b
Exploring novel 9(10H)-acridinone-1,2,3-triazole hybrids
we focused on 10-benzyl-9(10H)-acridinone derivatives
reported by Gao et al. (B, Fig. 1) [20]. Their study revealed
that a benzyl group bearing methoxy substituents showed
better antileukemic activitiy and, among them, 10-(3,5-
dimethoxy)benzyl-9(10H)-acridinone was the most potent
derivative with an IC50 of about 0.7 µM. Considering the
anticancer activity of the 1,2,3-triazole skeleton [30,31], we
decidedtocombinethe9(10H)-acridinoneand1,2,3-triazole
scaffolds and investigate the cytotoxicity profile of the cor-
responding products 8a–n (Scheme 1).
The synthesis of 9(10H)-acridinone-1,2,3-triazole
hybrids 8a–n is described in Scheme 1. At first, the Ullman
condensation reaction of 2-bromobenzoic acid 1 with various
aniline derivatives 2 in the presence of potassium carbonate
(K2CO3) and copper in EtOH under reflux conditions gave
2-arylamino benzoic acids 3 [37]. Then, the cyclization of
compound 3 in the presence of polyphosphoric acid (PPA)
at 100 ◦C afforded acridones 4 [38] which were reacted with
a
Fig. 1 Structure of designed (a) and reported (b) anticancer agents
teric replacement [23]. The introduction of click chemistry
by Sharpless and co-workers provided an efficient method for
the construction of the 1,2,3-triazole ring and drug discovery
investigations [24,25]. Their antibacterial [26], antifungal
[27], antitubercular [28], and anti-HIV [29] activities have
been well documented. Also, extensive attention has been
devoted to their anticancer activities [30,31].
Considering the many adverse effects and development
of tumor resistance to a wide variety of anticancer agents
[32], there is a big demand for novel and efficient anticancer
agents. Herein, in continuation of our studies on the develop-
ment of new anticancer agents [33–36] and focusing on the
versatile biological activity of acridone-1,2,3-triazole system
Scheme 1 Synthesis of
compounds 8a–n. Reagents and
conditions: a K2CO3, Cu,
EtOH, reflux, 7 h; b PPA,
100 ◦C , 3 h; c propargyl
bromide, KOtBu, DMSO, rt,
3 h; d NEt3, H2O/t-BuOH (1:1),
rt e CuI, 24–56 h
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Table 1 Cytotoxic activity
(IC50, µM) of compounds 8a–n
O
N
R2
R1
Y
N
N
N
H3CO
Y
Entry
R1
R2
Y
Cytotoxicity (IC50 µM)a
MCF-7
T-47D
MD-MB-231
8a
H
H
H
H
H
H
H
H
H
>100
48.4 4.3
>100
18.8 5.7
>100
8b
H
Cl
>100
8c
H
OCH3
11.0 4.8
>100
14.5 5.2
>100
16.6 5.9
>100
8d
H
Br
8e
H
CH2CH3
22.0 4.2
>100
88.5 4.7
>100
34.4 5.3
>100
8f
F
H
8g
OCH3
H
60.0 4.6
>100
50.0 5.5
>100
22.6 4.2
>100
8h
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
8i
H
Cl
>100
>100
>100
8j
H
OCH3
>100
>100
>100
8k
H
Br
>100
>100
>100
8l
H
CH2CH3
>100
>100
>100
8m
F
H
H
>100
>100
>100
8n
OCH3
>100
>100
>100
Etoposide
12.4 4.7
11.8 5.8
15.7 5.4
a
Values are the mean SD. All experiments were performed at least three times
propargyl bromide using potassium tert-butoxide in DMSO
at room temperature to obtain 10-(prop-2-yn-1-yl)acridin-9-
one derivatives 5. Using the click methodology described
by Sharpless et al. [24], the reaction of compound 5 and in
situ prepared 1-(azidomethyl)-4-methoxybenzene derivative
7 led to the formation of 9(10H)-acridinone-1,2,3-triazole
derivatives 8a–n. To obtain compound 7, 4-methoxy-benzyl
chloridederivative6andsodiumazidereactedinthepresence
of Et3N in H2O/t-BuOH (1:1) at ambient temperature for 1
h. Then, the mixture of compound 5 and CuI was added to the
mixture containing 7 and the reaction was conducted at room
temperature for 24–56 h to give the 9(10H)-acridinone-
1,2,3-triazole 8a–n in good yields.
activity than etoposide (IC50 = 12.4
4.8 µM). How-
ever, IC50 values against MDA-MB-231 and T-47D were
16.6 5.9 and 14.5 5.22 µM, respectively.
Compounds 8a–n could be categorized into two groups
considering the number of methoxy substituents on the pen-
dant benzyl group of 1,2,3-triazol ring: (i) mono-methoxy
(compounds 8a–g) and (ii) tri-methoxy (compounds 8h–n).
According to our results in Table 1, the first group (8a–g)
exhibited IC50 = 11.0 − 60.0 µM while the second group
(8h–n) did not show activity against breast cancer cell lines
(IC50 > 100 µM). It may relate to the compounds which
were not able to enter the cell.
As can be seen in Table 1, the kind of substituents as well
as their positions on the acridone moiety of compounds 8a–g
play important role in the obtained cytotoxicity. Compound
8a without substituents on the acridone ring showed no activ-
ity against MCF-7 (IC50 > 100 µM); however, it showed
Biological study
Cytotoxicity assay
moderate activity against T-47D (IC50 = 48.4
4.3 µM)
5.7 µM), respectively. Our
and MB-231(IC50 = 18.8
The cytotoxicity of products 8a–n was evaluated in vitro
against three human breast cancer cell lines comprising
MCF-7, T-47D, and MDA-MB-231 using the MTT tetra-
zolium salt assay [39]. The calculated IC50 values of com-
pounds 8a–n as well as etoposide (standard drug) are listed
in Table 1. Compounds 8c, being the most potent compound
against MCF-7 (IC50 = 11.0 µM), showed slightly better
results revealed that the presence of a halogen group (F, Cl,
and Br) at any position on the acridone moiety led to loss of
cytotoxic activity as 8b, 8d, and 8f were not active against
all cell lines. From the mono-methoxy group (compounds
8a–g), compound 8c (methoxy group at 2-postion) showed
the best activity in all three cell lines especially MCF-7
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Fig. 2 Morphological analysis of MCF-7 cells by acridine orange/ethidium bromide double staining: a control condition, b after exposure to
etoposide for 24 h, c cells treated with compound 8c for 24 h. White arrows indicate live cells, dashed arrows show apoptosis
Fig. 3 Flow cytometric analysis of MCF-7 cells treated with synthetic
compound 8c. Cells were stained with Annexin V-FITC/PI and quanti-
tated by flow cytometry. The cells treated with a DMSO 1 % (negative
control), b IC50 values of compound 8c for 12 h, c IC50 values of etopo-
side as positive control for 12 h
(IC50 = 11.0 4.8 µM). However, introducing the methoxy
group at the 4-position of acridone and also presence of an
ethyl substituent at the 2-position of the acridone decreased
anticancer activity (Table 1, 8g and 8e, respectively).
Compounds 8c and 8e having the methoxy and ethyl
group at the 2-position of acridone ring, respectively, exhib-
ited selective activity on MCF-7 cell. Compounds 8a and
8g having no substitution at the 2-position of acridone
moiety showed selective inhibition of MDA-MB-231 cell
growth.
Annexin V-FITC and propidium iodide (PI) double
staining
Apoptosis induction for compound 8c was further confirmed
by flow cytometry analysis [41] (Fig. 3). As shown in Fig. 3,
compound 8c induced 12.44 % apoptosis in the cancer cells.
Therefore, it is evident that the cytotoxicity of this compound
is related to inducing apoptosis in cancer cell lines.
Conclusion
In conclusion, novel 9(10H)-acridinone-1,2,3-triazole
hybrids were designed, synthesized, and evaluated as cyto-
toxic and apoptosis-inducing agents. The preliminary in
vitro anti-proliferative activity test was done against MCF-
7, T-47D, and MDA-MB-231 cells using MTT assay.
Among them, 2-methoxy-10-((1-(4-methoxybenzyl)-1H-
1,2,3-triazol-4-yl)methyl)acridin-9(10H)-one 8c with IC50
Acridine orange/ethidium bromide double staining
The most active compound 8c was selected to determine its
potential to induce apoptosis in MCF-7 cells morphologi-
cally by acridine orange/ethidiumbromide (AO/EB) double
staining test [40] (Fig. 2). Living cells have a normal green
nucleus, but apoptotic cells show orange-stained nuclei with
chromatin condensation or fragmentation. Analysis of the
AO/EB staining revealed that compound 8c clearly can be
inducer of apoptosis because the appearance of chromatin
condensation and nuclear fragmentation are evident in Fig. 2.
value of 11.0
side (IC50 = 12.4
4.8 µM was more potent than etopo-
4.7 µM) against MCF-7 cells. Also,
AO/EB staining and flow cytometry analysis using Annexin
V- FITC/PI double staining showed that compound 8c can
induce apoptosis.
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Experimental
(s, 1H, H1), 8.17 (s, 1H, triazole), 8.00 (d, J = 8.7 Hz, 1H,
H3), 7.94 (d, J = 8.7 Hz, 1H, H4), 7.83–7.82 (m, 2H, H5,
H6), 7.36 (t, J = 7.5 Hz, 1H, H7), 7.22 (d, J = 7.8 Hz,
Chemistry
ꢀ
ꢀ
ꢀ
ꢀ
2H, H2 , H6 ), 6.89 (d, J = 7.8 Hz, 2H, H3 , H5 ), 5.79 (s,
2H, CH2), 5.45 (s, 2H, CH2), 3.72 (s, 3H, OCH3). 13C NMR
(125 MHz, DMSO-d6): 175.6, 159.1, 142.4, 141.6, 140.4,
134.5, 133.8, 129.5, 127.7, 126.6, 126.1, 125.2, 123.1, 122.5,
121.9, 121.5, 119.1, 116.4, 114.1, 55.1, 52.4, 41.8. MS m/z
(%) 432 ([M+. + 2], 2), 430 (M+.6), 228 (9), 200 (10), 174
(12), 121 (100), 78 (11). Anal. Calcd for C24H19ClN4O2: C,
66.90; H, 4.44; N, 13.00. Found: C, 67.11; H, 4.23; N, 12.91.
Melting points are uncorrected and were measured using a
Kofler hot stage apparatus. H and 13C NMR spectra were
1
recorded on a Bruker FT-500, using TMS as an internal stan-
dardandDMSOasasolvent. Chemicalshiftsareexpressedas
δ (ppm). IR spectra were recorded on a Nicolet Magna FTIR
550 spectrophotometer using KBr disks. Mass spectra were
recorded on an Agilent Technology (HP) mass spectrome-
ter operating at an ionization potential of 70 eV. Elemental
analysis for C, H, and N was performed with an Elementar
Analysensystem GmbH VarioEL CHNS mode.
2-Methoxy-10-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-
yl)methyl)acridin-9(10H)-one (8c)
2-Arylamino benzoic acids 3, acridone derivatives 4, and
10-(prop-2-yn-1-yl)acridin-9-ones 5 were prepared accord-
ing to our recent report [36].
Yellow crystals; yield: 88 %, mp 177–179 ◦C. IR (KBr):
.
2934, 2834, 1742, 1617, 1595, 1498 cm−1 1H NMR
(500 MHz, DMSO-d6): 8.36 (dd, J = 8.0, 1.1 Hz, 1H, H8),
8.14 (s, 1H, triazole), 7.93–7.91 (m, 2H, H4, H5), 7.78–7.75
(m, 2H, H1, H6), 7.45 (dd, J = 9.4, 3.3 Hz, 1H, H3), 7.31 (t,
General procedure for the synthesis of
9(10H)-acridinone-1,2,3-triazole derivatives 8
ꢀ
ꢀ
J = 8.0 Hz, 1H, H7), 7.24 (d, J = 8.6 Hz, 2H, H2 , H6 ),
ꢀ
ꢀ
Amixture4-methoxybenzylchloridederivative6(1.1mmol), 6.88(d, J = 8.6 Hz, 2H, H3 , H5 ), 5.77 (s, 2H, CH2), 5.44
sodium azide (0.9 mmol), and Et3N (1.3 mmol) in water
(4 mL) and t-BuOH (4 mL) was stirred at room temperature
for 1 h. Then, a mixture of 10-(prop-2-yn-1-yl)acridin-9-
one derivative 5 (1 mmol) and CuI (7 mol%) was added
to prepared azide derivative 7 and the reaction mixture was
stirred at room temperature for 24–56 h. After completion of
the reaction (monitored by TLC), the reaction mixture was
diluted with water, poured onto ice, and the precipitate was
filtered off, washed with cold water, and purified by flash
chromatography on silica gel using petroleum ether/ ethyl
acetate (4:1) to afford desire product.
(s, 2H, CH2), 3.86 (s, 3H, OCH3), 3.71 (s, 3H, OCH3).13C
NMR (125 MHz, DMSO-d6): 176.0, 159.1, 154.1, 142.8,
141.6, 136.5, 133.8, 129.5, 127.8, 126.6, 123.9, 123.0, 122.4,
121.1, 120.9, 118.2, 116.0, 114.0, 106.1, 55.4, 55.0, 52.3,
41.6. Anal. Calcd for C25H22N4O3: C, 70.41; H, 5.21; N,
13.14. Found: C, 70.59; H, 5.08; N, 13.02.
2-Bromo-10-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-
yl)methyl)acridin-9(10H)-one (8d)
Yellow crystals; yield: 76 %, mp 237–239 ◦C. IR (KBr):
1
2922, 2849, 1735, 1632, 1598 cm−1. H NMR (500 MHz,
10-((1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)
acridin-9(10H)-one (8a)
DMSO-d6): 8.41 (d, J = 2.0 Hz, 1H, H1), 8.35 (d, J =
7.5 Hz, 1H, H8), 8.26 (s, 1H, triazole), 8.92 (dd, J = 9.0,
2.0 Hz, 1H, H3), 7.81 (t, J = 7.5 Hz, 1H, H6), 7.72 (d,
J = 9.0 Hz, 1H, H4), 7.68 (d, J = 7.5 Hz, 1H, H5), 7.37 (t,
Yellow crystals; yield: 84 %, mp 164–166 ◦C. IR (KBr):
3080, 2956, 2853, 1743, 1632, 1598cm−1
.
1H NMR (500
J = 7.5Hz, 1H, H7), 7.22(d, J = 8.4Hz, 2H, H2 , H6 ), 6.89
ꢀ
ꢀ
ꢀ
ꢀ
MHz, DMSO-d6): 8.37 (d, J = 8.0 Hz, 2H, H1, H8), 8.17
(s, 1H, triazole), 7.78 (t, J = 8.0 Hz, 2H, H3, H6), 7.69 (d,
J = 8.0 Hz, 2H, H4, H5), 7.35 (t, J = 8.0 Hz, 2H, H2, H7),
(d, J = 8.4 Hz, 2H, H3 , H5 ), 5.77 (s, 2H, CH2), 5.54 (s, 2H,
CH2), 3.73 (s, 3H, OCH3). 13C NMR (125 MHz, DMSO-d6):
175.6, 159.0, 142.1, 141.3, 140.3, 134.4, 133.8, 128.9, 128.4,
127.0, 126.6, 125.5, 123.4, 123.0, 122.0, 121.6, 119.4, 116.5,
114.1, 55.1, 52.7, 42.8. Anal. Calcd for C24H19BrN4O2: C,
60.64; H, 4.03; N, 11.79. Found: C, 60.81; H, 4.14; N, 11.63.
ꢀ
ꢀ
7.14 (d, J = 8.4 Hz, 2H, H2 , H6 ), 6.91 (d, J = 8.4 Hz, 2H,
ꢀ
ꢀ
H3 , H5 ), 5.75 (s, 2H, CH2), 5.55 (s, 2H, CH2), 3.73 (s, 3H,
OCH3). Anal. Calcd for C24H20N4O2: C, 72.71; H, 5.09; N,
14.13. Found: C, 72.93; H, 4.96; N, 13.96.
2-Ethyl-10-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-
2-Chloro-10-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-
yl)methyl)acridin-9(10H)-one (8e)
yl)methyl)acridin-9(10H)-one (8b)
Pale yellow crystals; yield: 79 %, mp 193–195 ◦C. IR (KBr):
Yellow crystals; yield: 79 %, mp 234–235 ◦C. IR (KBr):
3080, 2959, 2843, 1742, 1629, 1595, 1489 cm−1. 1H NMR
(500 MHz, DMSO-d6): 8.34 (d, J = 7.5 Hz, 1H, H8), 8.25
3071, 2928, 1735, 1635, 1598 cm−1. H NMR (500 MHz,
1
DMSO-d6): 8.35 (d, J = 7.5 Hz, 1H, H8), 8.17 (m, 2H, H1,
triazole), 7.91 (d, J = 7.5 Hz, 1H, H5), 7.86 (d, J = 8.8 Hz,
123

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ꢀ
ꢀ
1H, H4), 7.78 (t, J = 7.5 Hz, 1H, H6), 7.67 (dd, J = 8.8,
1.8 Hz, 1H, H3), 7.32 (t, J = 7.5 Hz, 1H, H7), 7.25 (d,
H2, H7), 6.56 (s, 2H, H2 , H6 ), 5.81 (s, 2H, CH2), 5.45 (s,
2H, CH2), 3.70 (s, 6H, OCH3), 3.69 (s, 3H, OCH3). Anal.
Calcd for C26H24N4O4: C, 68.41; H, 5.30; N, 12.27. Found:
C, 68.59; H, 5.18; N, 12.13.
ꢀ
ꢀ
ꢀ
ꢀ
J = 7.7Hz, 2H, H2 , H6 ), 6.86(d, J = 7.7Hz, 2H, H3 , H5 ),
5.75 (s, 2H, CH2), 5.45 (s, 2H, CH2), 3.72 (s, 3H, OCH3),
2.73 (q, J = 7.5 Hz, 2H, CH2), 1.30 (t, J = 7.5 Hz, 3H,
CH3).13C NMR (125 MHz, DMSO-d6): 176.4, 159.1, 142.8,
141.6, 140.1, 136.9, 134.4, 133.9, 131.2, 129.5, 127.8, 126.6,
124.5, 123.0, 121.6, 121.2, 116.4, 116.1, 114.0, 55.1, 52.3,
41.5, 27.3, 15.5. Anal. Calcd for C26H24N4O2: C, 73.56; H,
5.70; N, 13.20. Found: C, 73.74; H, 5.58; N, 13.03.
2-Chloro-10-((1-(3,4,5-trimethoxybenzyl)-1H-1,2,3-triazol-
4-yl)methyl)acridin-9(10H)-one (8i)
Yellow crystals; yield: 63 %, mp 244–245 ◦C. IR (KBr):
3114, 2953, 1787, 16031, 1594 cm−1. 1H NMR (500 MHz,
DMSO-d6): 8.35 (d, J = 7.5 Hz, 1H, H8), 8.26 (d, J =
2.3 Hz, 1H, H1), 8.22 (s, 1H, triazole), 8.01 (d, J = 9.0 Hz,
1H, H3), 7.96 (d, J = 9.0 Hz, 1H, H4), 7.83 (m, 2H, H5, H6),
4-Fluoro-10-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-
yl)methyl)acridin-9(10H)-one (8f)
ꢀ
ꢀ
7.37 (t, J = 7.5 Hz, 1H, H7), 6.56 (s, 2H, H2 , H6 ), 5.82 (s,
2H, CH2), 5.45 (s, 2H, CH2), 3.66 (s, 6H, OCH3), 3.61(s,
3H, OCH3). 13C NMR (125 MHz, DMSO-d6): 175.6, 152.9,
142.5, 141.6, 140.4, 137.2, 134.5, 133.8, 131.3, 126.5, 126.1,
125.2, 123.5, 122.6, 121.9, 121.6, 119.1, 116.4, 105.3, 59.9,
55.7, 53.0, 41.7. Anal. Calcd for C26H23ClN4O4: C, 63.61;
H, 4.72; N, 11.41. Found: C, 63.77; H, 4.58; N, 11.58.
White crystals; yield: 71 %, mp 132–133 ◦C. IR (KBr):
1
3150, 2937, 1738, 1638, 1608 cm−1. H NMR (500 MHz,
DMSO-d6): 8.29 (d, J = 7.3 Hz, 1H, H8), 8.18–8.16
(m, 2H, H1, triazole), 7.81–7.76 (m, 2H, H5, H6), 7.67
(ddd, J = 15.2, 7.6, 1.3‘Hz, 1H, H3), 7.36–7.29 (m, 2H,
ꢀ
ꢀ
H2, H7), 7.24 (d, J = 8.6 Hz, 2H, H2 , H6 ), 6.89 (d,
ꢀ
ꢀ
J = 8.6 Hz, 2H, H3 , H5 ), 5.69 (s, 2H, CH2), 5.47(s,
2H, CH2), 3.66 (s, 3H, OCH3). 13C NMR (125 MHz,
DMSO-d6): 176.0, 159.0, 151.3 (d, JC−F = 243.9 Hz),
144.2, 143.5, 134.5, 132.2, 129.4, 127.8, 126.4, 124.9,
122.9, 122.7, 122.2, 121.9 (d, JC−F = 7.6 Hz), 121.8,
121.1 (d, JC−F = 23.4 Hz), 116.6, 114.0, 55.1, 52.3, 47.1
(d, JC−F = 14.8 Hz). Anal. Calcd for C24H19F N4O2: C,
69.55; H, 4.62; N, 13.52. Found: C, 69.73; H, 4.51; N,
13.35.
2-Methoxy-10-((1-(3,4,5-trimethoxybenzyl)-1H-1,2,3-
triazol-4-yl)methyl)acridin-9(10H)-one (8j)
Yellow crystals; yield: 64 %, mp 193–194 ◦C. IR (KBr):
3112, 2931, 1735, 1631, 1594 cm−1. H NMR (500 MHz,
1
DMSO-d6): 8.36 (d, J = 7.5 Hz, 1H, H8), 8.19 (s, 1H, tri-
azole), 7.96–7.93 (m, 2H, H4, H5), 7.79–7.77 (m, 2H, H1,
H6), 7.46 (dd, J = 9.2, 3.0 Hz, 1H, H3), 7.32 (t, J = 7.5 Hz,
ꢀ
ꢀ
1H, H7), 6.59 (s, 2H, H2 , H6 ), 5.82 (s, 2H, CH2), 5.44 (s,
2H, CH2), 3.88 (s, 3H, OCH3), 3.65 (s, 6H, OCH3), 3.61
(s, 3H, OCH3). 13C NMR (125 MHz, DMSO-d6): 176.0,
154.1, 152.9, 142.8, 141.3, 137.1, 136.5, 133.8, 131.4, 126.6,
123.9, 123.4, 122.4, 121.1, 120.9, 118.3, 116.1, 106.2, 105.2,
59.9, 55.7, 55.4, 52.9, 41.6. Anal. Calcd for C27H26N4O5: C,
66.66; H, 5.39; N, 11.52. Found: C, 66.83; H, 5.21; N, 11.35.
4-Methoxy-10-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-
yl)methyl)acridin-9(10H)-one (8g)
Pale yellow crystals; yield: 69 %, mp 134–135 ◦C. IR (KBr):
1
3120, 2922, 1735, 1629, 1598 cm−1. H NMR (500 MHz,
DMSO-d6): 8.24 (dd, J = 8.0, 1.4 Hz, 1H, H8), 8.03 (s,
1H, triazole), 7.92 (dd, J = 7.6, 1.0 Hz, 1H, H1), 7.79–
7.72 (m, 2H, H5, H6), 7.43 (dd, J = 7.6, 1.0 Hz, 1H,
H3), 7.32–7.29 (m, 2H, H2, H7), 7.18 (d, J = 7.8 Hz,
2-Bromo-10-((1-(3,4,5-trimethoxybenzyl)-1H-1,2,3-triazol-
4-yl)methyl)acridin-9(10H)-one (8k)
ꢀ
ꢀ
ꢀ
ꢀ
2H, H2 , H6 ), 6.80 (d, J = 7.8 Hz, 2H, H3 , H5 ), 5.73
(s, 2H, CH2), 5.51 (s, 2H, CH2), 3.75 (s, 3H, OCH3),
3.69 (s, 3H, OCH3). Anal. Calcd for C25H22N4O3: C,
70.41; H, 5.20; N, 13.14. Found: C, 70.68; H, 5.04; N,
12.94.
Pale yellow crystals; yield: 62 %, mp 246–248 ◦C . IR (KBr):
3115, 2931, 1751, 1627, 1595 cm−1. H NMR (500 MHz,
1
DMSO-d6): 8.41 (s, 1H, H1), 8.35 (d, J = 7.8 Hz, 1H, H8),
8.22 (s, 1H, triazole), 7.97–7.95 (m, 3H, H3, H4, H5), 7.84–
7.81 (t, J = 7.8 Hz, 1H, H6), 7.38 (t, J = 7.8 Hz, 1H, H7),
10-((1-(3,4,5-Trimethoxybenzyl)-1H-1,2,3-triazol-4-
yl)methyl)acridin-9(10H)-one (8h)
ꢀ
ꢀ
6.56 (s, 2H, H2 , H6 ), 5.82 (s, 2H, CH2), 5.44 (s, 2H, CH2),
3.66 (s, 6H, OCH3), 3.61 (s, 3H, OCH3). MS m/z (%) 537
([M+. + 2], 10), 535 (M+.10), 534 (29), 274 (13), 244 (25),
228 (32), 203 (19), 181 (100), 165 (27), 148 (29), 135 (26),
121 (50), 106 (94), 91 (51), 77 (46), 51 (23). Anal. Calcd
for C26H23 Br N4O4: C, 58.33; H, 4.33; N, 10.46. Found: C,
58.51; H, 4.18; N, 10.29.
White crystals; yield: 68 %, mp 232–234 ◦C . IR (KBr): 3114,
2937, 1745, 1631, 1603 cm−1. 1H NMR (500 MHz, DMSO-
d6): 8.24 (dd, J = 7.5 Hz, 1.3 Hz, 2H, H1, H8), 8.22 (s, 1H,
triazole), 7.94 (d, J = 7.5 Hz, 2H, H4, H5), 7.82–7.78 (t,
J = 7.5 Hz, 2H, 2H, H3, H6), 7.35 (t, J = 7.5 Hz, 2H,
123

Mol Divers
2-Ethyl-10-((1-(3,4,5-trimethoxybenzyl)-1H-1,2,3-triazol-
Biological assays
4-yl)methyl)acridin-9(10H)-one (8l)
Cell culture
Yellow crystals; yield: 67 %, mp 197–198 ◦C. IR (KBr):
1
3111, 2925, 1735, 1639, 1594 cm−1. H NMR (500 MHz,
MCF-7, T-47D and MDA-MB-231 were purchased from
the National Cell Bank of Iran (NCBI). The cells were
cultured in RPMI 1640 medium supplemented with 10 %
heat-inactivated fetal calf serum (from GibcoeBRL, UK) and
100 mg/mL streptomycin and 100 U/mL penicillin at 37 ◦C
in 5 % CO2-humidified atmosphere.
DMSO-d6): 8.36 (dd, J = 8.0, 1.8 Hz, 1H, H8), 8.18–8.17
(m, 2H, H1, triazole), 7.93 (d,J = 8.0 Hz, 1H, H5), 7.88
(d,J = 9.0 Hz, 1H, H4), 7.80–7.76 (td, J = 8.0, 1.8 Hz,
1H, H6), 7.67 (dd, J = 9.0, 2.2 Hz, 1H, H3), 7.33 (t,
ꢀ
ꢀ
J = 8.0 Hz, 1H, H7), 6.55 (s, 2H, H2 , H6 ), 5.80 (s, 2H,
CH2), 5.44 (s, 2H, CH2), 3.65 (s, 6H, OCH3), 3.60 (s, 3H,
OCH3), 2.73 (q, J = 7.5 Hz, 2H, CH2), 1.24 (t, J = 7.5 Hz,
3H, CH3). 13C NMR (125 MHz, DMSO-d6): 176.7, 152.9,
142.8, 141.6, 140.1, 136.9, 134.4, 133.9, 131.4, 126.6, 125.4,
124.5, 123.4, 122.8, 121.6, 121.2, 116.4, 116.1, 105.2, 59.9,
55.7, 52.9, 41.5, 27.3, 15.5. Anal. Calcd for C28H28N4O4:
C, 69.41; H, 5.82; N, 11.56. Found: C, 69.31; H, 5.91; N,
11.32.
In vitro cytotoxicity assay
Three different breast cancer cell lines (MCF-7, T-47D and
MDA-MB-23) (5 × 104 cells/mL in 96-well culture plates)
were incubated for 48 h with different concentrations of
compounds 8a–n dissolved in DMSO (the final volume
of DMSO/medium was less than 1 % in all experiments).
EtoposideandDMSOwereusedaspositiveandnegativecon-
trols, respectively. After treatment, the medium was removed
and 200 µL of a phenol red-free medium containing MTT
(1 mg/mL, final concentration) was added to all wells. After
4 h of incubation, the culture medium was replaced with
100 µL of DMSO to each well. The absorbance was mea-
sured at 492 nm with a multi-well plate reader (Gen5,
Power wave xs2, BioTek, America). All experiments were
performed at least three times and the IC50 values for all
compounds were calculated by nonlinear regression analysis
and expressed in mean SD compared with the control [39].
4-Fluoro-10-((1-(3,4,5-trimethoxybenzyl)-1H-1,2,3-triazol-
4-yl)methyl)acridin-9(10H)-one (8m)
Yellow crystals; yield: 62 %, mp >250 ◦C . IR (KBr): 3120,
2938, 1742, 1639, 1597 cm−1. 1H NMR (500 MHz, DMSO-
d6): 8.31 (d, J = 7.7 Hz, 1H, H8), 8.23 (s, 1H, triazole),
8.19 (d, J = 7.6 Hz, 1H, H1), 7.79–7.78 (m, 2H, H5,
H6), 7.68 (ddd, J = 15.3, 7.6, 1.1 Hz, 1H, H3), 7.38–
ꢀ
ꢀ
7.31 (m, 2H, H2, H7), 6.52 (s, 2H, H2 , H6 ), 5.73 (s, 2H,
CH2), 5.47(s, 2H, CH2), 3.64 (s, 6H, OCH3), 3.61 (s, 3H,
OCH3). 13C NMR (125 MHz, DMSO-d6): 179.1, 152.9,
151.4 (d, JC−F = 254.2 Hz), 144.4, 143.5, 134.5, 132.2,
AO/EB staining method
131.5, 126.4, 124.9, 123.3, 122.7, 122.2, 121.9 (d, JC−F
=
18.9 Hz), 121.8, 121.2, 121.0, 116.6, 105.1, 59.9, 55.7, 52.9,
47.1 (d, JC−F = 14.8 Hz). Anal. Calcd for C26H23F N4O4:
C, 65.81; H, 4.89; N, 11.81. Found: C, 65.64; H, 5.07; N,
11.98.
MCF-7 cell grown in 6-well plates (3 × 105 cells/well) were
treated with and without compound 8c for 24 h. Plates were
washed three times by phosphate buffered saline (PBS) and
9 µL of cell suspension was stained with 1 µL of dye mix-
ture (100 mg/mL AO and 100 mg/mL EB in PBS). 10 µL of
stained cell suspension were placed on a clean microscope
slide and covered with a coverslip and examined by fluores-
cence microscope (Axoscope 2 plus, Zeiss, Germany) [40].
4-Methoxy-10-((1-(3,4,5-trimethoxybenzyl)-1H-1,2,3-
triazol-4-yl)methyl)acridin-9(10H)-one (8n)
Yellow crystals; yield: 61 %, mp 182–184 ◦C . IR (KBr):
1
3113, 2945, 1732, 1623, 1598 cm−1. H NMR (500 MHz,
Flow cytometric analysis of apoptosis
DMSO-d6): 8.23 (d, J = 7.5 Hz, 1H, H8), 8.05 (s, 1H,
triazole), 7.92 (d, J = 7.5 Hz, 1H, H1), 7.79–7.72 (m, 2H,
H5, H6), 7.42 (d, J = 7.5 Hz, 1H, H3), 7.29 (t, J = 7.5 Hz,
Annexin V-FITC/propidium iodide (PI) double staining test
was performed using an Annexin-V- FITC kit (Biovision)
as described in protocol. The MCF-7 cells were treated
with IC50 concentrations of the compound 8c, etoposide and
DMSO 1 %. After 24 h incubation, the cells (5 × 105 cells)
were collected and washed twice with cold PBS and resus-
pended in 500 µl of 1X binding buffer. Then, the cells were
double stained with 5 µL of Annexin V-FITC and 5 µL of
PI solution. Finally, the samples were incubated for 5 min at
room temperature and then analyzed by flow cytometry [41].
ꢀ
ꢀ
2H, H2, H7), 6.57 (s, 2H, H2 , H6 ), 5.74 (s, 2H, CH2), 5.45
(s, 2H, CH2), 3.78 (s, 3H, OCH3), 3.68 (s, 6H, OCH3), 3.62
(s, 3H, OCH3). 13C NMR (125 MHz, DMSO-d6): 176.9,
152.9, 149.7, 145.5, 144.8, 137.2, 134.4, 133.9, 131.6, 126.1,
124.8, 123.4, 122.4, 122.2, 121.7, 118.1, 117.3, 116.3, 105.2,
59.94, 56.4, 55.8, 52.9, 48.4. Anal. Calcd for C27H26N4O5:
C, 66.65; H, 5.39; N, 11.52. Found: C, 66.76; H, 5.22; N,
11.39.
123

Mol Divers
Acknowledgments This work was supported by Grant from the
ResearchCouncil ofTehranUniversityofMedical SciencesunderGrant
No. 94-01-33-28706.
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