Synthesis of novel benzoxanthone analogues as non-Camptothecin topoisomerase i inhibitors

Article abstract of DOI:10.3109/14756366.2011.595712

Structure modification of the side chain of the lead compound benzoxanthone provided a series of benzoxanthone analogues and 12 of them were first reported. The results showed that most of these compounds had moderate cytotoxicity against tumour cells with the 50% inhibition concentration in the micromolar range. Furthermore, benzoxanthone derivatives 5, 6c, 7a and 7e, showed potent topoisomerase I (Topo I) inhibitory effect and the results indicated that some compounds had potential for development as non-Camptothecin (CPT) topoisomerase I inhibitors.

Full text of DOI:10.3109/14756366.2011.595712

Journal of Enzyme Inhibition and Medicinal Chemistry, 2012; 27(3): 437–442
© 2012 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2011.595712
REsEaRch aRtIclE
Synthesis of novel benzoxanthone analogues as
non-Camptothecin topoisomerase I inhibitors
Pengfei Cheng, Lingjian Zhu, Wei Guo, Wenfeng Liu, Jianzhong Yao, Guoqiang Dong,
Yongqiang Zhang, Chunlin Zhuang, Chunquan Sheng, Zhenyuan Miao, and Wannian Zhang
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People’s Republic of China
abstract
Structure modification of the side chain of the lead compound benzoxanthone provided a series of benzoxanthone
analogues and 12 of them were first reported. The results showed that most of these compounds had moderate
cytotoxicity against tumour cells with the 50% inhibition concentration in the micromolar range. Furthermore,
benzoxanthone derivatives 5, 6c, 7a and 7e, showed potent topoisomerase I (Topo I) inhibitory effect and the
results indicated that some compounds had potential for development as non-Camptothecin (CPT) topoisomerase
I inhibitors.
Keywords: Benzoxanthone, structural modification, anti-tumour, topoisomerase I inhibitor
Introduction
designed 9,11-substituted benzoxanthones for improv-
Xanthone1, one of the secondary metabolites from
higher plants and micro-organisms, shows diverse
biological profiles including anti-hypertensive2, anti-
oxidative, anti-thrombotic and anti-cancer activities3.
Simple structural scaffold and diverse biological spec-
tra of xanthone had led many scientists to synthesize
xanthone analogues for the development of prospec-
tive drug candidates.
Over the past several decades, DNA topoisomerase
I (Topo I) has been recognized as an effective tar-
get enzyme for development of chemotherapeutic
agents4. Among the topoisomerase I inhibitors, two
camptothecin (CPT) derivatives topotecan5 and iri-
notecan6 had been approved for ovarian and colon
cancers treatment. But the intrinsic instability of the
highly electrophilic α-hydroxylactone of CPT leads to
rapid hydrolysis of E ring to the biologically inactive
carboxylate form under physiological conditions. To
overcome the drawbacks of CPTs, the discovery of non-
CPT Topo I inhibitors has recently emerged as a prom-
ising field to find better anti-tumour agents. Based on
our knowledge about topoisomerase I inhibitor, we
ing their anti-cancer activities. However, Cho and
co-workers7 had designed a series of new benzoxan-
thone analogues possessing epoxy or thioepoxy groups
during our study about benzoxanthone. ey have
synthesized 12 oxiranylmethoxy- or thiiranylmethoxy-
substituted benzoxanthone analogues and compound
1,3-bis(oxiran-2-ylmethoxy)-12H-benzo[b]-xanthen-
12-one as potent topoisomerase I and II inhibitor was
the most efficient among these compounds. Recently,
we carried out structure modification on the side chain
of benzoxanthone for finding more potent anti-tumour
agents.
Experimental
Chemistry
All reagents and solvents were reagent grade or were
1
purified by standard methods before use. H and 13C
spectra were recorded at 300 MHz or 500 MHz with a
Bruker instrument, and reported with TMS as internal
standard and DMSO-d6 as solvent. Chemical shifts
(δ values) and coupling constants (J values) are given
Address for Correspondence: Chunquan Sheng, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai
200433, People’s Republic of China. E-mail: shengcq@hotmail.com; Wannian Zhang: Tel:/Fax: 86-21-81871243;
E-mail: zhangwnk@hotmail.com; Zhenyuan Miao: Tel: 86-21-81871233; E-mail: miaozhenyuan@hotmail.com
(Received 21 January 2011; revised 01 June 2011; accepted 03 June 2011)
437

438 P. Cheng et al.
in ppm and Hz, respectively. e mass spectra were
recorded on an Esquire 3000 LC-MS mass spectrometer.
Elemental analyses were performed with a MOD-1106
instrument and were consistent with theoretical values
within 0.4%. TLC analysis was carried out on silica
gel plates GF254 (Qindao Haiyang Chemical, China).
Flash column chromatography was carried out on silica
gel 300–400 mesh. Anhydrous solvent and reagents
were all analytical pure and dried through routine
protocols.
H]. Anal. calcd. for C17H10O4: C, 73.38; H, 3.62. Found: C,
73.47; H, 3.63.
9,11-dibromo-8,10-dihydroxy-7H-benzo[c]xanthen-7-one(2)
1H NMR (500 MHz, CDCl3) δ 7.70 (m, 3H), 7.91 (m, 1H),
8.16 (d, J= 8.7 Hz, 1H), 8.74 (m, 1H), 13.97 (s, 1H). ESI-MS:
m/z, 435.62 [M - H]. Anal. calcd. for C17H8Br2O4: C, 46.83;
H, 1.85. Found: C, 46.70; H, 1.85.
8,10-dihydroxy-9,11-diiodo-7H-benzo[c]xanthen-7-one(3)
1H NMR (500 MHz, DMSO) δ 7.80 (m, 1H), 7.87 (m, 2H),
8.00 (m, 1H), 8.07 (m, 1H), 8.62 (m, 1H), 10.85 (br s, 1H).
ESI-MS: m/z, 529.22 [M - H]. Anal. calcd. for C17H8I2O4: C,
38.52; H, 1.52. Found: C, 38.64; H, 1.52.
General procedure for the synthesis of the
benzoxanthone analogues
8,10-dihydroxy-7H-benzo[c]xanthen-7-one is synthe-
sized as shown in Scheme 1. We treated 1,3,5-trihydroy-
benzene with 1 equiv. of 1-naphthol-2-carboxylic acid in
phosphorus oxychloride at 70°C. e desired product 18
was obtained in 35.8% yield after a reaction time of 6 h.
As depicted in Scheme 2, starting from 8,10-dihydroxy-7-
H-benzoxanthen-7-one (1), we carried out modification
to prepare a variety of novel benzoxanthone analogues
with different side chain. Treated 1 with Br2 in acetic
acid at room temperature to produce bromide deriva-
tive 2 or 49. And treated 1 with NIS in DMF at room tem-
perature to produce iodides derivative 310. Treatment of
compound 1 with 2-hydroxybenzyl alcohol and ZnCl2 in
dioxane solution at 100°C for 6 h gives derivative 511. On
treatment of compound 1 with different acyl chloride
provided 6a–c12. e target compound 7a was prepared
from 1, which was treated with benzyl bromide and
K2CO3 in the presence of acetone at reflux for 4 h. en
the 8-hydroxyl of 7a was esterified with corresponding
acyl chloride to give the compounds 7b–d13. And 8,10-
dihydroxyl of 1 were esterified with corresponding acyl
chloride to give the compound 7e (Scheme 2). e struc-
5,9,11-tribromo-8,10-dihydroxy-7H-benzo[c]xanthen-7-
one(4)
1H NMR (500 MHz, CDCl3) δ 7.60 (m, 1H), 7.73 (m, 1H),
8.08 (s, 1H), 8.16 (d, J= 8.4 Hz, 1H), 8.45 (d, J= 8.3 Hz, 1H),
11.93 (s, 1H). ESI-MS: m/z, 514.65 [M + H]. Anal. calcd.
for C17H7Br3O4: C, 39.65; H, 1.37. Found: C, 39.59; H, 1.37.
8,10-dihydroxy-9,11-bis(2-hydroxybenzyl)-7H-benzo[c]
xanthen-7-one(5)
1H NMR (500 MHz, DMSO) δ 13.23 (s, 1H),10.02(br s,3H),
8.54 (s, 1H), 8.04 (m,2H), 7.90 (m,1H), 7.80 (m,1H), 7.73
(m,1H), 7.68 (m,2H), 6.90 (m,4H), 6.67 (m,1H), 6.58
(m,1H), 4.29 (s, 2H), 3.96 (s, 2H). ESI-MS: m/z, 489.30 [M
- H]. Anal. calcd. for C31H22O6: C, 75.91; H, 4.52. Found: C,
75.77; H, 4.53.
8-hydroxy-7-oxo-7H-benzo[c]xanthen-10-yl acetate(6a)
1H NMR (500 MHz, CDCl3) δ 2.37 (s, 3H), 6.63 (d, J= 2 Hz,
1H), 7.00 (d, J= 2 Hz, 1H), 7.74 (m, 3H), 7.92 (m, 1H), 8.21
(m, 1H), 8.61 (m, 1H), 12.90 (s, 1H). ESI-MS: m/z, 319.60
[M - H], 321.25 [M + H]. Anal. calcd. for C19H12O5: C, 71.25;
H, 3.78. Found: C, 71.33; H, 3.78.
1
tures of target compounds were confirmed by H NMR
data and 13C NMR.
e synthesized compounds are listed in Schemes 1
and 2 and the obtained spectral data are as follows:
8-hydroxy-7-oxo-7H-benzo[c]xanthen-10-yl isonicotinate(6b)
1H NMR (500 MHz, CDCl3) δ 6.76 (d, J= 2 Hz, 1H), 7.12 (d,
J= 2 Hz, 1H), 7.72 (m, 3H), 7.92 (m, 1H), 8.17 (m, 2H), 8.21
(m, 1H), 8.59 (m, 1H), 8.92 (m, 2H), 12.97 (s, 1H). ESI-MS:
m/z, 384.60 [M + H]. Anal. calcd. for C23H13NO5: C, 72.06;
H, 3.42; N, 3.65. Found: C, 72.11; H, 3.43; N 3.64.
8,10-dihydroxy-7H-benzo[c]xanthen-7-one(1)
1H NMR (500 MHz, CDCl3), δ 12.91 (s, 1H), 10.24 (s, 1H),
8.62 (d, J= 7.9 Hz, 1H), 8.14 (d, J= 8.7 Hz, 1H), 7.94 (d,
J= 7.9 Hz, 1H), 7.72 (m, 3H), 6.60 (d, J= 1.9 Hz, 1H), 6.36
(d, J= 1.9 Hz, 1H). 13C NMR (500 MHz, DMSO-d6), δ 94.79,
99.00, 103.14, 115.86, 120.15, 122.87, 123.29, 124.52,
127.89, 128.61, 130.45, 136.48, 153.29, 157.45, 162.88,
165.89, 179.95. ESI-MS: m/z, 277.90 [M - H], 279.95 [M +
8-hydroxy-7-oxo-7H-benzo[c]xanthen-10-yl nicotinate(6c)
1H NMR (500 MHz, CDCl3) δ 6.78 (d, J = 2 Hz, 1H),
7.14 (d, J = 2 Hz, 1H), 7.52 (m, 1H), 7.75 (m, 3H), 7.92
Scheme 1. Reagents and conditions: (a) POCl3, 70°C.
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis of novel benzoxanthone analogues 439
Scheme 2. Reagents and conditions: (a) Br2 (2 eq), AcOH, r.t.; (b) NIS, DMF, r.t.; (c) Br2 (3 eq), AcOH, r.t.; (d) 2-hydroxybenzyl alcohol, ZnCl2,
100°C, dioxane; (e) different acyl chloride, Et3N, acetone, r.t.; (f) benzyl bromide, K2CO3, acetone, ref.; (g) corresponding acyl chloride,
NaH, THF (dry), r.t.; (h) 3-methoxybenzoyl chloride, Et3N, acetone, r.t., then 3-bromobenzoyl chloride, NaH, THF (dry), r.t.
(m, 1H), 8.19 (m, 1H), 8.48 (m, 1H), 8.52 (m, 1H),8.91
(d, J = 4.8 Hz, 1H), 9.44 (s, 1H), 12.97 (s, 1H). ESI-MS:
m/z, 382.92 [M - H], 384.93 [M + H]. Anal. calcd. for
C23H13NO5: C, 72.06; H, 3.42; N, 3.65. Found: C, 72.13;
H, 3.42; N 3.66.
[M + H]. Anal. calcd. for C24H16O4: C, 78.25; H, 4.38. Found:
C, 72.34; H, 4.37.
10-(benzyloxy)-7-oxo-7H-benzo[c]xanthen-8-yl
4-fluorobenzoate(7b)
1H NMR (300 MHz, CDCl3) δ 5.25 (s, 2H), 6.87 (d, J= 2.7Hz,
1H), 7.16 (d, J= 2.7 Hz, 1H), 7.23 (m, 2H), 7.45 (m, 1H),
7.48 (m, 4H), 7.68 (m, 3H), 7.92 (m, 1H), 8.13 (m, 1H),
8.34 (m, 1H),8.60 (m,1H). ESI-MS: m/z, 491.80 [M + H].
Anal. calcd. for C31H19FO5: C, 75.91; H, 3.90. Found: C,
75.81; H, 3.90.
10-(benzyloxy)-8-hydroxy-7H-benzo[c]xanthen-7-one(7a)
1H NMR (500 MHz, CDCl3) δ 5.21 (s, 2H), 6.50 (d, J= 2
Hz, 1H), 6.72 (d, J= 2 Hz, 1H), 7.45 (m, 5H), 7.73 (m, 3H),
7.94(d, J= 7.9 Hz, 1H), 8.18 (d, J= 8.7 Hz, 1H), 8.62 (d, J= 8
Hz, 1H), 12.95 (s, 1H). ESI-MS: m/z, 367.82 [M - H], 369.70
© 2012 Informa UK, Ltd.

440 P. Cheng et al.
bromide at room temperature and photographed with
UV transilluminator.
10-(benzyloxy)-7-oxo-7H-benzo[c]xanthen-8-yl
2-chlorobenzoate(7c)
1H NMR (500 MHz, CDCl3) δ 5.26 (s, 2H), 6.90 (d, J= 2 Hz,
1H), 7.17 (d, J= 2 Hz, 1H), 7.46 (m, 1H), 7.52 (m, 7H), 7.70
(m, 3H), 7.91 (m, 1H), 8.18 (m, 1H), 8.75 (m, 1H), 8.62
(m, 1H). ESI-MS: m/z, 507.98 [M + H]. Anal. calcd. for
C31H19ClO5: C, 73.45; H, 3.78. Found: C, 73.54; H, 3.77.
Results and discussion
Chemistry
1
In the H NMR spectra, all non-substituted or mono-
substituted on hydroxy benzoxanthones (1–6c) showed
single peaks at δ 13.00 corresponding to the hydroxyl
hydrogen adjacent to the carbonyl group in the benzox-
10-(benzyloxy)-7-oxo-7H-benzo[c]xanthen-8-yl
4-chlorobenzoate(7d)
1H NMR (500 MHz, CDCl3) δ 5.25 (s, 2H), 6.87 (d, J= 2 Hz,
1H), 7.16 (d, J= 2 Hz, 1H), 7.44 (m, 5H), 7.52 (m, 2H), 7.62
(m, 3H), 7.90 (m, 1H), 8.12 (m, 1H), 8.24 (m, 2H), 8.62
(m, 1H). ESI-MS: m/z, 1036.19 [2M + Na]. Anal. calcd. for
C31H19ClO5: C, 73.45; H, 3.78. Found: C, 73.52; H, 3.78.
1
anthone ring7. ese single peaks disappeared in the H
NMR spectra of di-substituted derivatives (7a–e), which
indicates the introduction of two substituted groups on
two hydroxyl groups. With regard to compounds 2–5, the
chemical shifts of 9- and 11-hydrogen of benzoxanthones
ring were assigned at δ 6.30–7.20. Due to the benzoxan-
thone derivatives having several aromatic rings, there are
many multiple peaks at δ 7.50–8.50.
8-(3-bromobenzoyloxy)-7-oxo-7H-benzo[c]xanthen-10-yl
3-methoxybenzoate(7e)
1H NMR (500 MHz, CDCl3) δ 3.91 (s, 3H), 7.17 (d, J= 2 Hz,
1H), 7.47 (m, 3H), 7.75 (m, 5H), 7.80 (m, 1H), 7.84 (m,
1H), 7.92 (m, 1H), 8.18 (m, 1H), 8.25 (m, 1H), 8.48 (m,
1H), 8.62 (m, 1H). ESI-MS: m/z, 1213.18 [2M + Na]. Anal.
calcd. for C32H19BrO7: C, 64.55; H, 3.22. Found: C, 64.52;
H, 3.22.
Cytotoxicity
Many reports in recent years have shown that the inhi-
bition of DNA topoisomerase by numerous natural and
synthetic compounds is closely associated with the
cytotoxic potentials of these compounds14–16. e anti-tu-
mour activity of benzoxanthone analogues were assayed
in vitro against human lung adenocarcinoma cell lines
(A549), human breast cancer cell lines (MDA-MB-435)
and human colon cancer cell lines (HCT-116). TPT was
used as the positive drug and the results were shown in
Table 1. It appeared that benzoxanthone derivatives with
polyhydroxy had broad-spectrum anti-tumour activity
and the other compounds had moderate anti-tumour
activity against one cell line or two cell lines. Among the
13 compounds, only five showed a significant cytotoxic-
ity with relatively low IC50 values of 14.27 μM, 15.80 μM
Cytotoxicity
One thousand two hundred cells per well were plated in
96 well plates. After culturing for 24 h, test compounds
were added onto triplicate wells with different con-
centration, and 0.1% DMSO for control. After 3 days of
incubation, 20 μL MTT (3-[4,5-dimethylthiazol-2-yl]-2,
5-diphenyl- tetrazolium bromide) solution (5 mg/mL)
was added to each well, and after shaking for 1 min, the
plate was incubated further for 4 h. Formazan crystals
were dissolved with 100 μL DMSO. e absorbance
(OD) was quantitated with microplate spectrophotom-
eter at 570 nm. Wells containing no drugs were used as
blanks for the spectrophotometer. e survival of the
cells was expressed as percentage of untreated control
wells.
Table 1. e IC50 (μM) values of the synthesized compounds
against three tumour cell lines.
Compounds
A549
151.58
102.23
56.99
87.75
14.27
>200
96.02
57.85
42.8
MDA-MB-435
179.54
127.87
121.57
86.18
HCT116
26.8
1
DNA topoisomerase I activity assays
2
72.51
59.65
60.47
5.17
Camptothecin was obtained from the company of
Tianzunzezhong in China. Topo I (calf thymus), buffer,
BSA, loading buffer and supercoiled DNA pBR322 were
all from TaKaRa Biotechnology CO., Ltd.
3
4
5
15.8
6a
6b
6c
7a
7b
7c
7d
7e
TPT
>200
117.17
>200
28.66
>200
>200
153.61
>200
28.94
1.1
All reactions were carried out in 20 μL volumes (16 μL
double distilled water, 2 μL DNA Topo I buffer, 2 μL 0.1%
BSA)including0.25μgsupercoiledDNA, 0.5 UTopoIwith
or without drug. e reactions were incubated at 37°C for
15 min and then stopped by adding SDS (0.5% final con-
centration). To the reaction mixtures, 3.5 μL 6 × loading
buffer (0.1 mM EDTA, 7% Glycerol, 0.01% Xylene Cyanol
FF, Bromopenol Blue 0.01%) was added. e mixtures
were electrophoresed in 0.8% agarose gel in TAE buffer
for 40 min at 120 V. e gel was stained with ethidium
>200
>200
>200
>200
>200
>200
50.2
153.19
59.65
171.6
>200
3.16
0.448
Note: Cancer cells: A549: Lung cancer cell, HCT116: Colon
cancer cell, MDA-MB-435: Breast cancer cell.
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis of novel benzoxanthone analogues 441
compound 5 was found to exert the strongest interfer-
ence (Figure 1, lane 4), while compounds 6c, 7a and 7e
showed a potent inhibitory effect (Figure 1, lanes 6, 7 and
8, respectively).
and 5.17 μM against A549, MDA-MB-435 and HCT-116
cells, respectively.
Structure-activity relationships
In conclusion, all the benzoxanthone analogues
exhibited moderate cytotoxicity against A549, MDA-MB-
435 and HCT-116 cell lines. Among these compounds,
compound 5 was the most effective in the tested can-
cer cell lines. Compounds 5, 6c, 7a and 7e also showed
potent inhibitory activities against DNA relaxation by
topoisomerase I. According to the biological activities,
benzoxanthone derivatives indicated potential for devel-
opment as non-CPT topoisomerase I inhibitors by means
of elaborate structure optimization.
Base on the above data, we found that polyhydroxy deriv-
atives exhibited higher activity than hydroxyl-substituted
compounds. Among the halogen-substituted derivatives,
bromine-substituted compound (2) are less active than
iodine-substituted compound (3). And the tri-substituted
derivative (4) showed improved anti-tumour activity
compared with the di-bromine substituted compound
(2). For the position of halogen, the o-position substi-
tuted derivative, such as compound 7c, exhibited higher
inhibitory activity than p-position substituted derivatives
(compounds 7b and 7d). Interestingly, compared with
the mono-phenol ester compounds (e.g., compounds
7b, 7c and 7d), the di-phenol ester-substituted deriva-
tive (7e) lost anti-tumour activity against MDA-MB-435,
while maintaining anti-tumour activity against A549
and HCT-116. In addition, the ether compound (7a),
heterocyclic derivatives (6b and 6c) displayed moderate
cytotoxicity against A549, while they were not sensitive
to MDA-MB-435.
Declaration of interest
is research was supported in part by the Key Project of
Science and Technology of Shanghai (No. 09431901700),
Major Special Project for the Creation of New Drugs
(Grant Nos. 2009ZX09301-011) and Shanghai Leading
Academic Discipline Project (Project Nos. B906).
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