Synthesis and antitumor activity of 10-substituted benzylidene anthrone

Article abstract of DOI:10.1016/j.bmcl.2003.11.053

Fifteen compounds of 10-substituted benzylidene anthrone were prepared with moderate yield by reaction of anthrone and substituted benzaldehydes under the presence of pyridine and piperidine as catalyst. Their antitumor activities in vitro were evaluated.

Full text of DOI:10.1016/j.bmcl.2003.11.053

Bioorganic & Medicinal Chemistry Letters 14 (2004) 621–622
Synthesis and antitumor activity of 10-substituted
benzylidene anthrone
Weixiao Hu* and Wei Zhou
Department of Pharmaceutical Science, Zhejiang University, of Technology, Hangzhou, 310014, PR China
Received 24 July 2003; revised 18 November 2003; accepted 19 November 2003
Abstract—Fifteen compounds of 10-substituted benzylidene anthrone were prepared with moderate yield by reaction of anthrone
and substituted benzaldehydes under the presence of pyridine and piperidine as catalyst. Their antitumor activities in vitro were
evaluated. The results show that the electron-withdrawing substitutes decrease the activities, the electron-donor substitutes increase
the activities; the compound with substitute at ortho or para position has stronger activities than that of compound with the same
substitute but located at the meta position. There are six compounds which appear as strong effective inhibition for A-549 cancer
cell growth. This is a kind of good leading compound which is worth researching further.
#
2003 Elsevier Ltd. All rights reserved.
It was well known that many compounds containing
anthraquinone skeleton have good bioactivities. Some
of them are good antitumor medicines, such as, dau-
1
2
3
4
norubicin, doxorubicin, mitoxantrone, bisantrene
and so on. It was reported that the derivatives of
5
anthrone, 10-substituted benzylidene anthrone and the
6
Schiff base of anthrone with substituted anilines also
have good antitumor activities.
Scheme 1.
We are interested in how the substitutes in 10-sub-
stituted benzylidene anthrone affect the antitumor
activities. Therefore, we designed fifteen 10-substituted
benzylidene anthrones, in which the substitutes include
electron-withdraw groupand electron-donor and the
same substitute but located at the ortho/para or meta
position. These compounds were synthesized according
Table 1. Synthesis of 10-substituted benzylidene anthrone
ꢁ
Entry
R
Mp( C)[lit.]
Isolated yield
%)
Purity
(HPLC)
(
10
11
1
2
3*
4
5
H
m-NO
p-F
o-OH
p-OH
118–119[117–118]
171–173[170–172]
105–108
35.5
45.0
23.3
81.6
35.6
14.0
40.5
74.3
51.5
75.3
51.3
69.5
63.2
31.6
68.7
98.4
99.4
99.6
99.3
99.7
99.2
99.6
99.4
99.4
99.1
99.8
99.1
99.9
99.1
97.4
2
7ꢀ9
to the literature method, The synthetic reaction is
shown in Scheme 1, the results are summarised in Table 1.
1
2
2
220–221[223–225]
235–236[245–248]
90–93
1
6
7
8
9
1
1
1
1
1
1
*
o-CH
3
m-CH
It was found that under literature reaction condition, the
anthrone can be oxidated to anthraquinone even at room
temperature. The ratio of conversion reached as high as
11
3
110–111[112–114]
7
P-CH3
o-OCH
m-OCH
3
P-OCH
o-Cl
m-Cl
P-Cl
147–150[147–149]
149–152[146–147]
113–115
7
3
0*
1
2
3*
4
5
5
oxidant, the reaction between anthrone and substituted
5%. With the addition of p-methoxy phenol as anti-
13
3
142–145[142]
110–113[115]
113–115
14
1
5
benzaldehyde might proceed normally.
14
158–160–162
180–183[180–182]
11
3,4-diOCH
3
Keywords: 10-Substituted benzylidene anthrone; Antitumor activity;
Relationshipbetween structures and activities.
*New compound; the structures of all compounds were characterized
by IR/MS and HNMR, besides, the elemental analysis was also made
for four new compounds.
*
Corresponding author. Tel.:+86-571-88320557; fax:+86-571-
8320557 or +86-571-85133199; e-mail: huyang@mail.hz.zj.cn
8
0
960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.11.053

622
W. Hu, W. Zhou / Bioorg. Med. Chem. Lett. 14(200 4) 621–622
The antitumor activities of those compounds were eval-
uated in vitro using MTT method for P-388 cancer cell
and SRB method for A-549 cancer cell. The results are
shown in Tables 2 and 3, respectively.
electron-donor substitute at ortho or para position. So
this kind of compound is a potential antitumor medi-
cine which is worth to research further.
It is clear from the data of Tables 2 and 3 that the
compounds with electron-donor substitute such as CH3,
CH O, OH have more strong activities than that of those
Acknowledgements
The authors are thankful for the National Center for
Drug screening, Shanghai, China to evaluate the anti-
tumor activities. We also thank the National Natural
Science Foundation of China for founding (project
20272053).
3
compounds with electron-withdrawing substitute such as
Cl, F, NO . The compound without any substitute has
2
no antitumor activity. It is also clear that the compounds
with the electron-donor substitute at ortho or para posi-
tion have stronger activities than that of compounds with
the same substitutes but at meta position.
References and notes
To the A-549 cancer cell, there are six compounds with
electron-donor substitute at ortho or para which have
strong bioactivity. To the P-388 cancer cell, there are
two compounds having strong activity and three com-
pounds having weak activity. All five compounds have
1
. Wovkulich, P. M.; Uskokovie, M. R. J. Am. Chem. Soc.
981, 103, 3956.
1
2. White, R. J.; Stroshane, R. M. Drugs Pharm. Sci. 1984,
22, 569.
3
. Zeecheng, R. K. Y.; Cheng, C. C. J. Med. Chem. 1978, 21,
91.
2
Table 2. The inhibition ratio for A-549 growth
4
5
. Murdock, K. C. J. Med. Chem. 1982, 25, 505.
. Kenneth, D.; Pall, C. M. L.; Louis, M.; Ernest, H. Cancer
Research 1992, 52, 3892.
Compd
R
Concentration (mol/L)
Remark*
ꢀ4
ꢀ5
ꢀ6
ꢀ7
ꢀ8
10
1
0
10
10
10
6. Nadkarny, V. V.; Sanzgiri, M. N. J. Indian. Chem. Soc.
990, 67, 513.
1
. Rappoport, Z.; Apelolg, Y.; Green, B. J. J. Am. Chem.
Soc. 1980, 102, 3837.
. Nadkarny, V. V.; Sanzgiri, M. N. Indian J. Chem. Soc.
1983, 60, 306.
. Igram, V. M. J. Chem. Soc. 1950, 2, 318.
1
2
3
4
5
6
7
8
9
H
m-NO
p-F
95.4 79.9 9.8
96.0 91.8 12.4
96.8 88.2 56.5 18.5 49.2
96.3 94.8 89.3 83.0 85.2
92.9 87.0 87.2 88.7 60.0
1.0
7.7
4.4
13.2
n
w
w
s
7
8
9
2
o-OH
p-OH
o-CH
s
3
90.9 84.8 18.5
93.0 18.2
0
0
5.7
0
n
n
s
s
w
s
n
w
w
s
m-CH
3
0
10. Zhou, J. F.; Xu, J. M.; Zhu, F. X. Chinese Journal of
Synthetic Chemistry 2000, 8, 556.
11. Tewari, R. R.; Gupta, K. C. India J. Chem. Soc. Sect B
p-CH
o-OCH
m-OCH
3
95.2 91.8 90.0 92.7 84.7
89.3 81.7 85.7 86.8 66.3
95.8 92.5 25.1 38.1 6.2
90.0 84.7 87.0 85.4 84.8
89.9 53.0 0.3
97.1 92.0 62.9
96.0 87.3 41.9 33.6 41.7
95.7 92.8 87.0 90.6 81.7
3
1
1
1
1
1
1
0
1
2
3
4
5
3
1
979, 17B, 637.
p-OCH
o-Cl
m-Cl
p-Cl
3,4-diOCH
3
1
2. Zhu, C. F.; Yuang, Y. Chinese Journal of Applied Chem-
istry 2001, 18, 569.
6.0
5.7
5.9
12.5
1
1
3. Elshafie, S. M. M. Indian J. Chem. Sect. B 1978, 16B, 828.
4. Bergmann, E. D.; Rabinovitz, M.; Glily, S. Tetrahedron
Sppl 1966, 141.
3
ꢀ
5
ꢀ5
ꢀ6
*
1
n: 10 mol/L<85%; w: 10 mol/Lꢂ85% or 10 mol/L>50%; s:
15. Representative procedure: To a mixture of anthrone (3.9
g, 0.02 mol), 4-methoxy phenol(2.0 g, 0.016 mol) and 3-
methoxy benzaldehyde (3.4 g, 0.025 mol) were added
pyridine (30 mL) and piperidine (0.5 g, 0.006 mol). The air
of the system was removed by aspirator, then put in the
nitrogen gas, the operation was repeated three times.
Then let the nitrogen gas bubble through the mixture all
the time until the reaction finished. The reaction mixture
was refluxed for 6 h. The anthrone was reacted completely
by TLC test. The mixture was cooled down to room tem-
perature and poured into methanol (75 mL). It was put in
the refrigerator overnight. The precipitate was collected
ꢀ
6mol/Lꢂ85% or 10ꢀ7 mol/L>50%.
0
Table 3. The inhibition ratio for P-388 growth
Compd
R
Concentration (mol/L)
Remark*
ꢀ4
ꢀ5
ꢀ6
ꢀ7
ꢀ8
1
0
10
10
10
10
1
2
3
4
5
6
7
8
9
H
m-NO
p-F
97.8 56.2 17.8
89.8 55.8 23.9 22.1 30.7
83.3 31.4 18.4 10.3 5.2
95.6 88.2 65.8 44.9 38.5
100 72.0 41.6 27.1 42.8
84.1 42.4 24.9 8.0 13.1
53.3 7.2
0
2.7
n
n
n
w
n
n
n
w
w
n
s
2
o-OH
p-OH
o-CH
and recrystallized with ethanol to afford yellow crystal
ꢁ
4
.7g, yield: 75.3%, mp: 113–115 C, purity: 99.1%
3
ꢀ1
m-CH
3
0
0
0
(HPLC). IR (KBr, cm ): 3061 (ArH), 3000 (¼C–H),
p-CH
o-OCH
m-OCH
3
69.0 42.4 48.6 49.3 56.5
82.2 76.1 55.4 47.0 32.7
2936 (–CH ), 2832 (–CH ), 1652 (C¼O, s), 1600 (C¼C, s),
3
3
3
1576, 1491, 1474, 1424, 1374, 1316, 1279, 1160, 1048,
10
11
12
13
14
15
3
96.0 48.2 27.2
76.7 72.5 76.5 64.3 75.5
58.4 23.7
89.2 39.4 11.9 19.3 10.9
70.0 36.0 3.9 2.8 4.4
95.7 80.2 56.0 53.6 50.9
7.1
1.0
1
932, 882, 782, 763, 684. HNMR (400 MHz, CDCl
3.71 (s, 3H, -OCH
), 7.56 (s, 1H, ¼C–H), 6.83–8.30 (m,
12H, ArH). MS (m/z, %): 312 (M , 100), 311 (70), 297
3
):
p-OCH
o-Cl
m-Cl
p-Cl
3,4-diOCH
3
3
0
0
0
n
n
n
s
+
(
29), 281 (42), 268 (34), 252 (30), 239 (52), 120 (38). Elem.
anal. (C22 ) C, H: calcd (%), 84.59, 5.16, found (%),
4.32, 5.15.
16 2
H O
3
8