Synthesis and antitumor activity of tanshinone analogues

Full text of DOI:10.1023/B:CONC.0000003428.26731.7f

Chemistry of Natural Compounds, Vol. 39, No. 4, 2003
SYNTHESIS AND ANTITUMOR ACTIVITY OF
TANSHINONE ANALOGUES
1
2
2
Haji Akber Aisa , Wei Lu , and Junchao Cai
UDC 547.824:615
Diterpenoid tanshinones, which often bear an o-quinone moiety(such as compounds 1 and 2), have attracted particular
attention ofmedicinal chemists and clinicians because manyofthem exhibit significant antibacterial [1], antidermatophytic [2],
antioxidant [3], antiinflammatory [4], antineoplastic [5], and antiplatelet aggregation [6] activities. Przewaquinone A (l), a
natural ortho-quinone isolated from Salvia Przewalskii Maxim. var. Mandarinorum Stib [7], showed antitumor activity in a
variety of tumor models, such as Lewis lung carcinoma, melanoma B , sarcoma 180, and leukemia P-388, both in vitro and
1
6
in vivo [8]. Sapr-ortho-quinone (2) was isolated from the roots of Salvia prionitis Hance [9], a plant used in Chinese folk
medicine as an antiphlogistic, antibacterial, and antitubercular drug [10]. Sapr-ortho-quinone (2) was also obtained by acidic
treatment of 15-deoxyfuerstione (2a), a component of the roots of Salvia moororaftiana, by Simoes et al [11]. The initial
bioassay showed that sapr-ortho-quinone had activity in leukemia P-388 test [12]. Through the comparison between 1 and 2,
it seems that the furan ring in Przewaquinone might not be essential to its biological activity. Therefore, in order to seek more
effective compounds that are easily synthesized, we designed and synthesized two analogues of tanshinone, namely 3 and 4.
O
O
O
O
CH OH
2
O
O
HO
O
R
O
1
2
2a
3: R = H;
: R = CHOHCH
4
3
Startingfrom anisole(5), compound10waspreparedthrough a five-stepprocedureandthen treatedwith methyllithium
in ether to give alcohol 11. After cyclization of compound 11 with boron trifluoride etherate in dichloromethane, the removal
of the methyl group of the resulting cyclization product 12 was effected with boron tribromide to afford key intermediate 13,
which was oxidized with Fremy’s salt to yield the title compound 3.
The intermediate 12 was also able to undergo smooth reaction with acetyl chloride and aluminum chloride in
dichloromethane to give 14, which was then converted to "phenol" 15 by demethylation with boron tribromide. Compound 15
was easily reduced to give alcohol 16, which was oxidized with Fremy’s salt to give the target molecule 4. The synthesized title
compounds 13, 14 were determined to possess the structure of 3 and 4.
–
1
+
1
The data for 3: mp 142–145°C. IR(KBr): 1686, 1657, 1578, 1248 cm . EIMS m/z: 240 (M ), 226, 212, 197. H NMR
300 MHz, CDCl , δ, ppm, J/Hz) 1.32 (6 , s, CH ), 1.66 (2 , m, CH ), 1.80 (2 , m, CH ), 3.20 (2 , t, J = 6.4, CH ), 6.38
(
(
3
3
2
2
2
1 , d, J = 9.9, ArH), 7.16 (1 , d, J = 8.0, ArH), 7.38 (1 , d, J = 9.9, ArH), 7.63 (1 , d, J = 8.0, ArH). Anal. Calcd: C 79.97%;
H 6.71%. Found: C 79.91%; H 6.61%.
1
) Xinjiang Technical Institute of Physics & Chemistry, Chinese Academy of Sciences, No. 40 Beijing South Road,
Urumqi, China; 2) Shanghai Institute of Materia Medica, Chinese Academyof Sciences, 294 Taiyuan Road, Shanghai 200031,
P. R. China. Published from Khimiya Prirodnykh Soedinenii, No. 4, pp. 327-328, July-August, 2003. Original article submitted
March 24, 2003.
©
0
009-3130/03/3904-0404$25.00 2003 Plenum Publishing Corporation
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04

TABLE 1. Inhibition (%) of P-388 and A-549 Tumor Cell Line in vitro
C (mol/L)
Compound
Cell line
-4
-5
-6
-7
-8
10
10
10
10
10
a
3
4
P-388
97.0
89.3
97.0
83.9
98.5
32.1
98.9
0
6.1
30.4
33.0
0
3.0
30.0
4.3
0
b
A-549
a
P-388
100.0
94.5
100.0
70.9
b
A-549
_
_____
a. 48 h, MTT assay; b. 72 h, SRB assay.
OMe
OMe
OMe
OMe
OMe
i
ii
iii
iv
HO
v
HO C
HO C
2
2
O
O
CO Me
2
5
6
7
8
9
OMe
OMe
OMe
OH
O
O
vi
vii
viii
ix
CO Me
2
HO
1
0
11
12
13
3
OMe
OMe O
OH
O
OH OH
O
OH
O
x
xi
xii
xiii
1
2
14
15
16
4
i. 1.2 eq. succinic anhydride, 2.5 eq. AlCl , CH NO , 0°C 25°C, 12 h, 73.4%;
3
3
2
ii. 3.0 eq. NH NH ·H O, 5.0 eq. KOH, DEG, 130 - 150°C 3 h, then 175 - 195°C 4 h, 95%;
2
2
2
iii. 25 eq. 85% H PO , 20 eq. P O 70 - 80°C 3 h, 87.7%;
3
4
2 5
iv. 4 eq. Zn, 3.5 eq. methyl-4-bromocrotonate, THF, 85.5%;
v. 0.3 eq. palladium black, 230 - 260°C 2h, 48.3%; vi. 7 eq. methyllithium, 0°C 4 h, 81.7%;
vii. 25 eq. BF ·Et O, CH Cl , 20°C 1 h, 92.5%; viii. 3 eq. BBr CH Cl , 0°C 3 h, 95.4%;
3
2
2
2
3
2
2
ix. 4 eq. Fremy's salt, KH PO buffer, acetone, 30°C 10 h, 42.4%;
2
4
x. 5.8 eq. AlCl , 7.5 eq. acetyl chloride, CH Cl , 0°C - 25°C 12 h, 75%; . 12 eq. BBr CH Cl , 0°C 6 h, 78.9%;
3
2
2
xi
3
2
2
xii. 4 eq. LiA1H ; 0°C - 25°C 10 h, 70.9%; xiii. 4 eq. Fremy's salt, KH PO buffer, acetone, 25°C, 40%
4
2
4
THF = tetrahydrofuran, DEG = Diethylene glycol.
–
l
+
The data for 4: mp 47–50°C. IR (KBr): 1655, 1261, 1144 cm . EIMS m/z: 284(M ), 268, 254, 240, 225. HRMS:
1
2
84.1412 for C
H
O , Calcd. 284.1407. H NMR (300 MHz, CDCl , δ, ppm, J/Hz) 1.25 (6 , s, CH ), 1.38 (3 , d,
1
8 20 3
3
3
405

J = 6.3, CH ), 1.58 (2 , t, J = 5.6, CH ), 1.70 (2 , m, CH ,), 2.25 (1 , br, OH), 3.11 (2 , t, J = 6.3, CH -Ar), 4.76 (1 , m,
3
2
2
2
CH), 7.05(1 , d, J = 8.0, ArH), 7.18 (1 , s, ArH), 7.53(1 , d, J = 7.7, ArH).
The cytotoxic effect of the target compounds on tumor cells was evaluated as assayed by the in vitro MTT method for
the P-388 cell line and the SRB method for the A-549 cell line. As shown in Table 1, the synthesized compounds 3 and 4
–
6
exhibited relatively high activity against the P-388 cell line even at 10 M concentration.
In conclusion, usinganisoleas the startingmaterial, wesynthesizedtwoanaloguesoftanshinone, namely8,8-dimethyl-
5
,6,7,8-tetrahydrophenanthrene-3,4-dione 3 and 8,8-dimethyl-2-(1'-hydroxyethyl)-5,6,7,8-tetrahydrophenanthrene-3,4-dione
4
. Compounds 3 and 4 exhibited high activity against leukemia P-388 cell lines. Chemical synthesis and biological
investigations of a series of structural analogues of the title compounds are in progress.
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