Y. Aoyagi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1947–1949
1949
OH
O
O
activity. The present result suggested that the cytotoxic
activity of triptolide (1) series may not be explained so
simply as done by Kupchan et al. The activity seems to
owe more to the 3D-alignment of the C-ring substituents,
which may easily and inevitably be affected by the intro-
duction of new groups or by changes of the groups
attached to ring C or by the changes of C-ring structure
itself, which may then affect the cytotoxic activity of the
compounds.
O
O
O
a)
b)
1
60 %
quant. yield
O
O
O
O
H
5
7
H
O
O
Scheme 2. Alternative synthesis of 5. Reagents and conditions: (a)
Et2NH/MeOH/phosphate buffer (pH 7.4); (b) Dess–Martin period-
inane/CH2Cl2/rt.
In summary, in the present study, epoxide-transposition
analogues (6 and 7) of triptolide (1) and some semisyn-
thetic analogues of triptolide (1) were prepared. The re-
sults suggested the possible effect of the 3D-alignment of
the C-ring substituents on the cytotoxic activity of the
compounds of this series.
Table 1. Cytotoxicity of triptolide analogues 1, 2, 5–11, and 13 against
A549 human lung and HT29 human colon tumor cells
Compound
IC50 (lg/mL)
A549
0.0013
HT29
0.00010
1
2
0.0035
0.85
<0.00046
0.70
5
Acknowledgment
6
>10
>10
7
0.27
0.024
0.081
5.0
0.15
8
0.004
0.017
0.88
This work was supported by a Grant-in-Aid for Scientif-
ic Research from the Ministry of Education, Science and
Culture.
9
10
11
13
0.059
1.2
0.0091
0.67
References and notes
1. Kupchan, S. M.; Court, W. A.; Dailey, R. G., Jr.; Gilmore,
C. J.; Bryan, R. F. J. Am. Chem. Soc. 1972, 94, 7194.
2. Kutney, J. P.; Hewitt, G. M.; Kurihara, T.; Salisbury, P. J.;
Sindelar, R. D.; Stuart, K. L.; Townsley, P. M.; Chalmers,
W. T.; Jacoli, G. G. Can. J. Chem. 1981, 59, 2677.
3. Duan, H.; Takaishi, Y.; Momota, H.; Ohmoto, Y.; Taki,
T.; Tori, M.; Takaoka, S.; Jia, Y.; Li, D. Tetrahedron 2001,
57, 8413.
4. Buckanin, R. S.; Chen, S. J.; Frieze, D. M.; Sher, F. T.;
Berchtold, G. A. J. Am. Chem. Soc. 1980, 102, 1200.
5. Yang, D.; Ye, X.-Y.; Xu, M. J. Org. Chem. 2000, 65, 2208.
6. Crystallographic data for compounds 5 and 7 have been
deposited with the Cambridge Crystallographic Data Cen-
tre as supplementary publication No. CCDC287799 and
No. CCDC287800, respectively. Copies of the data can be
obtained, free of charge, on application to the Director,
CCDC (e-mail: deposit@ccdc.cam.ac.uk).
The cytotoxic activities of triptolide 1 and its analogues
2, 5–11, and 13 on A549 human lung and HT29 human
colon tumor cells are shown in Table 1. Comparison of
the activities of compounds 1 and 8 with those of com-
pounds 11 and 10, respectively, may imply the impor-
tance of the stereochemistry of the 14-oxygen
functional group: those compounds with 14b-oriented
substituents are more cytotoxic than those with 14a-ori-
ented ones. Kupchan et al.8 suggested that the cytotoxic
activity of compound 1 is due to the activation of the
9,11-epoxide group by the hydrogen bonding between
the 14b-hydroxyl group hydrogen atom and the 9,11-
b-epoxide oxygen atom. However, compounds 8 and
11, which cannot form the corresponding hydrogen
bonding, are still cytotoxic, and compound 9, with a
diepoxide system on the B/C-ring and no 14-oxygen
functional group, has almost the same cytotoxic activity
as 14-epi-triptolide 11. The epoxide-transposition ana-
logues 6 and 7, with 7,8-, 9,11-, and 13,14-b-epoxides,
and 12-hydroxy group, showed only very low to marginal
7. (a) Yu, D. Q.; Zhang, D. M.; Wang, H. B.; Liang, X. T.
Chin. Chem. Lett. 1991, 2, 937; (b) Yu, D. Q.; Zhang, D.
M.; Wang, H. B.; Liang, X. T. Yaoxue Xuebao 1992, 27,
830.
8. Kupchan, S. M.; Schubert, R. M. Science 1974, 185, 791.