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C. Tsukano, M. Sasaki / Tetrahedron Letters 47 (2006) 6803–6807
Table 1. Cytotoxicity of gymnocin-A (1) and synthetic analogues
(5–10, 19, and 29) against P388 murine leukemia cells
References and notes
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Compounds
Cytotoxicity IC50, lM
1
1.3
>100
>10
1.0
2.9
>100
>100
>100
>100
5
6
7
8
9
10
19
29
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(24 ! 26), and reductive desulfurization under radical
conditions14 (26 ! 27). Protective group manipulations
of 27 led to primary alcohol 28, which was then
converted to allylic alcohol 29 by a four-step sequence.
Finally, oxidation of allylic alcohol 29 with MnO2 led
to truncated analogue 10.
With gymnocin-A analogues 5–10, 19, and 29 in hand,
the biological activity of these compounds was evalu-
ated by their inhibitory activity against the murine leu-
kemia cell line (P388D1) using the XTT assay15 and
the results are summarized in Table 1. a,b-Unsaturated
aldehydes 7 and 8 exhibited cytotoxicity with IC50
values of 1–3 lM, comparable to that of the natural
gymnocin-A, whereas a,b-unsaturated ester 5 and
carboxylic acid 6 did not show cytotoxicity even at a
concentration of 100 lM. These results clearly indicate
that the a,b-unsaturated aldehyde functionality is
crucial for its cytotoxicity. This is probably due to
nucleophilic addition of biological macromolecules to
a reactive electrophilic center. In addition, nonacyclic
analogue 10 somewhat decreased proliferation of P388
cells at 100 lM, whereas truncated analogues 9, 19,
and 29 showed no detectable cytotoxicity even at
100 lM. Consequently, the molecular length was also
important for exhibiting cytotoxicity.
In summary, the present structure–activity relationship
studies revealed that the structural elements required
for cytotoxicity of gymnocin-A are not only the a,b-
unsaturated aldehyde functionality of the side chain
but also the molecular length, probably over ten contig-
uous trans-fused rings. These studies would help to
understand the relation between the common polycyclic
ether motif and diverse biological activities.
Acknowledgments
9. (a) Sasaki, M.; Fuwa, H.; Inoue, M.; Tachibana, K.
Tetrahedron Lett. 1998, 39, 9027–9030; (b) Sasaki, M.;
Fuwa, H.; Ishikawa, M.; Tachibana, K. Org. Lett. 1999, 1,
1075–1077; (c) Sasaki, M.; Ishikawa, M.; Fuwa, H.;
Tachibana, K. Tetrahedron 2002, 58, 1889–1911; (d)
Sasaki, M.; Fuwa, H. Synlett 2004, 1851–1874.
10. Compounds 2–4 were re-evaluated for cytotoxicity against
P388 cells by the XTT assay and showed no inhibitory
activity even at 100 lM.
This work was financially supported by the Nagase
Science and Technology Foundation and a Grant-
in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology,
Japan. A fellowship for C.T. from the Japan Society
for the Promotion of Science is gratefully
acknowledged.