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H. Uchiro et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2699–2702
values are listed in Table 1. No significant correlation
was observed between cytotoxicity and the structural
properties of synthesized MOSBs. It is noteworthy that,
among the examined MOSBs, b-naphthyl-type deriva-
tive 4f with the broadest antifungal spectrum showed
the lowest cytotoxicity. In contrast, 9-methoxy-
strobilurin K (3) inhibited the growth of MRC-5
cell in 30–500-fold lower concentration than other
MOSBs; however, the IC50 value was still 40–100-fold
higher than those previously reported for several
human-derived tumor cell lines. The strong growth-
inhibitory activity is probably due to the specific bind-
ing affinity of 3 to a target protein in the mammalian
cell, which is based on its hindered ether-type sidechain
moiety.
2. Sauter, H.; Steglich, W.; Anke, T. Angew. Chem., Int. Ed.
Engl. 1999, 38, 1328 and references cited therein.
3. Zapf, S.; Werle, A.; Anke, T.; Klostermeyer, D.; Steffan,
B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1995, 34, 196.
4. Wood, K. A.; Kau, D. A.; Wrigley, S. K.; Beneyto, R.;
Renno, D. V.; Ainsworth, A. M.; Penn, J.; Hill, D.; Killacky,
J.; Depledge, P. J. Nat. Prod. 1996, 59, 646.
5. Nicholas, G. M.; Blunt, J. W.; Cole, A. L. J.; Munro,
M. H. G. Tetrahedron Lett. 1997, 38, 7465.
6. (a) Uchiro, H.; Nagasawa, K.; Aiba, Y.; Kobayashi, S.
Tetrahedron Lett. 2000, 41, 4165. (b) Uchiro, H.; Nagasawa,
K.; Aiba, Y.; Kotake, T.; Hasegawa, D.; Kobayashi, S. Tet-
rahedron Lett. 2001, 42, 4531. (c) Aiba, Y.; Hasegawa, D.;
Marunouchi, T.; Nagasawa, K.; Uchiro, H.; Kobayashi, S.
Bioorg. Med. Chem. Lett. 2001, 11, 2783.
7. Physical data of synthesized compounds: 4a: 1H NMR
(CDCl3, 300MHz) d 1.91 (s, 3H), 3.68 (s, 3H), 3.72 (s, 3H),
3.82 (s, 3H), 3.82 (s, 3H), 6.51 (d, 1H, J=16.0 Hz), 6.68 (d,
1H, J=16.0 Hz, H-7), 6.76 (d, 1H, J=7.9 Hz), 6.90 (s, 1H),
6.98 (d, 1H, J=7.8 Hz), 7.22 (dd, 1H, J=7.8, 7.9 Hz), 7.40 (s,
1H); EI–MS 318 (M+); 4b: 1H NMR (CDCl3, 300MHz) d 1.90
(s, 3H), 3.67 (s, 3H), 3.71 (s, 3H), 3.80 (s, 3H), 3.81 (s, 3H),
6.38 (d, 1H, J=15.8 Hz), 6.66 (d, 1H, J=15.8 Hz), 6.84 (d,
2H, J=8.6 Hz), 7.31 (d, 2H, J=8.6 Hz), 7.39 (s, 1H); EI–MS
318 (M+); 4c: 1H NMR (CDCl3, 300 MHz) d 1.91 (s, 3H), 3.68
(s, 3H), 3.72 (s, 3H), 3.82 (s, 3H), 3.88 (s, 3H), 3.90 (s, 3H),
6.37 (d, 1H, J=16.0 Hz), 6.66 (d, 1H, J=16.0 Hz), 6.81 (d,
1H, J=8.3 Hz), 6.89 (d, 1H, J=1.7 Hz), 6.96 (dd, 1H, J=1.7,
8.3 Hz), 7.40 (s, 1H); EI–MS 348 (M+); 4d: 1H NMR (CDCl3,
300 MHz) d 1.90 (s, 3H), 3.66 (s, 3H), 3.71 (s, 3H), 3.81 (s,
3H), 5.94 (s, 2H), 6.52 (d, 1H, J=16.0 Hz), 6.71 (d, 1H,
J=16.0 Hz), 6.81 (d, 1H, J=8.3 Hz), 6.89 (d, 1H, J=1.7 Hz),
6.96 (dd, 1H, J=1.7, 8.3 Hz), 7.18–7.40 (m, 3H); 7.40 (s, 1H);
Conclusion
Several 9-methoxystrobilurin-type b-methoxyacrylate
antibiotics (MOSBs) having variotus aromatic sub-
structures were synthesized. The antifungal activity of
synthesized MOSBs is closely related to their aromatic
substructures. The b-naphthyl-type derivative 4f showed
the broadest antifungal spectrum and the lowest cyto-
toxicity. This derivative is expected to be a lead com-
pound as a new and effective disinfectant with a broad
antifungal spectrum. Due to lack of significant corre-
lation between cytotoxicity against MRC-5 and the
structural properties of MOSBs, the strong growth-
inhibitory activity of human-derived tumor cell lines
to 9-methoxystrobilurin K should be related to its
hindered ether-type substructure. Further extensive
studies are now in progress for the design and develop-
ment of a new ‘cell-specific’ growth inhibitor.
1
EI–MS 332 (M+); 4e: H NMR (CDCl3, 300 MHz) d 1.96 (s,
3H), 3.72 (s, 3H), 3.79 (s, 3H), 3.82 (s, 3H), 6.58 (d, 1H,
J=15.6 Hz), 7.40 (s, 1H), 7.50 (d, 1H, J=15.6 Hz), 7.41–7.56
(m, 3H), 7.74 (d, 2H, J=8.1 Hz), 7.83 (dd, 1H, J=2.4, 7.1
1
Hz), 8.18 (dd, 1H, J=2.0, 7.1 Hz); EI–MS 338 (M+); 4f: H
NMR (CDCl3, 300 MHz) d 1.94 (s, 3H), 3.72 (s, 3H), 3.74 (s,
3H), 3.83 (s, 3H), 6.65 (d, 1H, J=15.8 Hz), 6.88 (d, 1H,
J=15.8 Hz), 7.38–7.48 (m, 2H), 7.44 (s, 1H), 7.56 (dd, 1H,
J=1.8, 8.5 Hz), 7.71–7.82 (m, 4H); EI–MS 338 (M+).
References and Notes
8. Otoguro, K.; Kohana, A.; Manabe, C.; Ishiyama, A.; Ui,
H.; Shiomi, K.; Yamada, H.; Omura, S. J. Antibiotics 2001,
54, 658.
-
1. Anke, T.; Oberwinkler, F.; Steglich, W.; Scharmm, G. J.
Antibiotics 1977, 30, 806.