Y. Aoyama et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1695–1697
1697
Figure 2. 1-Oxacephem human chymase inhibitor 15 and hemiketal intermediate 16.
Nakajima, M.;Mitsutomi, N.;Kuwahara, S.;Ohtsuka, T.;
Fukaya, C.;Miyazaki, M.;Nakamura, N. Bioorg. Med. Chem.
2001, 9, 301. (c) Hayashi, Y.;Iijima, K.;Katada, J.;Kiso, Y.
Bioorg. Med. Chem. Lett. 2000, 10, 199. (d) Groutas, W. C.;
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Fukami, H.;Okunishi, H.;Miyazaki, M. Curr. Pharm. Des.
1998, 4, 439 and references therein.
1
5. The IR, MS, and H NMR data of methyllinderone 1 iso-
lated from Lindera erythrocarpa Makino (Lauraceae) were
identical with those reported by Leong (Leong, Y.-W.;Harri-
son, L. J.;Bennett, G. J.;Kadir, A. A.;Connolly, J. D. Phy-
tochemistry 1998, 47, 891).
6. Kiang, A. K.;Lee, H. H.;Sim, K. Y. J. Chem. Soc. 1962, 4338.
7. (a) Lee, H. H.;Tan, C. H. J. Chem. Soc., Sect. C 1967,
1583. (b) Bennett, G. J.;Lee, H. H. J. Chem. Soc., Perkin
Trans. 1 1986, 633.
Figure 3. Overlap of compound 12 (black) with hemiketal inter-
mediate 16 (gray).
8. Corey, E. J.;Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
9. Liebeskind, L. S.;Mitchell, D.;Foster, B. S. J. Am. Chem.
Soc. 1987, 109, 7908.
Conclusion
10. The IR, MS, and 1H NMR data of synthetic methyllin-
derone 1 were identical with those reported by Leong.5
We have achieved a short-step total synthesis of chy-
mase inhibitor methyllinderon 1. We also developed an
efficient synthetic method for methyllinderon deriva-
tives, and identified compound 12 as an active chymase
inhibitor. Finally, we have proposed the inhibition
mechanism of compound 12 against human chymase.
11. Inayama, S.;Mamoto, K.;Tetsuichi, S.;Hirose, T.
Med. Chem. 1976, 19, 433.
J.
12. Casy, G.;Patterson, J. W.;Taylor, R. J. K. Org. Synth.
1988, 67, 193.
13. Miki, T.;Hiraga, K.;Asako, T.;Masuya, H.
Pharm. Bull. 1967, 15, 670.
Chem.
14. The structures of methyllinderone derivatives 9, 11, 12, and
1
14 were confirmed by H NMR, IR, and mass spectrometric
analysis.
Acknowledgements
15. The human chymase assay was performed as follows.
First, human chymase was purified according to the method
of Takai (Takai, S.;Siota, N.;Sakaguchi, M.;Muraguchi,
The authors wish to thank Prof. M. Miyazaki, Osaka
Medical College, for the kind gift of human chymase.
H.;Matsumura, E.;Miyazaki, M.
Clin. Chim. Acta 1997,
265, 13). The purified chymase was preincubated with test
compounds dissolved in DMSO at 37 ꢂC for 30 min in 0.1 M
Tris–HCl (pH 8.0) containing 1.8 M NaCl, after then the
chymase reaction was started by adding succinyl-Ala-Ala-
Pro-Phe-p-nitroanilides (Sigma Chemical Co.). The change of
absorbance was measured at 405 nm after 2 h incubation at
37 ꢂC. The IC50 value was calculated from the inhibition of p-
nitroaniline formation at each concentration of the test com-
pound.
16. The three-dimensional model of compound 12 was con-
structed based on the published X-ray structure of sodium
lucidonate (Takai, M.;Liu, S.-Y.;Ogihara, Y.;Iitaka, Y.
Chem. Pharm. Bull. 1977, 25, 1404). Low energy conforma-
tion, the LUMO coefficients of compound 12 were calculated
using the AM1 semiempirical method as implemented in the
MOPAC version 6.0 system.
References and Notes
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(b) Takai, S.;Yuda, A.;Jin, D.;Nishimoto, M.;Sakaguchi,
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Bioorg. Med.
Chem. Lett. 2000, 10, 2397. Aoyama, Y.;Uenaka, M.;
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Akahoshi, F.;Ashimori, A.;Yoshimura, T.;Imada, T.;
17. See ref 4a for the three-dimensional model of hemiketal
intermediate 16 derived from 1-oxacephem 15.