Leptosins A B, C, D, E and F, chaetocin derivatives, have been isolated from the mycelium of a strain of Leptosphaeria sp. attached to the marine alga Sargassum tortile. Their stereostructures, with a different configuration from that of related compounds, have been elucidated by spectroscopic analyses using various 1 D and 2D NMR techniques and some chemical transformations. All the compounds showed potent cytotoxicity against cultured P388 cells, and leptosins A and C exhibited significant antitumour activity against Sarcoma 180 ascites.' 3C NMR spectra of 1 (Table 1) by distortionless enhancement by polarization transfer (DEPT) and 'H-'H and 'H-13C correlation spectroscopy (COSY) experiments and comparison with spectral data for related compounds revealed signals for two hydroxy methine groups (C-31 and C-11') linked to two quaternary sp3-hybridized carbons, two methines (C-5a and C-5'a) bearing two nitrogens and a quaternary sp3-carbon, four quaternary sp3-carbons (C-3, C-12, C-3' and C-12') each 1 x = 4

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Previously, we reported that levels of chymase activity and its mRNA in cardiac tissues were significantly increased along with progression of cardiac fibrosis in cardiomyopathic hamsters, but the involvement of chymase in the progression of fibrosis has been unclear. In cultured human fibroblasts, the concentration of transforming growth factor-␤ in the supernatant of medium was significantly increased after injection of human chymase. Furthermore, human chymase dose dependently increased cell proliferation, and this chymase-dependent proliferation was completely suppressed by a chymase inhibitor, Suc-Val-Pro-Phe p (OPh) 2 (10 M) or an anti-transforming growth factor-␤ antibody (100 g/ml). In this study, we used Bio14.6 and F1B hamsters as cardiomyopathic and control hamsters, respectively. Cardiomyopathic hamsters were orally administered a novel chymase inhibitor, 4-[1-{[bis-(4-methylphenyl)-methyl]-carbamoyl}-3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid (BCEAB; 100 mg/kg per day), or placebo from 5-to 45-week-old. In the placebo-treated group, the cardiac chymase activity in cardiomyopathic hamsters 45 weeks old was significantly increased compared with that in control hamsters. BCEAB significantly reduced the cardiac chymase activity. The indexes (ϩdP/dt and -dP/dt) of cardiac function were significantly improved by treatment with BCEAB. The mRNA levels of collagen I and collagen III in the placebotreated hamsters were significantly reduced to 69.6 and 76.5% by treatment with BCEAB, respectively. The fibrotic area in cardiac tissues in the BCEAB-treated hamsters was significantly suppressed to 50.7% compared with that in the placebo-treated treated hamsters. Therefore, the activation of transforming growth factor-␤ by chymase may play an important role in the progression of cardiac fibrosis and cardiac dysfunction in cardiomyopathy.

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