Reticulol

To discover antifood allergic components from deep-sea-derived microorganisms, we performed a systematic chemical investigation of the Atlantic hydrothermal fungus Graphostroma sp. MCCC 3A00421. Consequently, nine new (1-9) and 19 known (10-28) polyketides were isolated. The planar structures of the new compounds were elucidated mainly by detailed analysis of their nuclear magnetic resonance and high-resolution electrospray ionization mass spectrometry data, while the absolute configurations were established using the modified Mosher's method in association with electronic circular dichroism spectra. Graphostrin A (1) is a novel chlorinated polyketide derivate bearing an oxazole moiety. All isolates were tested for antifood allergic bioactivities in immunoglobulin E-mediated rat basophilic leukemia-2H3 cells. Reticulol (10) significantly decreased the rates of degranulation and histamine release with IC50values of 13.5 and 13.7 μM, respectively, suggesting reticulol could be a potential antifood allergic medicine.

Reticulol was isolated from the culture broth of the strain Streptoverticillium sp. NA-4803. Recticulol (M.W. 222.2) exhibited a potent in vitro cytotoxicity against A427, a human lung tumor cell line, and B16F10, a mouse melanoma cell line. In the trypan blue staining assay for B16F10 cells, the cell viability by reticulol treatment was significantly decreased in a dose-dependent manner. The in vivo assay for the lung metastasis-blocking effect showed that reticulol injected intravenously suppressed the increase in colonies on the lung in a dose-dependent manner. In addition, the survival rate of tumor-implanted mice treated with reticulol was closely associated with its antitumoral efficacy. Reticulol administered via the peritoneum of mice showed less metastasis inhibition than that injected intravenously. To demonstrate the mechanism for inhibition of metastasis, the inhibitory effect of reticulol for matrix metalloproteinase-2 or -9 involved in melanoma metastasis was investigated; however, they were not observed on zymogram gel. In addition, the antitumor efficacy of reticulol was not associated with cell cycle arrest or apoptosis. Therefore, it was inferred that reticulol known as a phosphodiesterase inhibitor directly inhibited the growth of B16F10 melanoma, showing necrotic response. These results suggest that reticulol protects its lung metastasis via the bloodstream by inhibiting the growth of B16F10 melanoma at the cellular level.

A new dimeric isocoumarin, bireticulol, was isolated from the terrestrial Streptomyces sp. and characterized as a 5-5' dimer of reticulol. In addition, reticulol and 8-hydroxy-6,7-dimethoxy-3-methyl isocoumarin, together with other known polyketides piericidin A, 2'-(2-hydroxyphenyl)-2,4'-bibenzoxazole-4-carboxylic acid methyl ester (UK-1) and 3-benzyl-4-hydroxy-5-methyldihydrofuran-2-one were also obtained. Bireticulol exhibited cytotoxic effects against KB (human epidermoid carcinoma, ATCC CCL-17) and NCI-H187 (human small cell lung cancer, ATCC CRL-5804) cell lines with IC(50) values of 24.4 and 8.31 μg ml(-1), respectively.