Antitumor activity of heptelidic acid chlorohydrin.

In the course of our search for newanti-tumor substances, it was found that a strain ofAcremonium sp. produced a cytotoxic metabolite 1 against tumor cells. It was identified as heptelidic acid chlorohydrin which was formerly reported as a toxic compound to spruce budwormdescribed by Calhoun et al}\ The producing fungi strain No. 618 was identified as Acremonium species, and named Acremonium sp. No. 618. Strain No. 618 was isolated from a rotten wood collected at Minoh city, Osaka prefecture, Japan. It has been deposited in the National Institute of Bioscience and HumanTechnology Agency of Industrial Science and Technology, Ministry of International Trade and Industry, Tsukuba-shi, Japan, under the accession No. FERM P-14211. à" Strain No. 618 was inoculated into 100ml of potato-dextrose mediumin a 500-ml Erlenmeyer flask, and cultured at 28°C for 7 days on a rotary shaker (200rpm) to obtain the seed culture. One liter of this culture was inoculated into a 10-liter jar fermentor containing 6 liters of potato-dextrose medium. The fermentation was continued for 4 days at 28°C with an air-flow rate of 0.5v/v/m and an agitation rate of 200rpm. The pH of the culture filtrate was 5.4. Active compound 1 (180mg) was obtained from six liters of culture filtrate. The isolation scheme is summarized in Fig. 1. The physico-chemical properties of 1 are shown in Table 1. It was soluble in benzene, chloroform, acetonitrile, dimethyl sulfoxide, and methanol, but insoluble in water. The XH and 13C NMRassignments and relative stereochemistry of 1 were confirmed by analyses of 2D H-H COSY, C-H COSY, HMBC and NOESY spectral data as follows; XH NMR (300MHz, CDCI3)8 7.28 (1H, d,.7=4.5Hz, 12-H), 5.ll (2H, s, 3-H), 4.75 (1H, d, /=12.1Hz, 7-H), 3.77 (1H, d,