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Bioflavonoids, extracted from flower petals, were examined for their growth inhibitory effect on cells in culture. They were found to significantly suppress the growth of the cultured cells. Anthocyanins tended to show greater inhibitory effect than other flavonoids. Commercially synthesized or purified aglycones of flavonoids were also studied for their suppression of tumor cells. The anthocyanins were more effective than other flavonoid aglycones, although the aglycones were easily inactivated under the culture conditions.

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Streptomyces amphibiosporus R310-104 (ATCC53964) produced a novel antibiotic lactimidomycin which showed inhibitory activity against fungi and prolonged the survival time of mice transplanted with experimental tumors. Structural studies clarified that lactimidomycin is a new glutarimide antibiotic having a unique unsaturated 12-memberedlactone ring.In the course of screening for new antibiotics effective against experimental tumors, we have isolated a novel antibiotic designated lactimidomycin from the culture broth of Streptomyces amphibiosporus R310-104 collected in Akita city1'2*. The antibiotic exhibited strong cytotoxicity against various tumor cells and inhibitory activity against fungi but no antibacterial activity. It demonstrated prolongation of life span in mice bearing P388 leukemia and B l 6 melanoma. The structure oflactimidomycin was determined by spectroscopic analyses and 13C-enriched biosynthetic studies to be a novel glutarimide group antibiotic having a unique 12-memberedlactone ring as a side chain.In this paper, we describe the production, isolation, physico-chemical properties, structure determination and biological activity of lactimidomycin. Antibiotic Production A loopful mature slant culture of S. amphibiosporus R3 10-104 was inoculated into 100 ml of vegetative mediumconsisting of soluble starch (Nichiden Kagaku) 2%, Pharmamedia(Traders Protein) 1%, ZnSO4-7H2O0.003% and CaCO3 0.4% in a 500-ml Erlenmeyer flask (pH 7.0 before sterilization).The flask was incubated at 32°C for 7 days on a rotary shaker (200rpm) and 5 ml of vegetative inoculum was added to 100ml of sterile production medium containing Protein-S (Ajinomoto Co.) 3%, glucose 3%, Pharmamedia 0.5%, yeast extract (Oriental Yeast Co.) 0.1% and CaCO3 0.3%, pH 7.0 in a 500-ml Erlenmeyer flask. The flask was incubated at 28°C on a rotary shaker (200rpm). Antibiotic production was monitored by the in vitro cytotoxicity against B16 melanomacells and it reached maximumafter 4 days incubation. Isolation and PurificationThe fermentation broth (18 liters, pH 7.4) was stirred with 1-butanol for one hour. The solvent layer was separated from the aqueous layer and mycelial cake by use ofa Sharpies type centrifuge and concentrated under reduced pressure. The residue (30 g) was suspended in water (1 liter) and extracted three times with Lactimidomycin was originally called as BU-4146T or BMY-28886.

Quinones were studied for their growth inhibitory effect on cultured malignant cells. HCT-15 cells derived from human colon carcinoma were used for these experiments. Quinones used were arbutin in the benzoquinone group, juglone and lawsone in the naphthaquinone group, alizarin, emodin, 1,8-dihydroxyanthraquinone, and anthraquinone in the anthraquinone group, and xanthone. Cultured cells were incubated with various concentrations of the quinones for four days in a 5% CO2 incubator, after which cell numbers were counted and significance of differences was analyzed by Student's t test. Anthraquinones and naphthaquinones used in these experiments were more effective than the monocyclic quinone. The 50% suppression dose was less than 12.5 micrograms/ml for them. The number of OH groups seemed to play an important role in the degree of the cell growth inhibition: anthraquinones with 2 or 3 OH groups were more effective than those with no OH group like, 9,10-dioxoanthracene and xanthone. In fact, anthraquinones with no OH group and xanthone were not significantly effective. Flow cytometric histograms revealed a specific pattern; that is, lawsone and juglone in the naphthaquinone group and alizarin and 1,8-dihydroxy-anthraquinone in the anthraquinone group blocked mainly the S phase, and emodin in the anthraquinone group blocked the G1 to S phase of the cell cycle.