Screening of crude extracts of the bark of Annona bullata showed cytotoxic and pesticidal activities. By monitoring with brine-shrimp lethality, two novel, extremely potent acetogenins, bullatacin [1] and bullatacinone [2], were isolated. Spectral and chemical methods identified bullatacin as a diastereomer of asimicin. Bullatacinone represents bullatacin with the lactone cleaved and reformed at the 4-OH. Compounds 1 and 2 show selective cytotoxicities in human tumor cell lines, and certain susceptible cells give ED50 values as low as 10(-12)-10(-15) micrograms/ml. Bullatacin was pesticidal at concentrations as low as 1 ppm, but bullatacinone lacked pesticidal activities. The known compounds liriodenine and (-)-kaur-16-en-19-oic acid were also isolated and were lethal to brine shrimp but were not significantly cytotoxic.
Galsky et al. (10, 11) have reported that the inhibition and growth of crown gall tumors, initiated on potato discs by Agrobacterium tumefaciens, apparently has good agreement with 3PS in vivo antileukemic activity in mice. We have now modified and evaluated this assay for its potential use as a prescreen and fractionation monitor of plant extracts for 3PS activity. The modified assay was performed on a series of natural compounds and plant extracts (known to have 3PS activity) and on extracts of seeds of 41 Euphorbiaceae species. The results suggest that the potato disc assay is a safe, simple, rapid, in-house, low cost, prescreen for 3PS antitumor activity; it detects some false positives, but few false negatives; it is statistically much more predictive (p = 0.002) of 3PS activity than either the 9KB (p = 0.140) or the 9PS (p = 0.114) cytotoxicity assays. Its extended use could easily obviate the expense and extensive need for animals in the initial stages of antitumor screening and plant fractionation.
Bioactivity-directed fractionation, using brine shrimp lethality and murine hypoglycemia, of an ethanol extract prepared from Tillandsia usneoides, led to the isolation of four apparently bioactive compounds from the water-soluble fraction. The compounds were identified as citric acid, succinic acid, 3-hydroxy-3-methylglutaric acid (HMG), and 3,6,3',5'-tetramethoxy-5,7,4'-trihydroxyflavone-7-O-beta-D-g lucoside. The brine shrimp lethality of the acids was simply due to acidity; however, HMG elicited significant hypoglycemic responses in fasting normal mice. Ethyl and methyl esters of citric acid were prepared and tested in the murine hypoglycemic assay. Five of the predominant sugars were identified by tlc. Free thymidine was also isolated. Further evaluation of HMG and other potential inhibitors of HMG CoA lyase, in the treatment of symptoms of diabetes mellitus, is suggested.
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