Tubercidin, toyocamycin, and the corresponding 5'-o:-D-glucopyranose derivatives of the nucleosides are frequently responsible for muchof the cytotoxicity and antimycotic activity associated with extracts of cultured cyanophytes belonging to the family Scytonemataceae.The 5'-a:-D-glucopyranoses of tubercidin and toyocamycin, for example, are the major cytotoxic and fungicidal nucleosides in Fijian Plectonema radiosum and Hawaiian Tolypothrix tenuis, respectively.The blue green algae provide an excellent source of new bioactive compounds15. Over the past 6 years we have mass cultured over 700 clonal isolates from a variety of terrestrial, freshwater and marine environments and screened hydrophilic and lipophilic extracts of these cyanophytes for cytotoxicity and antifungal activity. About 6% of the extracts show cytotoxicity at <20 jug/ml against the KBcell line (a human epidermoid carcinoma of the nasopharynx) and roughly 9 % of the extracts show antifungal activity at 500 /^g/disc against one or more test organisms, viz. Aspergillus oryzae, Candida albicans, Penicillium notatum, Saccharomyces cerevisiae and Trichophyton mentagrophytes.Several of the active hydrophilic extracts (obtained with 30 % ethanol in water) show both cytotoxicity and antifungal activity and many are cyanophytes belonging to the family Scytonemataceae. Twodistinct classes of compoundsare responsible for the cytotoxicity and fungicidal activity of the Scytonemataceae listed in Table 1 , viz. scytophycin-type macrolides and tubercidin/toyocamycintype nucleosides. Scytophycins account for the cytotoxicity and antifungal activity of Scytonema pseudohofmanni (strain BC-l-2)2>3).Tolytoxin, a scytophycin-related compound that was first isolated from field-collected Tolypothrix conglutinata var. colorata°, is responsible for both the cytotoxicity and antifungal activity of Scytonema mirabile (BY-8-1) and Scytonema ocellatum (DD-8-1) (unpublished results). In an earlier report we showed that tubercidin
The biosynthesis of the nucleoside antibiotic aristeromycin (1) was investigated by administration of radioactive and 13C-labeled precursors to Streptomyces citricolor. The results of these studies indicate that the adenine ring of 1 is formed in the manner expected for prokaryotes and that the cyclopentane ring of the antibiotic is generated by C-C bond formation between C-2 and C-6 of D-glucose. Additional incorporation experiments with specifically tritiated and deuterated forms of D-glucose suggest that the cyclization of glucose proceeds by oxidation at C-5 or C-4 of the hexose followed by formation of a cyclopentenone derivative. This conclusion is supported by the isolation of the related antibiotic neplanocin A (2) from the fermentation broth of S. citricolor. A stereochemical analysis of the cyclization reaction was carried out by administration of (6R)-and (6S)-[6-1 23 1979; p 147.
The aim of this study was to (1) determine if the organochlorine artificial sweetener sucralose is metabolized in rat intestine with repeated dosing and (2) examine whether sucralose might bioaccumulate in rat adipose tissue. Sucralose was administered to 10 rats by gavage daily for 40 days at an average dosage of 80.4 mg/kg/day. The dosages were within the range utilized in historical toxicology studies submitted for regulatory approval in North America, Europe, and Asia. Feces and urine were collected individually from each animal for every 24-hr period during the 40day dosing period. Analysis of the urine and fecal extracts by ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) revealed two new biotransformation products that have not previously been reported. These two metabolites are both acetylated forms of sucralose that are less polar and hence more lipophilic than sucralose itself. These metabolites were present in urine and feces throughout the sucralose dosing period and still detected at low levels in the urine 11 days after discontinuation of sucralose administration and 6 days after sucralose was no longer detected in the urine or feces. The finding of acetylated sucralose metabolites in urine and feces do not support early metabolism studies, on which regulatory approval was based, that claimed ingested sucralose is excreted unchanged (i.e. not metabolized). The historical metabolic studies apparently failed to detect these metabolites in part because investigators used a methanol fraction from feces for analysis along with thin layer chromatography and a low-resolution linear radioactivity analyzer. Further, sucralose was found in adipose tissue in rats two weeks after cessation of the 40-day feeding period even though this compound had disappeared from the urine and feces. Thus, depuration of sucralose which accumulated in fatty tissue requires an extended period of time after discontinuation of chemical ingestion. These new findings of metabolism of sucralose in the gastrointestinal tract (GIT) and its accumulation in adipose tissue were not part of the original regulatory decision process for this agent and indicate that it now may be time to revisit the safety and regulatory status of this organochlorine artificial sweetener ARTICLE HISTORY
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