Triazolam disposition.

Triazolam (T) is a new, potent hypnotic with a short duration of action in man. After an 0.88-mg oral dose of T-14C in six male subjects, mean recovery of 14C radioactivity was 85% in urine and 8% in feces. The major urinary metabolites were alpha-hydroxytriazolam (alpha-HT) and 4-hydroxytriazolam (4-HT), accounting for 69% and 11% of the urinary 14C, and these were mostly in conjugated form. alpha, 4-Dihydroxytriazolam and three dichlorotriazolylbenzophenone analogs were minor metabolites. At least 85% of the dose was rapidly absorbed; mean absorption half-life (t1/2A) was 2.8 min. After reaching a mean peak plasma level (Cmax) of 8.8 ng/ml at mean time (tmax) of 1.3 hr, plasma T decreased rapidly with a mean elimination half-life (t1/2E) of 2.3 hr. The remainder of the plasma 14C consisted predominantly of glucuronides of alpha-HT and 4-HT. Mean plasma parameters for these metabolites were as follows: alpha-HT-glucuronide, t1/2E = 3.9 hr, tmax = 1.3 hr, Cmax = 6.1 ng/ml; 4-HT-glucuronide, t1/2E = 3.8 hr, tmax = 2.5 hr, Cmax = 6.1 ng/ml. Nonconjugated alpha-HT and 4-HT were present in plasma but in insufficient amounts for kinetic analysis. The results are consistent with the short duration of action.

Chemical modification of aminoglycosides. 3. Synthesis of 2"-deoxykanamycins from neamine.

The preparation of 2"-deoxykanamycin B (12) and 2",3',4'-trideoxykanamycin B (14) from neamine (1) is described. Key intermediates in the synthesis of these 2"-deoxyaminoglycoside antibiotics are 3',4'-bis-O-(p-nitrobenzoyl)-1,2',3,6'-tetrakis-N-(trifluoroacetyl)neamine (6) and 3',4'-dideoxy-1,2',3,6'-tetrakis-N-(trifluoroacetyl)neamine (9). The amino groups of these intermediates are blocked by the trifluoroacetyl group, a blocking group not widely used in aminoglycoside chemistry.

Isolation and identification of gamma-aminobutyric acid in Streptomyces lincolnensis.

Gamma-aminobutyric acid was isolated from ruptured cells of Streptomyces lincolnensis. Its isolation and purification by preparative liquid-solid chromatography and subsequent identification by gas chromatography-mass spectroscopy are reported.

Biological studies with alpha-dehydrobiotin.

A growing culture of Streptomyces lydicus converted biotin-(14)C to alpha-dehydrobiotin-(14)C. The conversion was demonstrated by isolating crystalline alpha-dehydrobiotin-(14)C from fermentation liquors supplemented with biotin-(14)C. The addition of pimelic acid-(14)C to the growing culture did not produce any radioactive alpha-dehydrobiotin. alpha-Dehydrobiotin did not substitute for biotin in Lactobacillus plantarum or in Saccharomyces cerevisiae. Antimicrobial activity of alpha-dehydrobiotin was abolished by avidin. alpha-Dehydrobiotin appears to be different from several biotin vitamers described in the literature. It is concluded that alpha-dehydrobiotin is a product of biotin catabolism in S. lydicus.

Two new antimetabolites of biotin: alpha-methyldethiobiotin and alpha-methylbiotin.

Two new antimetabolites of biotin were isolated from culture filtrates of Streptomyces lydicus: beta-methyldethiobiotin and beta-methylbiotin. (14)C-biotin or (14)C-pimelic acid was not incorporated into either of these antimetabolites by the growing culture. Neither of the compounds could substitute for the biotin requirement in Saccharomyces cerevisiae. Both compounds had a strong and rather specific antimicrobial effect against mycobacteria. Their antimicrobial activities were reversed by biotin. Both compounds had an affinity for avidin.

Reductive microbial conversion of anthracycline antibiotics.

Reductive conversion of several anthracycline glycosides to their 7-deoxyaglycones occurs during their microaerophilic incubation with strains of Aeromonas hydrophila, Citrobacter freundii, and Escherichia coli. Further, extracts of microaerophilically grown A. hydrophilia catalyze DPNH-dependent reductive conversion of the same compounds. Anthracycline substrates cleaved by both whole cells and by the cell-free system include steffimycin, steffimycin B, nogalamycin, cinerubin A, and daunomycin. Investigation of glycoside cleavage as a function of both time and anthracycline concentration demonstrated the superiority of A. hydrophila over C. freundii and E. coli in regard to reaction rate and efficiency of conversion. Interestingly, some degree of anaerobicity was required for glycoside cleavage by all three organisms. Evidence supporting 7-deoxyaglycone formation via direct reductive cleavage, as opposed to a multienzyme-catalyzed process involving hydrolysis followed by dehydration and reduction, includes the following. Equilibrium mixtures of glycoside substrate and 7-deoxyaglycone product prepared using both whole cells and their extracts display no anthracycline hydrolysis products. Further, authentic steffimycinone (aglycone), the expected product of hydrolytic sugar cleavage of steffimycin, was shown to be converted to 7-deoxysteffimycinone (7-deoxyaglycone) at a rate slower than steffimycin. These data indicate that, if steffimycinone were present as an unbound metabolic intermediate, it should have been visible in the equilibrium mixture, but none was detected.