Microbial transformation of aklanonic acid, a potential early intermediate in the biosynthesis of anthracyclines.
Sir: Recently, we isolated a new pigment from fermentations of Streptomyces sp. ZIMET 43717". The close structural relationship of this compound (aklanonic acid, Ia, Fig. 1) to anthracyclinones induced us to attempt its biotransformation to anthracyclines by daunorubicin-negative mutants derived from different daunorubicin producing organisms. The results of our experiments provided evidence that aklanonic acid very probably is an early intermediate in the biosynthetic pathway of anthracyclines. Thus, aklanonic acid, its methyl ester, and aklanone, a chemical conversion product of aklanonic acid (Fig. 1)", were fed to fermentations of the mutant strains O3P; and IP,. Both mutant strains were isolated after N-methyl-N'nitro-N'-nitrosoguanidine treatment of daunorubicin-producing Streptomyces griseaus strains. Strain O1P; was derived from IMET JA 5142. Strain IP, is a negative mutant of strain 1P which produces a mixture of new red and blue pigments"'. The chemical structures of the two main red components designated 1P/I and IP/II3) are shown in Fig. 1. Fermentations of the strains O1P; and 1P, were carried out as described2) in 500-m1 flasks each containing 80 ml of medium for 24 hours. Then 3 ml of a solution of substrate in methanol (1 mg/ml) were added to each flask and cultivation continued for 24 hours. Extracts of mycelium with acetone and chloroform (1: 1) were purified by chromatography on KH2PO4 buffered silica gel (chloroform acetone, 10: 2). Identification of the biotransformation products was performed as indicated in Table 1. Glycosides extracted from the culture filtrate were hydrolyzed with 0.1 N HCI. Compound IP/II was purified by column chromatography on silica gel with benzene. The results are listed in Table 1. Aklanonic acid as well as its methyl ester were transformed by mutant O,P, to give e-rhodomycinone, 7deoxy-e-rhodomycinone and glycosides of dauno-
Isolation and chemical structure of aklanonic acid, an early intermediate in the biosynthesis of anthracyclines.
The fermentation, isolation and structure elucidation of aklanonic acid are described. The compound was isolated from fermentations of Streptomyces strain ZIMET 43,717. Aklanonic acid is a yellow-orange crystalline substance, melting at 203-204 degrees C (dec), having the molecular formula C21H16O8, and possessing UV maxima at 258, 282 (sh) and 438 nm (CHCl3). In dimethyl sulfoxide or pyridine aklanonic acid is unstable and a new compound (aklanone) is formed as a conversion product. The elucidation of the structures has shown that aklanonic acid and aklanone are derivatives of 1,8-dihydroxyanthraquinone.
Stereoselective interaction between the R enantiomer of warfarin and cimetidine.
The stereoselectivity of the pharmacokinetic interaction between warfarin and cimetidine was investigated in eight healthy volunteers. The warfarin enantiomers were given separately as single doses (15 mg) alone and during chronic administration of cimetidine (1 g day-1). Cimetidine did not interact with S warfarin but there was an interaction with the R enantiomer of warfarin. Cimetidine caused a significant increase in the mean plasma half-life of R warfarin (from 47.8 h to 57.8 h) and a significant decrease in its mean plasma clearance (from 2.3 to 1.7 ml h-1 kg-1) (P less than 0.02). Administration of a pharmacological dose of vitamin K1 together with the enantiomers of warfarin was necessary clinically and resulted in elevation of vitamin K1 2,3-epoxide concentrations, which were similar in each case.