Daunorubicin (daunomycin; NSC 82151) is a fermentation-derived anthracycline antibiotic that is clinically useful in the treatment of human leukemias. Daunorubicin itself is found rarely in microbial fermentations, but is present normally in the form of glycoside derivatives that yield the free drug on simple acid hydrolysis. A major by-product of daunorubicin fermentations is usually the structurally related anthracycinone e-rhodomycinone. We have used mutants of a daunorubicin-producing Streptomyces species to study the biosynthetic relationship between E-rhodomycinone and daunorubicin. We found that exogenously added E-rhodomycinone can be converted to daunorubicin glycosides by a nonproducing mutant and by a mutant that produces daunorubicin glycosides but not E-rhodomycinone. Molar conversion efficiencies were in the 15 to 30% range.The latter mutant was also shown to convert exogenous "C-labeled E-rhodomycinone to "C-labeled daunorubicin glycosides, again at conversion effitiencies of about 25%. The same biotransformation was observed with daunorubicin production strain C5, which normally accumulates both E-rhodomycinone and daunorubicin glycosides. A significant percentage (16 to 37%) of exogenously added e-['4C]rhodomycinonewas metabolized by strain C5, and 22 to 32% of the metabolized radioactivity could be recovered as daunorubicin glycosides. A mathematical model of E-rhodomycinone metabolism was constructed based on plausible assumptions concerning the kinetics of E-rhodomycinone accumulation and catabolism. When analyzed according to this model, our data indicate that most (63 to 73%), but not all, of the daunorubicin glycosides accumulated in the experiments with production strain C5 derived from e-rhodomycinone. A pathway network for the biosynthesis of daunorubicin glycosides is proposed that is in agreement with these data. In this proposed pathway network, e-rhodomycinone is an intermediate in one of at least two pathways which yield daunorubicin glycosides.Daunorubicin (Fig. 1) is an anthracycline antibiotic that is elaborated by several Streptomyces species

Two new anthracyclinone antitumor antibiotics, maggiemycin (6, NSC-D344012) and anhydromaggiemycin (8) have been isolated from a culture of an unspeciated Streptomyces (ATCC No. 39235). Bioautography against Bacillus subtilis was used for the preliminary detection of these anthracyclinones. Structures were proposed based on their UV-visible, IR, *H NMR,13C NMR spectra, electron impact (El) and high-resolution EI-MS and confirmed by partial synthesis and a direct correlation with e-rhodomycinone. Both the anthracyclinones are active against KB, P388 and L1210 murine tumor cell lines; however, anhydromaggiemycin was more active than maggiemycin. A number of related anthracyclinones have also been prepared and their biological activity has been determined. The structure-activity relationship of these new anthracyclinones is also discussed.

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Microorganisms reduced the side-chain carbonyl of daunorubicin to yield 13-dihydrodaunorubicin (daunorubicinol; daunomycinol). This microbial transformation occurred under aerobic conditions in agitated baffled shake flasks incubated at 37°C . The microorganisms were first grown in a medium which supported dense growth. Daunorubicin-HCl was then added. Following a period of incubation, broths were adjusted to pH 10.0 and extracted with chloroform. Daunorubicinol was recovered and purified from the chloroform extracts by preparative TLC. Identity of the daunorubicinol was established by TLC and spectroscopy (UV-vis, IR, NMR, MS, CD and ORD).N-Acetyldaunorubicin was likewise reduced microbially to N-acetyldaunorubicinol. N-Acetyldaunorubicinol appears to be a new compound which is yet to be tested for antitumor activity.WILEY and MARSHALL1) have reported in a recent communication to this journal on anaerobic microbial reductive cleavage of several anthracycline antibiotics to yield 7-deoxyanthracycline aglycones. Their work was undertaken because many anthracycline antibiotics exhibit antitumor activities, and microbial transformation is one method with potential for modifying anthracycline structures to produce new agents for antitumor testing. For the same reason, we too have been exploring microbial transformation of anthracycline antibiotics. During the course of our studies, we have observed under aerobic conditions the microbial reduction of the side-chain carbonyl of daunorubicin to yield 13-dihydrodaunorubicin (daunorubicinol; daunomycinol); structures are shown in Fig. 1. N-Acetyldaunorubicin is likewise reduced. A report of the findings of this aspect of our work follows.

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