Microbial reduction of the side-chain carbonyl of daunorubicin and N-acetyldaunorubicin.

Abstract

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.

Microbial conversion of saframycin A to 25-dihydrosaframycin A and 21-decyano-25-dihydrosaframycin A (25-dihydrosaframycin B) and their biological activities.

“…[4][5][6][7][8] The antitumor activity of a novel antibiotic, saframycin A, with a unique structure consisting of a dimer of 6-methyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline-5,8-dione, as the basic skeleton, has been reported . [9][10][11][12] In our studies on the microbial conversion of SA into antibiotics possessing antitumor spectra different from those of the parent compound (SA), reduction of the side chain carbonyl group of SA was observed.…”

Preparation and biological evaluation of 4-O-demethyldaunorubicin (carminomycin I) and of its 13-dihydro derivative.

“…3) The general appearance of the PMR spectrum of compound 4 both as free base and as hydrochloride was similar to that of 13-dihydrodaunorubicin (3, daunorubicinol)4~7) the only difference being the absence of the methoxy signal and the presence of an additional phenolic OH signal. Mild acid hydrolysis afforded a red aglycone (7) and an aminotrideoxysugar, C6H13O3N, which was identified as daunosamine (3-amino-2,3,6-trideoxy-L-lyxo-hexose)8) by direct comparison with an authentic sample. The aglycone (7) showed IR ( Tables 2 and 3.…”

Microbial conversion of steffimycin and steffimycin B to 10-dihydrosteffimycin and 10-dihydrosteffimycin B.

“…It has been shown that steffimycin (1) and steffimycin B (2) are reduced at the C-10 carbonyl by Actinoplanes utahensis, UCR-5885 and Chaetotnium sp., UCR-4634, respectively. Using cell-free extracts of the latter organism, the optimum conversion time, pH, and enzyme concentration have been determined for the conversion of 2 to 4.…”