Anthracycline glycosylation

Anthracyclines glycosylated at the 4-position are very rarely mentioned in the literature, and 4-0-(/l-D-glucopyranosyl)-fi-rhodomycinone (39a) isolated from a mutant of Actinomadura roseoviolacea was the first one of this series. It exhibited no antibacterial or cytotoxic activity [66]. However, its glucuronic acid derivative histomodulin (39b), isolated from Streptomyces ruber JCM3131, was reported as an up-regulator of MHC class-I molecules in B16/BL6 cells [67]. 

Complex glycosylated compounds like macrolides, anthracyclines, aureolic acids, cardiac glycosides, orthosomycines and tetronic acids are of considerable scientific as well as pharmaceutical interest. Obviously, each of them is responsible for certain therapeutic effects with respect to different diseases. Anthracyclines and aureolic acids are applied in cancer chemotherapy, orthosomycines are active as antibiotics against Gram-positive bacteria, and the cardiac glycosides are used in the treatment of cardiac insufficiency. 

Although there are remarkable exceptions (see below), it has nonetheless often been shown that glycosyl transfer happens always at the very end of a biosynthetic sequence. For example, the biosynthesis of aclacinomycin A (37), a less cardiotoxic anthracycline than doxorubicin (30), proceeds via aklavinone (38)... 

Kolar, C, Kneissl, G, Semisynthetic rhodomycins novel glycosylation methods for the synthesis of anthracycline oligosaccharides, Angew. Chem. Int. Ed. Engl, 29, 809-811, 1990. 

It was observed that anthracyclines containing several glycosyl moieties have, in general, less side effects. For example, marcellomycin (36) and aclacinomycin A (37) show lower car-diotoxicity than daunomycin. 

Since the successful apphcation of daunorubicin (daunomycin, la) and especially doxorubicin (adriamycin, lb) as anticancer drugs, international research activities have led to the discovery of an enormous number of new natural and especially synthetic anthracyclines. The natural derivatives came from a fairly low number of streptomycetes and rare actino-mycetes the majority were, however, isolated from mutants, especially from S. galilaeus (see e.g. [89]) many others were obtained by fermentative transformation of related precursors, e.g. by microbial glycosylation of anthracy-clinones [90]. Progress in genetic techniques will certainly further increase their number. 

In the daunorubicin-doxorubicin group of anthracyclines, is removed by tailoring reactions after glycosylation. DauP [14] produces the free 10-carboxylic acid from the methyl ester (Scheme 3). 

Anthracyclines with daunosamine glycosylation may also initially have a second sugar attached to carbon 4 however, this sugar is further modified to yield baumycins [41], products in which this sugar appears to have been oxidatively cleaved. The hypothetical initial glycoside component has not been identified. 

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