Daunorubicin Daunosamine

To a solution of 8 g (14 mmol) of daunorubicin hydrochloride in 500 ml of dry MeOH, 5.9 ml (79 mmol, 5.6 eq.) of acetylchloride was added. After refluxing for 1 h the solvents were evaporated in vacuo. Addition of CHCI3 to the residue caused precipitation of daunosamine. After the aminosugar had been filtered off, the filtrate was evaporated in vacuo. Diisopropylether was added to the remaining solid and the mixture was sonicated for 15 min to yield... 

Nevertheless, a few biosynthetic studies have shown that glycosyl transfer can occur much earlier, sometimes well before construction of the aglycon moiety is complete. In the perhaps best-known example, the biosynthesis of daunomycin (= daunorubicin, 29) and adriamycin (= doxorubicin, 30), glycosyl transfer of daunosamine is postulated to occur either at the aklavinone (38) stage [86], as in the biosynthesis of aclacinomycin A 37 (see above), or after 11-hydroxylation to -rhodomycinone [87], i. e., six to seven biosynthetic steps prior to completion of adriamycin formation (30, Scheme 17) [88]. 

The dehydratase gene drtrM from S. peucetius is located in the daunorubicin biosynthetic cluster. Although the gene was believed to be required for the synthesis of daunosamine, a frameshift in the DNA sequence was detected which causes premature termination of translation. Inactivation of dnrM did not prevent daunorubicin production. The data indicate that the product of a second dehydratase gene detected outside of the biosynthetic gene cluster is involved in the biosynthesis of daunomycin (29) [144]. 

Derivatives of three related amino sugars, daunosamine (386), the carbohydrate component of adriamycin and daunorubicin, acosamine, a C-4 epimer of daunosamine, and ristosamine, the carbohydrate component of ristomycin, have been prepared from lactaldehyde 689. All three syntheses begin with the same first step, the addition of methyl propiolate to 689. 

Idarubicin (Fig. 42.17) is the 4-desmethoxy analogue of daunorubicin. The loss of the C4-ether flattens the D ring, facilitating intercalation between DNA base pairs. In turn, this orients the daunosamine sugar in the minor groove in a way that better stabilizes the ternary complex between drug, DNA, and topoisomerase (42). 

Furanoside analogues of daunorubicin or adriamycin have been prepared, derived from D-ribofuranose and daunosamine the latter sugar coupled to daunomycinone gave compounds which were less active than the pyranosyl analogue, but were much. less toxic and... 

The structures of several new anthracycline antibiotics have been elucidated including rudolphomycin, which possesses the trisaccharide unit (17) containing a novel unsaturated amino-glycosulose. Disaccharide fragments obtained from carminomycin II and III by catalytic hydrogenation were found to contain daunosamine and an acyclic hemiacetal of 2,4-dideoxy-tetrose. Fermentation broths have yielded a number of daunorubicin analogues (modified in the tetracycline unit)." " ... 

Synthetic approaches to anthracycline antibiotics have been reviewed. Several papers report syntheses of daunorubicin analogues by the glycosidation of daunomycinone derivatives with amino-sugars glycosides of daunomycinone have been prepared from 3-epf-L-daunosamine, D-acosamine, D-daunosamine, D-ristosamine, and 3-ep(-D-daunosamine, and 4-demethoxy-9-deoxy-9-methyl... 

Ktiigel 11, Schumann G, Hanel F, Fiedler G. Nucleotide sequence analysis of five putative Screpcomyces griseus genes, one of which complements an early function in daunorubicin biosynthesis that is linked to a putative gene cluster involved in TDP daunosamine foima tion. Mol Gen Genet 1993 241 193-202. 

New anthracycline antibiotics rubomycins F and H, isolated from S. coeruleorubidus along with other daunomycinone derivatives, have been shown to be A -acylated derivatives of daunorubicin. Rubomycin M and N are disaccharide derivatives of daunomycinone, having a daunosamine unit glycosylated at C-4 with either of two 2,6-dideoxy-L-hexopyranoses. 

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