Anthracycline sugars

In order to solve this problem, we concieved a series of triparte prodrugs in which the enzyme substrate was attached to the anthracycline through a self-immolative spacer. In these prodrugs, the spacer was linked to the amino group of the anthracycline sugar unit, which is also critical for the biological activity. 

The present contribution centers on stereoselective syntheses of mono- and in particular oligo-saccharides of the 2-deoxy- and the 2,6-dideoxy series as well as some branched-chain species. These are the principal sugar portions in a large number of important natural glycosides, such as the cardiac glycosides (3), the orthosomy-cins (D, the tetronic acids (5), the aureolic acids (6, see below), and the anthracyclines (2, see below), to name just a few. 

J. Thiem and D. Springer, Synthesis and hydrogenation studies of 3-azidohex-2-enopyranosides, precursors of the sugar constituents of anthracycline glycosides, Carbohydr. Res., 136 (1985) 325-334. 

In all cases, 2,6-dideoxy sugars of the d- or L-series are common and important parts of these various molecules. In general, the specific therapeutic effect is thought to be caused by the aglycone, and the sugar residue to be responsible mainly for regulating the pharmacokinetics. Thus, parameters like bioavailability, resorption, distribution, or therapeutic width are influenced by the carbohydrate moieties. By modification of the carbohydrate moiety it is, e.g., possible to enhance the efficacy of unspecific aglycones like anthracyclines or aureolic acids, or also to reduce possible side effects. Such as approach is followed in the field of class-I and -II anthracyclines in order to decrease their considerable cardiotoxicity. 

Anthracyclines isolated from stieptomyces show a 2,3,6-trideoxy-3-amino-L-/yxo-configurated sugar oc-attached to the aglycon. Therefore, the first interest centered on the synthesis of aminodeoxy sugars in the l-lyxo series, e.g., daunosamine [46-50]. Several new glycosides were prepared [51] in order to evaluate structure-activity relationships. 

Rhodinose (174) is the sugar linked in the antibiotic streptolydigin (177)1,259 and is a component of the oligosaccharides present in the rhodomycin family of anthracycline antibiotics. 1,260... 

Figure 30. The temperature dependence of the daunomycin anthracycline Ring D aromatic protons (7.3 to 7.7 ppm), the anomeric sugar H-V proton (5.1 to 5.5 ppm), and the anomeric CH.,-5 proton (1.2 to 1.3 ppm) of the daunomycin poly-(dA-dT) complex, Nuc/D = 25, 9 and 5 in 1M NaCl, lOmM cacodvlate, ImM EDTA, 2HjO. The poly(dA-dT) concentration was fixed at 19.3mM in phosphates and the daunomycin concentration was varied to make the different Nuc/D ratio...

The importance of uptake rates in relation to the RF was considered in a later paper [131] for four anthracyclines with identical amino sugar moiety (doxorubicin, daunorubicin, idarubicin, and 8(S)-fluoroidarubicin). The kinetics of uptake showed... 

Several fully saturated heterocyclic systems which have been formed by cycloaddition reactions have found use in natural product synthesis. Cycloadducts (27) and (28) were prepared as part of an investigation into the synthesis of the benzoxocin fragment of the antitumor anthracycline nogalomycin <9lJOCl364> and cycloadducts (245) and (248) were intermediates in the synthesis of amino sugar derivatives <84JA5598>. 

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