Anthracyclines sugar moiety

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... 

The anthracycline antibiotic drugs approved for antitumour drug therapy include doxorubicin (adriamycin), epirubicin, daunorubicin, idarubicin, and aclarubicin. These drug substances are structurally similar and characterized by a tetracyclic aglycone linked to amino sugar moieties. Particularly in solutions, the anthracyclines are photolabile. The formation of inactive aglyconesand polymeric substances as a result of the irradiation of anthracycline solutions has been reported. 

The cyclohexylidene protecting group has been employed in several syntheses. A preparation of 2,3-0-cyclohexylidene-4-deoxy-L-threose (445) fi om L-( + )-diethyltartrate (lb) in seven steps illustrates one synthetic application (Scheme 99). Conversion of the monobenzyl protected alcohol 443 to its tosylate followed by reduction with sodium borohydride provides the deoxy intermediate 444, which is reductively deprotected and Swem oxidized to 445 in good overall yield. Treatment with benzylamine provides an imine that undergoes a stereoselective carbon-carbon bond forming reaction with a-lithio-A, A -dimethylacetamide in the presence of the Lewis acid zinc bromide to furnish, after Cbz-amine protection, the j9-aminoamide 446. This is converted in four steps to A -acetyl-L-daunosamine (447), a sugar moiety particularly important as the carbohydrate constituent of the anthracycline antibiotics [149]. 

Zunino F, Pratesi G, Perego P. Role of the sugar moiety in the pharmacological activity of anthracyclines development of a novel series of disaccharide analogues. Biochem Pharmacol 2001 61 933-938. 

Generally, fluorinated anthracyclines are obtained via total synthesis of the aglycone or sugar moieties to introduce the fluorine into the specific position. 

Anthracyclinones fluorinated on the D-ring were used to obtain the different anthracyclines 9 and also derivatives modified on the sugar moiety, such as morpholinyl-10 [11] or 4 -epi-4 amino-anthracyclines 11 (Fig. 3) [12]. 

The literature reports several examples of substitution of the natural sugar moiety of anthracyclines (daunosamine) with different modified sugars. One of these modifications was the use of a fluorinated sugar. 

Deoxy-4 -fluoro-DOXO was the object of studies, together with several other derivatives, for determination of the influence of lipophilicity on the cytotoxicity of anthracyclines in LoVo and LoVo/Dx human cell lines. The lipophilic character of selected anthracyclines was measured by means of reverse-phase HPLC, under appropriate experimental conditions. The results obtained in these in vitro models indicate that lipophilicity plays a role in anthracycline activity, influencing drug availability at the site of action. The introduction of a fluorine atom in the sugar moiety structure increases the lipophilicity and cytotoxicity of the drug [84]. 

Compounds 11 and 15 with equatorial-A -OW showed similar activity, while compound 16 (substituted 4 -OH with ox/aM -Ns in the sugar moiety) lost its cytotoxicity. This suggests that 4 -OH in the sugar may also be important for sugar containing anthracycline as an anticancer agent. Further SAR studies are required to clarify this finding. 

The sugar moieties of anthracyclines are extremely important for both in vitro and in vivo activities. Anthracyclinones, that is, aglycones lacking the sugar moieties, are not biologically active. In general, within the aclaniNcin series, disaccharides and trisaccha-... 

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. 

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