Aglycones modification

SCHEME 6.9 Huang s (a) postsynthetic aglycone modifications and (b) one-pot synthesis of tetrasaccharide 51. 

Scheme 34 Thioglycosides reactivity tuning by postsynthetic aglycon modifications [106]...

Chemical modification of glycopeptide antibiotics with macrocyclic aglycones 98MI48. 

In their synthesis of convallatoxin, Reichstein and coworkers16 made some minor modifications in the Meystre-Miescher procedure. Because of the low solubility of strophanthidin (2) in benzene, the anhydrous aglycon was dissolved in a small volume of absolute p-dioxitne. Pure, dry silver carbonate was introduced and, under efficient stirring, a solution of the halide in benzene was added over a period of three hours, while distillation was maintained at a rate equal to that of the addition, thus keeping the volume of the solution in the flask at a constant (and small) volume. After addition of the halide was complete, a small volume of absolute benzene was added dropwise over a period of one hour, with distillation maintained as in the foregoing. By this procedure, the yield of tri-O-acetylcopvalla-toxin amounted to 44%. 

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. 

Daunorubicin (67) found independently by Di Marco et al. [35] and Du Bost et al. [36] was the first antileucemic agent in this group [37]. Adriamycin (68), discovered by Arcamone et al. [38] in 1969, marked an advantage in the development of chemo-therapeutics. It is presently one of the most valuable substances in clinical application [39]. Modifications carried out both in the aglycone and the saccharide residue are still of main interest. 

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