MODIFICATION OF AMINOGLYCOSIDES
Neomycin and kanamycin are two of the most-studied aminoglycoside antibiotics. Neomycin belongs to a group of aminoglycosides containing a 4,5-disubstituted 2-deoxystreptamine core (ring II), while kanamycin contains a 4,6-disubstituted 2-deoxystreptamine core. In general, there are two types of approaches reported for syntheses of new aminoglycoside antibiotics (Figure 1). The first one is direct modification of existing aminoglycosides. The second approach is to apply glycosylation strategies on the selected cores, such as 2-deoxystreptamine and neamine (rings I and II), and create libraries of new aminoglycosides.
Figure 1. General strategies for the synthesis of neomycin and kanamycin classes of aminoglycosides.
Neomycin B and kanamycin A are two cheap aminoglycosides that can be used as starting materials for chemical modifications. Although commercially available neomycin B is usually mixed with 10–20% neomycin A and C and kanamycin A is commonly mixed with 10–20% kanamycin B, these minor components do not constitute significant difficulty in the chemical synthesis and characterization of the synthesized compounds.
The more frequently used protecting groups for amino functions are carbamates and azide. The first one is more cost effective. However, the poor solubility of the polycarbamate-containing compounds makes purification and characterization of these compounds very difficult. using the azido group to mask the amino groups of aminoglycosides has the advantage of generating compounds with higher solubility in organic media, facilitating their extraction from aqueous media.
The most challenging issue in synthesizing aminoglycoside derivatives is the regioselective differentiation of amino groups that has been extensively studied, especially in neomycin, kanamycin, and neamine. In general, these methods utilize metal-mediated chelation or cyclization ion. Since neamine is the pivotal component of both neomycin and kanamycin, a readily accessible library of unusual sugars will provide obetween the selected carbamate protected amino group and its vicinal hydroxyl groups. Selectivity of these two strategies closely depends on the scaffolds of parent aminoglycosides.
The stereochemistry of the glycosidic
bond to which the carbohydrate component is attached at the neamine core is
essential for antibacterial activity . The neomycin class aminoglycoside
consists of a neamine core and a β-linked carbohydrate component attached at the
O-5 position, while the kanamycin class aminoglycoside consists of a neamine
core with α-linked carbohydrate
1. Suami, T.; Nashiyama, S.; Ishikawa, Y.; Katsura, S. Carbohydr. Res. 1976, 52, 187–196.
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