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SYNTHESIS OF KANAMYCIN LIKE AMINOGLYCOSIDES

Direct Modification of Kanamycin

The synthesis of aminoglycoside derivatives by direct modification of kanamycin A have been extensively described. A number of approaches based on differentiation of amino groups, have been reported aiming to increase the activity, especially against aminoglycoside-resistant bacteria. For example, cyclic carbamate formation can be carried out by appropriate base by using a Cbz protecting group,  (Scheme 1) [1].

Scheme 1. Synthesis of kanamycin derivatives via direct modification

Compound 1, 6 ,3 -di-N-methyl kanamycin B, displayed activity against various resistant strains, while compound 2 showed highly reduced activity demonstrating the key role of amino groups in the SAR of aminoglycosides (Table 1).

TABLE 1. Minimum Inhibitory Concentration (MIC) of kanamycin Derivatives

Bacterial Strains Kan A Kan B 1 2
S. aureus 1 0.5 4 >125
S. aureus (APH(3 )-IV) >125 >125 8 >125
E. coli 4 2 16 >125
E. coli (APH(3 )-I) >125 >125 63 >125
E. coli (ANT(2 )) 125 32 63 >125
E. coli (AAC(6 )) >125 32 63 125
P. aeruginosa 63 63 8 >125
P. aeruginosa (APH(3 ) + AAC(3)-I) 32 32 8 >125
P. aeruginosa (APH(3 )-IV) >125 >125 8 >125
P. aeruginosa (APH(3 )-I+ AAC(6 )) >125 >125  8 >125
P. aeruginosa (perm. mutant) >125   >125 16 >125

Unit, μg/mL; Kan, kanamycin; S. aureus, Staphylococcus aureus; P. aeruginosa, Pseudomonas aeruginosa; AAC, aminoglycoside acetyltransferase; ANT, aminoglycoside nucleotidyltransferase; Perm. mutant, mutant strain impermeable to kanamycin A and B.

Kanamycin Derivatives via Glycosylation

Kanamycin derivatives can be prepared by glycosylation of the O-6 hydroxy group of neamine derivatives or 2,5-dideoxystreptamine. A regioselective glycosylation on the O-6 hydroxy group of 3 ,4 -di-O-protected neamine can be readily achieved as the O-5 OH is sterically hindered. The challenge is to form the desired a-glycosidic bond since those with a b-glycosidic bond have weaker antibacterial activity.

Glycosylation using 2,3,4,6-tetra-O-acetylglucopyranosyl bromide provided the b-anomer as the major product due to the neighboring group
assistance (Scheme 2) [2]. The desired a-anomer can be separated from the less active b-anomer, and assayed individually (Table 2).
The synthesis of interesting C2-symmetrical kanamycin derivatives from glycosylation of diazido-2,5-dideoxystreptamine, has also been reported (Scheme 3) [3].

 

Scheme 2.Synthesis of kanamycin derivatives via glycosylation

 

TABLE 2. Zone of Inhibition of Kanamycin Derivatives

Compounds S. aureus B. subtillis E. coli K-12 M. smegmatis
Neamine 19.5 31.5 28.9 26.5
3 18.5 30.4 31.3 18.9
4 0 12.0 16.4 0

Unit, mm; B. subtillis, Bacillus subtillis; M. smegmatis, Mycobacterium smegmatis

Scheme 3. Synthesis of kanamycin analogs via glycosylation

Synthesis of Kanamycin B Analogs via Glycodiversification

Libraries of kanamycin B analogs based on glycosilation methodology have been prepared (Scheme 4) [4]. The strategy, which is termed glycodiversification, is to change the original carbohydrates with the synthetic carbohydrates and further structural modifications. Attachment of various carbohydrates bearing designed modifications for probing the efficacy of various structural modifications, allowed to verify the SAR of this class of compouds. The use of the azido groups as masked form of the amino groups facilitated the purification. The glycosylation donors that have benzyl or azido groups at the C-2 position favor the formation of an a-glycosidic bond under the influence of anomeric and solvent effects. A wide range of structural features can be introduced following the same strategy.

Scheme 4. Synthesis of kanamycin derivatives via glycosylation

 


1. Kumar, V.; Remers, W. A. J. Med. Chem. 1979, 22, 432436.

2. Suami, T.; Nashiyama, S.; Ishikawa, Y.; Katsura, S. Carbohydr. Res. 1976, 52, 187196.

3. Seeberger, P. H.; Baumann, M.; Zhang, G.; Kanemitsu, T.; Swayze, E. E.; Hofstadler, S. A.; Griffey, R. H. Synlett. 2003, 13231326.

4. Li, J.; Wang, J.; Czyryca, P. G.; Chang, H.; Orsak, T. W.; Evanson, R.; Chang, C.-W. T. Org. Lett. 2004, 6, 13811384.

 

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