Direct Modification of Neomycin and Paromonmycin

there are several papers reporting the synthesis of neomycin derivatives [1-3]. Structural studies involving the aminoglycoside-bound rRNA molecules have provided new concepts for the modification of aminoglycosides [4-7]. Analysis of the X-ray structure of neomycin B bound to the APH(3 ) combined with ADP, showed that 5 -OH was  not involved in binding [7]. Glycosylation at O-5 allowed the synthesis of 5 -glycosylated neomycin derivatives (Figure 1) [8-9]. Compounds, 4 displays improved antibacterial activity against resistant strain (APH(3 )) as compared to the parent aminoglycoside, neomycin B (Table 1).

Figure 1. Structures of 5 -Glycosylated Neomycin


TABLE 1. MIC of 5 -Glycosylated Neomycin Derivatives

Compounds Kan Neo 1 2 3 4
E. coli (ATCC 25922)
_ 8–10 95 40–50 25–30 10–11
E. coli (APH(3 ))
260–270 50–60 >200 >200 >200 35–45
S. epidermidis (ATCC 12228)
_ 0.3–0.4 5.5–7 1.5–1.8  1.4–1.8 0.2–0.4
B. subtilis (ATCC 6633)
— 0.8–0.9 8.5–10 3.5–4  1.4–1.8 0.6–0.8
Salmonella virchow (APH(3 )) 500–570 200–250 >1250  >1250 >1250 75–125

P. aeruginosa (ATCC 27853)
450–500 55–60 110–130 30–35 40–50 60–65

Unit, μg/mL; Neo, neomycin B.

Two research groups have independently synthesized conformationally constrained neomycin derivatives, with the 2 -NH2 group linked to the C-5 (Scheme 1) [10-11]. The X-ray crystallography data revealed a drastic conformational “flipping” of the 2-deoxystreptamine moiety between the binding sites of rRNA and ANT(4 ) [12]. This observation led to the hypothesis that an intramolecular link may obstruct the needed conformational change for ANT(4 )-catalyzed modification. Compound 6 shows lower activity against susceptible strains of bacteria; however, it maintains its activity against resistant bacteria expressing ANT(4) while the activity of neomycin decreases drastically (Table 2).

Scheme 1. Conformational constrained neomycin

TABLE 2. MIC of Conformational Constrained Neomycin

Compounds Neomycin B 6
S. epidermis 2 10
B. cereus 1 5
E. coli (BL21) 0.5 10
Alcaligenes faecalis 1 20
E. coli (DH5α) 3 20
E. coli (DH5α) (ANT(4 )) 60 20

Unit, μg/mL.

Neomycin Derivatives via Glycosylation

Neomycin can be selectively protected at 3 -OH with THP following selective cyclic carbamate formation,  (Scheme 2) [13]. The 5-OH can  then be glycosylated using a thiofuranose, creating the ribostamycin analog 10. In contrast to ribostamycin, compound 10 was found inactive against various bacterial strains. The result may be explained by the disruption of the H-bond between 2 -NH2 and 5 -O, which has been suggested to be pivotal for orienting the optimal conformation of ring I [4].

Scheme 2. Synthesis of kanamycin derivatives via glycosylation.

Ribostamycin analogs have been synthesized by glycosylation of tetraazidoneamine (Scheme 3) [14]. Aminoalkyl side chains were used to replace ring IV of neomycin B. Two such ribostamycin analogs, 16 and 17, showed similar activity to that of neomycin B and better than ribostamycin (Table 3). The results proved that the aminoalkyl group can be used as replacement for ring IV. However, compounds 16 and 17 were inactive against P. aeruginosa, which is intrinsically resistant to aminoglycosides.

Scheme 3. Synthesis of ribostamycin derivatives via glycosylation

TABLE 3. Antibacterial Assay of Ribostamycin Derivatives

S. aureus

 (ATCC 25923)

E. coli

(ATCC 25922)

P. aeruginosa

(ATCC 27853)

  Inhibition zone Inhibition zone MIC Inhibition zone
Ribostamycin 14.5 16.5 8 Inactive
Neomycin B 21.5 20.5 1.5 9.5
Paromomycin 19.5 18 5.5 Inactive
16 18.5 18.5 2.3 Inactive
17 21 19 1.4 Inactive

Unit, mm for inhibition zone, μg/mL for MIC.

Synthesis of Pyranmycin derivatives by Glycodiversification

Pyranmycins are a group of synthetic aminoglycoside antibiotics containing a 4,5-disubstituted 2-deoxystreptamine core, which is the main feature of neomycin class antibiotics [15-18]. The main difference with neomycin is the presence of a pyranose in place of furanose at the O-5 position of neamine. Replacement of the furanose ring (III) with an aminopyranose should increase the acid stability and, hopefully, reduce the cytotoxicity due to the lower administered dosage needed for achieving the therapeutically effective concentration of antibiotics [19-20].

Pyranmycin derivatives containing both D-pyranose and L-pyranose at ring III, have been synthesized (Scheme 4). The b-glycosidic bond between rings II and III was directed by neighboring acetyl group of glycosyl trichloroacetimidate donors. The antibacterial assay result reveals three leads, compounds 22-24. The presence of 6 -CH3 was found to be an important factor in increasing the antibacterial activity for D-pyranose, while 6 -CH2OH is important for L-pyranose. Introduction of a side chain on ring III did not increase the antibacterial activity [15].

Scheme 4. Synthesis of pyranmycin derivatives.

1. Umezawa, S.; Tsuchiya, T. In Aminoglycoside Antibiotics; Umezawa, H.; Hooper, I. R., Ed.; New York: Springer-Verlag, 1982, pp. 37–110.

2. Hanessian, S.; Haskell, T. H. In Antibiotics Containing Sugars; Pigmann, H.; Horton, D., Eds.; New York/London: Academic Press, 1970, pp. 139–211.

3. Haddad, J; Kotra, L. P.; Mobashery, S. In Glycochemistry Principles, Synthesis, and Applications; Wang, P.G.; Bertozzi, C. R., Eds.; New York/Basel: Marcel Dekker, 2001, pp. 307–424.

4. Fourmy, D.; Recht, M. I.; Blanchard, S. C.; Puglisi, J. D. Science 1996, 274, 1367–1371.

5. Fourmy, D.; Recht, M. I.; Puglisi, J. D. J. Mol. Biol. 1998, 277, 347–362.

6. Vicens, Q.; Westhof, E. Structure 2001, 9, 647–668.

7. Fong, D. H.; Berghuis, A. M. EMBO J. 2002, 21, 2323–2331.

8. Fridman, M.; Belakhov, V.; Yaron, S.; Baasov, T. Org. Lett. 2003, 5, 3575–3578.

9. Fridman, M.; Belakhov, V.; Lee, L. V.; Liang, F.-S.; Wong, C.-H.; Baasov, T. Angew. Chem. Int. Ed. 2005, 44, 447–452.

10. Asensio, J. L.; Hidalgo, A.; Bastida, A.; Torrado, M.; Corzana, F.; Chiara, J. L.; Garcia-Junceda, E.; Canada, J.; Jimenez-Barbero, J. J. Am. Chem. Soc. 2005, 127, 8278–8279.

11. Blount, K. F.; Zhao, F.; Hermann, T.; Tor, Y. J. Am. Chem. Soc. 2005, 127, 9818–9829.

12. Pedersen, L. C.; Benning, M. M.; Holden, H. M. Biochemistry 1995, 34, 13305–13311.

13. Kumar, V.; Remers, W. A. J. Org. Chem. 1981, 46, 4298–4300.

14. Alper, P. B.; Hendrix, M.; Sears, P.; Wong, C.-H. J. Am. Chem. Soc. 1998, 120, 1965–1978.

15. Elchert, B.; Li, J.; Wang, J.; Hui, Y.; Rai, R.; Ptak, R.; Ward, P.; Takemoto, J. Y.; Bensaci, M.; Chang, C.-W. T. J. Org. Chem. 2004, 69, 1513–1523.

16. Wang, J.; Li, J.; Tuttle, D.; Takemoto, J.; Chang, C.-W. T. Org. Lett. 2002, 4, 3997–4000.

17. Chang, C.-W. T.; Hui, Y.; Elchert, B.; Wang, J.; Li, J.; Rai, R. Org. Lett. 2002, 4, 4603–4606.

18. Wang, J.; Li, L.; Czyryca, P. G.; Chang, H.; Kao, J.; Chang, C.-W. T. Bioorg. Med. Chem. Lett. 2004, 14, 4389–4393.

19. Bochkov, A. F.; Zaikov, G. E. Chemistry of the O-Glycosidic Bond: Formation and Cleavage; Elmsford, NY: Pergamon Press, 1979.

20. Shallenberger, R. S.; Birch G., G. Sugar Chemistry; Westport, Conn.: Avi Pub. Co., 1975.


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