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SYNTHESIS OF NEAMINE DERIVATIVES

Preparation of Neamine

Neamine is the core molecule that can be used for synthesizing aminoglycosides of both kanamycin and neomycin classes. Acid hydrolysis of neomycin B, followed by purification using Amberlite IRA 410 (OH), is the most convenient method of obtaining neamine (Scheme 1) [1]. Such a protocol can be used for producing kilograms although the purity of neamine prepared in such quantity is only about 5060%. However, further purification can be performed using Amberlite CG50.

Scheme 1. Synthesis of neamine from acid hydrolysis of neomycin B.

Modification of Neamine

Since aminoglycosides contain multiple amino groups, the carbamate type of protecting groups are commonly used for direct synthetic modifications of aminoglycosides. After being incorporated on the aminoglycoside, these protecting groups can be selectively modified with their vicinal hydroxyl groups, leading to versatile structural modifications. For example, by using appropriate bases, carbamate protecting groups can be transformed into cyclic urea or carbamate with the neighboring function groups (Scheme 2) [2].

Scheme 2. Regioselective modification of neamine

Amino groups can also be differentiated using transition metals, such as Cu(II) and Zn (II) [3-4]. Rationale for the regioselectivity has been provided, which is based on the specific configurations of hydroxy and amino groups. It was commonly applied to kanamycin A and neamine. For example, all four amino groups on neamine can be selectively protected or unmasked using the metal chelating method (Scheme 3) [5].

Scheme 3. Selective exposure of amino groups on neamine

The two trans-diols (O-3 /O-4 and O-5/O-6) on neamine can be selectively protected by protecting groups, such as cyclohexylidene (Scheme 4) [6]. The O-3 /O-4 diol is less hindered than the O-5/O-6 diol. Therefore, the protection group at the O-3 /O-4 diol is more easily deprotected using acid catalysis. Consequently, in the appropriate acidic conditions, the formation of the O-5/O-6 diol protected neamine is the major product, which leads to the preparation of neamine with free O-5/O-6 diol. The O-5 hydroxy group is more sterically hindered than O-6, allowing the synthesis of 3 ,4 ,6-tri-O-protected neamine. Alternatively, a 3 ,4 ,6-tri-O-protected neamine, can be prepared from hydrolysis of protected neomycin B (Scheme 5) [7].

Scheme 4. Regioselective protection of hydroxy groups on neamine.

 

Scheme 5. Synthesis of 3 ,4 ,6-tri-O-protected neamine

Neamine has been converted into tetraazidoneamine by using TfN3  (Scheme 6) [8] . The azido group is highly lipophylic increasing  solubility in organic media, which is advantageous in the purification and characterization of poly-azido compounds. The preparation of 3 ,4 ,6-tri-Oprotected tetrazidoneamines  and 3 ,4 -di-O-protected tetrazidoneamines (19 and 20) can be achieved in a similar fashion as previously described, leading to the synthesis of neomycin and kanamycin analogs, respectively.

Scheme 6. Synthesis of azidoneamine derivatives

The synthesis of neamine derivatives bearing modified ring I with various amino groups at different positions has been reported
(Figure 1) [9]. The key step is the regioselective protection of the triol on 2-deoxystreptamine (ring II)  (Scheme 7).

Figure 1.Neamine derivatives                                                          Figure 2. Deaminated neamine derivatives

 

Scheme 7. Synthesis of neamine derivatives

Neamine analogs, in which four amino groups were individually replaced with hydrogen (deamination), were reported (Figure 2) [10]. Regioselective differentiation of amino groups using metal-chelation followed by deamination, provided four deaminated neamine derivatives: the amino groups were replaced by hydrogen (Scheme 8). With the exception of compound 4, all these neamine derivatives manifested better antibacterial activity against susceptible and resistant strains of Escherichia coli (Table 1).

Scheme 8. Synthesis of deaminated neamine derivatives

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

Compounds* E. coli E. coli (APH(3)-Ia) E. coli (APH(3)-IIa)
Neamine 3.9 15.5 15.5
1 1.6 1.5 1.5
2 3.1 4.4 4.4
3 0.8 0.7 1.4
4 14.7 14.7 14.7

* See figure 2. Unit, mM; APH, aminoglycoside phosphotransferase

Neamine mimics

Design of neamine mimics involving the disaccharide have been attempted (Figure 3) [11,12], however, disaccharide-based aminoglycosides are less active.

Figure 3. Structures of disaccharide-based aminoglycosides

 


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