Antibiotics aminoglycosidic, synthesis

Urease assay. When Proteus mirabilis grows in a urea-containing medium it hydrolyses the urea to ammonia and consequently raises the pH of the medium. This production of urease is inhibited by aminoglycoside antibiotics (inhibitors of protein synthesis Chapter 8). In practice, it is difficult to obtain reliable results by this method. 

The aminoglycosides are a closely related family of antibiotics produced almost exclusively by members of the genus Streptomyces and Micromonospora (Table 1.19). Most are polycationic compounds, composed of a cyclic amino alcohol to which amino sugars are attached. They all induce their bacteriocidal effect by inhibiting protein synthesis (apparently by binding to the 30 S and, to some extent, the 50 S, ribosomal subunits). Most are orally inactive, generally necessitating their parenteral administration. 

New concepts in the strategy of the synthesis of drugs rarely appear, such as from the observation that microorganisms often get resistance from enqrmes that inactivate the drug through phosphorylation. To avoid the problem, the aminoglycoside antibiotic kanamycin A was modified in a way that it was re-obtained whenever it was modified by the microorganism resistance enzymes (Haddad 1999). 

The selection of transformed chloroplasts usually involves the use of an antibiotic resistance marker. Spectinomycin is used most routinely because of the high specificity it displays as a prokaryotic translational inhibitor as well as the relatively low side effects it exerts on plants. The bacterial aminoglycoside 3 -adenyltransferase gene (ciadA) confers resistance to both streptomycin and spectinomycin. The aadA protein catalyzes the covalent transfer of an adenosine monophosphate (AMP) residue from adenosine triphosphate (ATP) to spectinomycin, thereby converting the antibiotic into an inactive form that no longer inhibits protein synthesis for prokaryotic 70S ribosomes that are present in the chloroplast. 

The aminoglycosides interfere with bacterial protein synthesis by binding irreversibly to ribosome and could cause cell membrane damage. They may be inactivated by bacterial resistant enzymes but bacteria could also display resistance through ribosomal modifications or by decreased uptake of antibiotic into the bacterial cell. 

Examples for the use of acetals such as 3, of 3-nitropropanal (1), and of 3-nitropropanol (2) or its O-protected derivatives are given in the references.22-24 A recent, notable application from this group is a short, high-yield synthesis of l-acosamine,25 the arabino isomer of 3-amino-2,3,6-trideoxyhexoses that form part of many antitumor aminoglycoside antibiotics 26... 

The glycoside/aminoglycoside antibiotics, like the macrolides, exert a bacteriostatic effect due to selective inhibition of bacterial protein synthesis, with the exception of novobiocin (26). The compounds neomycin (27), spectinomycin (28) and streptomycin (29) bind selectively to the smaller bacterial 30S ribosomal subunit, whilst lincomycin (30) binds to the larger 50S ribosomal subunit (cf. macrolides). Apramycin (31) has ribosomal binding properties, but the exact site is uncertain (B-81MI10802). Novobiocin (26) can inhibit nucleic acid synthesis, and also complexes magnesium ion, which is essential for cell wall stability. 

S. Umezawa, Structure and synthesis of aminoglycoside antibiotics, Adv. Carbokydr. Chem. Biodtem 3(7.111 <1974). 

The facile formation of the iodo compound, and the subsequent reduction with tributyltin hydride opens a new access to 2-amino-2,3-dideoxy-D-glucose (D-lividosamine) present in various aminoglycoside antibiotics [92], The same strategy been used in the synthesis of C-lO -C-l fragment of boromycin [93]. Displacement of the C-3 imidazylate ester of a 2-azido-2-deoxy-a-D-altropyranose derivative with benzoate occurred readily [94], compared with the corresponding tosylate [95],... 

These reactions were applied to the synthesis of phenol derivatives [32], aminoglycoside antibiotics [33] etc.. . and are of great interest in other synthetic applications, b) In the field of substitution reactions, a more recent application of photobromination reactions is described for the synthesis of L-iduronic acid derivatives from D-glu-curonic acid analogs 26. The C-5 photobrominated product 27 is reduced with tri-n-butyltin hydride to give a mixture of starting material and the L-idopyranuronate 28 by a supposed rapidly interconverting radical [29] (Scheme 14). 

S. Umezawa Recent advances in the synthesis of aminoglycoside antibiotics... 

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