Aminoglycosides analogs

Simple analogs of an aminoglycoside antibiotic, 2,6-dideoxy-4-0- (671) and -5-0-(2,3-dideoxy-2-fluoro-o -D-r/Z>o-hexopyranosyl)streptamine (672) were prepared by coupling of tri-O-acetyl-2-fluoro-D-glucal (666) with cyclitol derivatives 668 or 667 (through 669 and 670) as shown. 

The design of our conformationally constrained aminoglycosides is based on the structural information available for the RNA-paromomycin complex [21-26]. It is known that positions 05m and N2i are hydrogen bonded within the ribosome bound state. Thus, in our analogs, this interaction has been replaced by either a direct covalent bond, as in 2, a two-methylene bridge, as in 3, or by a salt bridge, as in 4 (see Fig. 9). 

Recently, Tor and co-workers have analysed the interaction between the cyclic analog 2 and the corresponding paromomycin derivative with the A-site sequence and also with the HIV TAR RNA fragment [47]. At pH 7.5, the decrease in affinity for the locked derivatives with respect to the parent aminoglycosides is 22-14 fold for the A-site and 11-2 fold for the HIV TAR sequence. The differences with respect to the natural ligands are significantly reduced at acid pH. 

E., Hofstadler, S. A., Griffey, R. H. Synthesis of neomycin analogs to investigate aminoglycoside—RNA interactions. Synlett 2003, 9,... 

The medically useful products demethyltetracycline and doxorubicin (adriamycin) were discovered by simple mutation of the cultures producing tetracycline and daunorubicin (daunomycin), respectively. The tectmique of mutational biosynthesis (mutasynthesis) has been used for the discovery of many new aminoglycoside, macrolide, and anthracycline antibiotics. In this tectmique, a non-producing mutant ( idiotroph ) is isolated and then fed various analogs of the missing moiety. When such a procedure leads to a return of antibiotic activity, it usually is due to the... 

SAR) among modified aminoglycosides. The lower activity against AAC(6 ), even with the presence of AHB group at N-1, was also observed in these fluoro-substituted amikacin analogs. 

The aminoacyl side chain of this drug, which is analogous to that of ceftazidime, is responsible for the high activity with respect to Gram-negative aerobic bacteria. The spectrum of use of aztreonam is very similar to the antimicrobial spectrum of aminoglycosides, and in the majority of cases it is a potential replacement. 

Drugs that may interact with zalcitabine include antacids, chloramphenicol, cisplatin, dapsone, didanosine, disulfiram, ethionamide, glutethimide, gold, hydralazine, iodoquinol, isoniazid, metronidazole, nitrofurantoin, phenytoin, ribavirin, vincristine, cimetidine, metoclopramide, amphotericin, aminoglycosides, foscarnet, antiretroviral nucleoside analogs, pentamidine, and probenecid. 

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). 

Cephalosporins Aminoglycosides Antineoplastic agents Nitrosoureas Cisplatin and analogs Radiographic contrast agents Halogenated hydrocarbons Chlorotriiluoroethylene Hexafluropropene Hexachlorobutadinene T richloroethylene Chloroform Carbon tetrachloride Maleic acid Citrinin Metals Mercury Uranyl nitrate Cadmium Chromium... 

One of many other types of carbohydrate/noncarbohydrate interactions that lead to bioactivity involves the aminoglycoside class of antibiotics, of which neamine 44 is a simple example. They bind to a specific part of the decoding region of prokaryotic ribosomal RNA to induce their activity, and this has led to the synthesis of analogs designed to have stronger binding [50]. 

---