Macrolide antibiotics, glycosidic

Macrolide antibiotics are glycosides with a macrocyclic lactone aglycon, which is formed in the polyketide biosynthetic pathway [38,39]. The lactone ring is 12-, 14-, 16-, or 18-mem-bered. The polyoxo-macrolides such as the classical antibiotic erythromycin are produced by streptomyces microorganisms and form a clinically important group of polyketide antibiotics. Erythromycin (O Fig. 5) is the major component out of a mixture of macrolide antibiotics which is formed by Saccharopolyspora erythraea. It contains two deoxysugars attached to the aglycon, L-cladinose and D-desosamine. 

The macrolide antibiotics are characterized by possessing molecular structures that contain large (12-16-membered) lactone rings linked through glycosidic bonds with amino sugars. 

P2j Z = 2 D = 1.17 R = 0.080 for 3,888 intensities. This is aconfigu-rational analysis of the macrolide antibiotic 23672RP from Streptomyces chryeus. All three sugar residues are pyranoid the conformation of the a-ketose is CX, with Q = 56 pm, 0 = 9° that of the / -D-mycinose (6-deoxy-2,3-di-0-methyl-D-allose) is 4Clt with Q = 59 pm, 0 = 6° and that of the / -L-mycarose (2,6-dideoxy-3-C-methyl-L-riho-hexose) is 1C4, with Q = 53 pm, 0= 177°. The O-5-C-l-O-l-C glycosidic torsion-angles are —71, —87, —83°. The atomic coordinates reported in the paper refer to the opposite enantiomer. 

Cyclic carbonic esters were also prepared, for example, from the cardiac glycoside proscillaridine[257] (where besides CDI the benzyloxycarbonylimidazole was successfully used), ingenol, 2581 the macrolide antibiotic tylosine,[259] and an erythromycin A derivative.12601... 

The importance of fermentation-derived antibiotics in veterinary medicine continues to increase. The following two classes of antibiotics, the macrolides and glycosides, were all obtained as metabolites of various Streptomyces species. 

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. 

Glycosidation of simple and complex aglycones without the need for protection of the hydroxy groups in the donor (e.g., macrolide antibiotics)... 

Complex glycosylated compounds like macrolides, anthracyclines, aureolic acids, cardiac glycosides, orthosomycines and tetronic acids are of considerable scientific as well as pharmaceutical interest. Obviously, each of them is responsible for certain therapeutic effects with respect to different diseases. Anthracyclines and aureolic acids are applied in cancer chemotherapy, orthosomycines are active as antibiotics against Gram-positive bacteria, and the cardiac glycosides are used in the treatment of cardiac insufficiency. 

D-Amicetose (173) is a constituent of the antibiotics of the antibiotics amice-tin,252 axenomycin,253 dutomycin,254 and polyketomycin.255 Amicetin is produced by Streptomyces spp. and the structure described in 1962.1,256 In polyketomycin (175) and dutomycin, the 3-C-methyl branched sugar L-axenose is a-(l ->4)-linked to amicetose,257 whereas in axenomycin, a macrolide antibiotic, the two deoxy sugars are p-linked in reverse order. Mild methanolysis (0.05 M HC1, rt) of axenomycine B gave among other products the glycoside 176.253... 

The aglycon of avermectin has poor antiparasitic activity. Positions 4 and 4" of the olean-drose moieties were modified partly because of feasibility. The synthesis of the 4 -amino-4 G deoxyoleandrose derivative of avermectin Bi and ivermectin was based on the observation that most macrolide antibiotics contained a basic amino group [61]. One of the derivatives, 4 -e/7t-acetamido-4 -deoxyavermectin Bi, is currently under development as a novel avermectin endectoside [61]. Besides, also 2"-a-fluoro (ax.) and 2"- 8-fluoro (eq.) derivatives of avermectins were prepared to strengthen the glycosidic bond. These derivatives have interesting activities in some bioassays compared to the parental compounds [62]. 

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