Macrolide antibiotics oleandomycin

The /hc and /hh couplings have been used by Novak et al in the conformational analysis of the 14-membered macrolide antibiotic oleandomycin and its 8-methylene-9-oxime derivative, and by Hayakawa et al in the structure elucidation of an antitumor antibiotic, tyroscherin (see also Table 3). 

Paterson s synthesis of oleandolide, the aglycon of the macrolide antibiotic oleandomycin, relied on an analogous use of macrocyclic stereocontrol for the introduction of an epoxide late in the route (Equation 5) [20]. The reaction between ketone 48 and trimethylsulfonium ylide thus furnished epoxide 49 in 83 % yield and dr >97 3. 

The sequential use of Panek s allyl silane reagents 137 and 138 provides convenient, rapid access to complex propionate subunits. The total synthesis of oleandolide (151), the aglycone of the macrolide antibiotic oleandomycin, demonstrates the tactical advantages of using these reagents (Scheme 5.25) [103]. Four sequential diastereoselective allylation reactions provided products 144, 147, 148, and 150 with excellent stereocontrol (dr s 20 1). 

Oleandomycin is a macrolide antibiotic produced by Streptomyces antibi-oticus. Oleandomycin and its triacetylated form, troleandomycin, are less effective than erythromycin against staphylococcal infections. They are usually administered orally or intravenously intramuscular administration is avoided because of the pain and tissue irritation it induces. Oleandomycin is also used in intramammary treatments and as a feed additive for growth promotion purposes. 

Cyclization via intramolecular olefination of complex phosphonates remains the most important method of synthesis for complex natural macrocycles. Examples include syntheses of 20-membered macrolide antibiotic, aglycones of venturicidins A and B,108 oleandomycin (a 14-membered macrolide antibiotic), 109 the 19-membered macrocyclic antibiotic, anti-tumour agent (-t-)-hitachimycin,ll0 and the macrocyclic lactones (183).1H Cyclization of the phosphonate (184) under Masamune-Roush conditions has been used to synthesize the 28-membered macrolactam myxovirescin B.112... 

More than 500 different representatives of the macrolide antibiotics are known, most of which are biologically active against Gram-positive bacteria, displaying a relatively low toxicity. Clinically used are erythromycin, oleandomycin, carbomycin and leucomycin (O Fig. 5). They act as inhibitors of the bacterial protein biosynthesis by binding to the 50S-ribosomal subunit. The synthesis of the two clinically important 16-membered ring macrolide antibiotics leucomycin A3 and carbomycin B could be started from D-glucose, which was chosen because it contained three of the required stereocenters [40]. 

These findings are interpreted to indicate that erythromycin resistance mutation in domain II caused an increase in the peptide and disrupted an indirectly functional interaction between domains II and V, because such a mutation could affect alteration of the stability of a secondary rRNA structure (hairpin sequence structure) in domain II. In addition, the Shine-Dalgamo (SD) sequence of the rRNA-encoded E-peptide ORE is sequestered in the hairpin structure. Thereby, SD and E-peptide codon are not accessible to ribosomes of wild-type E. coli. The conformational change of the hairpin structure by erythromycin resistance mutation can be recognized by ribosomes for the initiation of translation of E-peptide. Thus, the increase of the peptide is expected to show resistance to macrolide antibiotics such as erythromycin, oleandomycin, and spiramycin but not clindamycin and chloramphenicol without preventing their binding to the target. 

Motilin, a 22-amino acid peptide hormone found in the GIM cells and some entervchromajfin cells of the upper small bowel, is a potent contractile agent of the upper GI tract. The effects of motilin can be mimicked by erydiromycin and by other macrolide antibiotics (see Chapter 46), including oleandomycin, azithromycin, and clarithromycin. 

Celmer [200,201] reported a stereochemical and biogenetic model for the lactone ring of macrolide antibiotics such as oleandomycin, erythromycin and leucomycin. On the other hand, the structural similarity between the carbon skeleton (from C-5 to C-14) of the ansa chain of ansamycins, such as the rifamycins and the streptovaricins, and the lactone ring (from C-3 to C-12) of the macrolide antibiotics was also pointed out [1]. 

C7H14O4, Mr 162.19, cryst., mp, 62-63°C, [a] +13° (H2OX The deoxy sugar of the toxic glycoside olean-drin (oleandrigenin a-L-oleandroside, from oleander leaves) and of macrolide antibiotics such as the aver-mectins and oleandomycin. 

The macrolide antibiotics are a group of compounds which have as a nucleus a ma-crocyclic lactone ring to which one or more sugars are attached. These sugars are essential for the antibiotic activity. Only three of the macrolides, i.e., erythromycin, oleandomycin, and spiramycin are used in human clinical practice, while a fourth, tylosin, is used in veterinary medicine and as a food preservative in industrial canning. These are all weakly alkaline and only slightly soluble in water. Erythromycin is the most active antibiotic of this group (Fig. 7). All of them are able to inhibit bacterial protein synthesis and are characterized by their bacteriostatic qualities. The antibacterial spectrum is similar to that of benzylpenicillin. 

Oleandomycin, a 14-membered ring macrolide antibiotic, was isolated in 1956 from fermentation broths of Streptomyces antibioticus [360]. Some years later, oleandomycin was assigned the structure 340 on the basis of its chemical degradation [361]. Oleandomycin is effective, but less potently, against the same spectrum of bacteria as erythromycin, namely Gram-positive bacteria such as staphylococci, streptococci, and pneumococci. The antimicrobial activity of oleandomycin, when combined with tetracycline, is potentiated. In fact, in such a combination it is sold as an antibacterial agent for upper and lower respiratory tract infection. 

MaerolldM, macrolide antibiotics a group of antibiotics from various strains of Streptomyces, all with the same complex macrocyclic structure. M. inhibit protein synthesis by blocking transpeptidation, and translocation on the 50S ribosomal subunit (similar to Chloramphenicol, see). Examples of M. are erythromycin (Fig.), spiramycin, oleandomycin, carbo-mycin, angolamycin, leucomycin, picromycin. Almost all M. are used therapeutically as broad spectrum antibiotics. 

J. Zhou, Y. Chen and R. Cassidy, Separation and determination of the macrolide antibiotics (erythromycin, spiramycin and oleandomycin) by capillary electrophoresis coupled with fast reductive voltammetric detection. Electrophoresis, 2000, 21, 1349-1353. 

Erythromycin, from the actinomycete Saccharo-polyspora (formerly Streptomyces) erythraea, is the first member of this family of antibiotics to be marketed and successfully used clinically to treat infections in humans. It has an antimicrobial spectrum at least as wide as the penicillins, and interestingly, from our perspective, it is often used as a replacement for patients allergic to that group of drags. Besides erythromycin, other members of the macrolide family of antibiotics that are clinically useful include azithromycin, clarithromycin, dirithromycin, roxithromycin, telithromycin (these six are approved by the FDA), oleandomycin, and spiramycin. Clarithromycin, dirithromycin, and roxithromycin and the azalide azithromycin are more recent members of the group and can be regarded as newer generation macrolide antibiotics. 

Properties of some of the macrolide antibiotics are given in Table II. The same sugars are found in a number of different substances. Most of these sugars had not previously been encountered but oleandrose, obtained from oleandomycin, had been found in the cardiac glycoside oleandrin. 

Macrolide and lincosamide antibiotics are weakly basic compounds slightly soluble in water but readily soluble in common organic solvents. They are most composed of several closely related components that may vary in proportion depending upon the source of the formulation. Macrolides other than oleandomycin are stated to be unstable at both acidic and basic aqueous solutions. 

The macrolides form an important group of clinically useful antibiotics. Older members include erythromycin (6), oleandomycin, triacetyloleando-mycin and spiramycin, now joined by clarithromycin (44), roxithromycin (45) and azithromycin (46) [196]. Enterobacteria which show a high level of insusceptibility to erythromycin can inactivate the antibiotic by plasmid-encoded esterases that hydrolyse the lactone ring [197],... 

Among the many antibiotics isolated from the actinomycetes isthe group of chemically related compounds called the mac-mlides. In I9S0, picromycin, the first of this group to be identified as a macrolide compound, was first reported. In 1952. erythromycin and carbomycin were reported us new antibiotics, and they were followed in subsequent years by other macrolides. Currently, more than 40 such compounds ate known, and new ones are likely to appear in the future. Of all of these, only two, erythromycin and oleandomycin, have been available consistently for medical use in the United States. In recent years, interest has shifted away from novel macrolides isolated from soil samples (e.g.,. spiramycin, josamycin, and rosamicin), all of which thus far have proved to be clinically inferior to erythromycin and semisynthetic derivatives of erythromycin (e.g., clarithromycin and azithromycin), which have superior pharmacokinetic properties due to their enhanced acid stability and improved distribution properties. 

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