14-Membered macrolides oleandomycin

Semisynthetic Derivatives. Erythromycin has been the principal subject of modification of 14-membered macrolides some of the derivatives are being commercially launched. Derivatives of erythromycin and oleandomycin include 2-U-nee ly I erythromycin (C331129NO t. 2 -O-propionylerythromycin (QoHtiNOm), erythromycin ethyl carbonate (C/0H71NO15), erytliromydn ethyl succinate (C 3H75NOi2), tn-O-acetyloleandomycin (C4iHc7NOi5), erythromycin-11,12-carbonate... 

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... 

Since the previous review by Sakakibara and Omura [1], progress has been made in the study of the modification and the stmcture-activity relationships of 1, and over the past 15 years various derivatives have been reported, as described in Sections II.B through II.D. First, however, we summarize the chemical modification of 14-membered macrolides (mainly 1) (Figs. 2 through 5 ) described in the first edition. The modification of other 14-membered macrolides, such as oleandomycins and megalomicins, have been omitted because less progress has been made on them since 1985. 

In the case of inducible MLS-resistant bacteria, their exposure to uninducible macrolides such as 16-membered-ring macrolides or certain 14-membered-ring macrolides (oleandomycin for a strain bearing the ermA gene, for example) gives rise to constitutive MLS-resistant mutants. 

Several 14-membered macrolides other than erythromycin have been discovered and characterized [16]. However, only minimal effort has been directed toward structural modification of these compounds, and the success of this effort has been limited. The structures of erythromycin and oleandomycin, those 14-membered macrolides whose structural modifications will be described in this section, are illustrated in Fig. 1. 

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). 

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],... 

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]. 

The 12-membered ring macrolides are not represented by clinical agents in the United States. The most prominent members of the 14-unit rings are the erythromycins (EM) and oleandomycins. Oleandomycin (which forms a spiro-oxirane with the C8 of EM-A) and its triacetate, has been discontinued in the United States. 

The effects of other macrolide compounds on gastrointestinal motility were also investigated in conscious dogs. Oleandomycin, which has a 14-membered ring like EM, showed about one-tenth of the activity of EM in stimulating... 

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. 

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. 

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