Erythromycin intramolecular cyclization

The acid-instabihty of erythromycin makes it susceptible to degradation in the stomach to intramolecular cyclization products lacking antimicrobial activity. Relatively water-insoluble, acid-stable salts, esters, and/or formulations have therefore been employed to protect erythromycin during passage through the stomach, to increase oral bioavakabihty, and to decrease the variabiUty of oral absorption. These various derivatives and formulations also mask the very bitter taste of macroHdes. 

Another successhil strategy for derivatization of erythromycin employed modification of functional groups involved in intramolecular cyclizations. The C-9 ketone, C-6 hydroxyl group, C-8 proton, and/or C-ll,12-diol of erythromycin were converted into functional groups which participate poorly, if at all, in intramolecular cyclizations. Some derivatives which have been extensively evaluated in preclinical and clinical trials exhibit such desirable properties as better stabiUty under acidic conditions, greater oral bioavadabihty, and higher and more prolonged concentrations of antibiotic in semm and tissues. 

CHEMISTRY OF ERYTHROMYCIN Structure and physical-chemical data Total synthesis Intramolecular cyclization... 

Another synthetic strategy for partially or completely inhibiting intramolecular cyclization of erythromycin to hemiketal (8) and spiroketal (9) is modification of the functional groups that participate in the cyclization reactions. These groups include the C-9 ketone, C-6 hydroxyl, and C-8 proton in addition to the 11,12-diol discussed above. These approaches have led to a variety of semi-synthetic derivatives of erythromycin, some of which have been recently approved by regulatory agencies or are in late stages of clinical trials [12-17],... 

Since oximes of erythromycin are less prone to intramolecular cyclization than the parent compound, a structure-activity study was conducted on a series of 9-(0-alkyl)oxime derivatives of erythromycin [84]. From this work, roxithromycin, the 9-[D-(2-methoxyethoxy)methyl]oxime (12), was selected for further development. The isomer with E stereochemistry (oxime substituent syn to C-8 of lactone) is more active than the Z isomer [84]. The X-ray crystal structure of roxithromycin reveals a conformation of the lactone similar to that of erythromycin [85]. The similarity was also established by solution NMR studies, which suggested that the orientation of the oxime substituent helped to explain the increased hydrophobicity of roxithromycin and its greater penetration into certain tissues [86, 87]. 

Intramolecular cyclization products (8) and (9) were converted into novel 9,12-epoxy derivatives, such as A-69334 (24), which possessed better pharmacokinetic properties than erythromycin [134]. The structurally related bicyclic macrolide, L53-18A, was found in culture broths of an unidentified Saccharopolyspora species [135]. Several 8,9-difluoro-6,9-epoxy derivatives of erythromycin and 8-bromo derivatives of erythronolide B have been prepared [136, 137]. 

Modification of the C-9 ketone has been successfully accomplished in several ways. Conversion of the ketone to simple oximes was known to diminish intramolecular cyclization, but this transformation also reduced antibiotic activity. In order to increase antimicrobial activity, an expanded series of oximes was synthesized by 0-alkylation of the oxime of erythromycin with alkyl halides and base in aprotic solvents [29]. From evaluation of this series, roxithromycin, the 9-[0-(2-methoxyethoxy)methyl]oxime (see Fig. 4), was selected as the derivative with the best therapeutic index [29]. Roxithromycin has now been introduced in France as a new antibiotic. 

The cyclic 11,12-carbonate of erythromycin represents a previously recognized method for stabilization of erythromycin by maintaining an equilibrium between the 6-hydroxy-9-keto and 6,9-hemiketal forms [44]. A new direction within this approach was recently reported with a series of cyclic 11,12-carbamate derivatives of erythromycin and clarithromycin (see Fig. 5), prepared by a general sequence of 10,11-dehydration, 12-0-carbamoylation, and intramolecular cyclization [45, 46]. Other structural modifications within this part of the erythromycin molecule include 10,11-anhydroerythromycin, previously synthesized from the cyclic 11,12-carbonate [47],... 

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