Cephamycin 7-Methoxycephalosporin

The penicillins, discovered in 1929 by Fleming together with the cephalosporins, found in 1953 are named as the classic fi-h. a. With the exception of the cephamycins (7-methoxycephalosporin ) discovered in 1971, they are formed by fungi. Thousands of semisynthetic derivatives of the classical P-h. a. have been examined in order to improve the pharmacokinetic properties and to increase the resistance against the action of /3-lactamases (bacterial enzymes that cleave the lactam ring of /3-L. a. and thus inactivate... 

The most important a-alkoxy-a-amino acid compounds are the cephamycins (7-methoxycephalosporins) (1) (5, 271), which are of considerable therapeutic significance by virtue of their activity against Gram negative bacteria. Several methods have been developed for the conversion of penicillins and cephalosporins into their 6-(7-)methoxy derivative (44). 

The synthetic availability of 7a-methoxycephalosporanic acid (103) has allowed the preparation of not only 7a-methoxycephalosporin C (104) [204,205] but also the semisynthetic cephamycins and thus, similarly to semisynthetic penicillins they are now easily obtainable. 

These efforts to find a satisfactory route to 7a-methoxycephalosporins and 6a-methoxypenicillins proved to be reasonable, in so far as the cephamycin family (A, B, C) turned out to possess an advantageous antimicrobial spectrum and activity both in vivo and in vitro, with appreciable /3-lactamase stability. The latter feature is especially conspicuous in the case of cephamycin C (111c) [196-200] (Tables 8.19-8.22). 

The discovery of cephamycins in streptomycetes fermentation broth and the announcement of their close structural relationship to cephalosporin C spurred efforts in many laboratories to develop chemical methods for methoxylating C-6 penicillins and C-7 cephalosporins. This chemistry engendered yet other methods for introducing a wide variety of substituents at this position. A number of 7-methoxycephalosporins possess interesting and useful biological activity. On the other hand, sporadic attempts to modify cephalosporins at C-2 proved more difficult and have not provided many biologically active compounds. 

Soon after the discovery of 7a-methoxycephalosporins, it became evident that cephamycin C had the best overall activity of naturally occurring cephamycins (K. A. Miller et al., I972a,b). Although not highly active against gram-positive bacteria, its spectrum of antimicrobial activity is considerably broader than that of cephalosporin C (Table VII). 

A second unique feature of these new cephem compounds is the occurrence of a 7a-methoxyl function in their structures. Antibiotics containing this moiety are known as cephamycins. Many of their features are described in the chapter (3) on 7-methoxycephalosporins in Volume 1. This functionality imparts to the 3-lactam antibiotic great resistance toward 3-lactamases. The nature of these enzymes is detailed in Volume 3, Chapter 3. 

Some ten years after the structure of cephalosporin C had been established, the isolation of two naturally occurring cephalosporins possessing a 7(a)-methoxy group was reported (149). These were identified as 7-methoxycephalosporin C (202) and the C(3)-carbamate (203). Further examples of this type of natural product have been reported and are listed in Table 7. All possess the a-aminoadipic acid side chain, but vary in the substitution pattern at C(3). Collectively they are known as the cepha-mycins (174). A major point of interest with the cephamycin type of antibiotic is their intrinsically higher resistance to hydrolysis by 3-... 

The only natural derivatives of a-hydroxy-a-amino acids found to date are the 7-methoxycephalosporins (1) (cephamycins) (271), an important class of therapeutically valuable antibiotics. 

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