7- aminocephalosporinic acid

The patient s serum was tested for antibodies against five penicillins and 30 different cephems (that is all types of cephalosporins), using protocols to detect drug adsorption as well as immune-complex mechanisms. His serum contained an IgM antibody that formed immune complexes with 10 of the 30 cephems. The 10 drugs were classified as oxime-type cephalosporins, that is they had a common structural formula at the C7 position on 7-aminocephalosporinic acid. This antibody did not show any cross-reactivity with five kinds of penicillins (ampiciUin, aspoxicillin, carbenicil-lin, piperacillin, sulbeniciUin). The authors asked a difficult question Why did anaphylactic shock accompany acute hemolysis Their answer was that the complex of ceftizoxime with IgM anti-ceftizoxime might act like anti-A or anti-B. This hypothesis will surely be further tested. In the meantime, it would be wise not to use the newer cephalosporins too freely. 

Access to analogues with varied side-chains at the 7-position initially posed a problem. Unlike penicillins, it proved impossible to obtain cephalosporin analogues by fermentation. Similarly, it was not possible to obtain the 7-ACA (7-aminocephalosporinic acid) skeleton (Fig. 10.44) either by fermentation or by enzymic hydrolysis of cephalosporin C, thus preventing the semisynthetic approach analogous to the preparation of penicillins from 6-APA. 

All orally active (3-lactams carry an unsubstituted or modified D-phenylglycine side group in the A-terminus position and therefore should have affinities similar to di- and tripeptides with an A-terminal D-amino acid [14]. The stereoselective transport of (3-lactam antibiotics is of particular interest because the L-isomer of aminocephalosporin failed to be absorbed in vivo to a significant extent [15]. However, a study on d- and L-enantiomers of cephalexin and loracarbef demonstrated the higher affinity of the L-isomer to oligopeptide transporter than the o-isomer (Fig. 5) [16]. Consequently, the apparent low absorption rate of L-isomers of amino cephalosporines does not appear to be due to lack of transport by the peptide transporter, but, more likely, because of the rapid enzymatic... 

Removal of the ester group afforded the cephalosporin acid (205). 7-Amino- and 7-acylaminocephalosporin esters directly substituted at position 3 with a secondary acyclic amino group or a cyclic secondary amino group were reduced in dry solvents with diborane to yield 3-unsubstituted 3-cephems. The same 3-aminocephalosporins were reacted with an alkyl or aryl Grignard reagent to afford the corresponding 3-alkyl- or 3-aryl-3-cephem esters (U.S. Patent 4,065,618). 

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