Cepham antibiotics

At the beginning ofthe 1950s, resistance towards penicillin appeared for the first time on a larger scale. In particular. Staphylococci were more prone to develop resistance. Their penicillinases caused deactivation of many penam antibiotics. Cepham antibiotics with modified basic skeletons and altered side-chains offer an interesting starting point to address this issue. [26] Although a solution to this problem had already been discovered, it required several more years before effective remedies could be provided. 

The cephalosporins, discovered in the 1950s, are produced by various species of the mold Cephalosporium. Cephalosporin C (9.46) is the prototype of these antibiotics, and its structure shows a close similarity to the penam stmcture. The 5-thia-l-azabicyclo[4.2.0] octane ring system is therefore called the cepham ring. The parent compound carries the aminoadipate side chain, which can be cleaved to supply the 7-amino-cephalosporanic acid. This amine can easily be acylated and thus forms the basis of many useful derivatives. The 3-acetoxymethyl substiment is also amenable to modifications. 

The specifically 13C-enriched compounds were useful for the signal identification of the 13C NMR spectrum of this microbial product. Spectral comparison of cephalosporin C with a-aminoadipic acid-N-ethylamide, cephalexin, 3-methyl-7 (2-phenoxyacetamido)-3-cepham and 7-amino cephalosporanic acid led to the total signal identification of this antibiotic. The shifts are listed in Table 5.46. 

The naturally-occurring penicillins and cephalosporins, and thousands of their semisynthetic derivatives, are based on two fundamental structural units, the penam (1) [2] and cepham (2) [3] systems. The numbering of these bicyclic systems is different from that usual for heterocycles [4], The numbering system for penicillin is also used in the case of cephalosporins and other derivatives, including new members of the group of jS-lactam antibiotics [3]. 

Lactam Antibiotics.—Intramolecular Wittig reactions continue to be used in penam and cepham synthesis, e.g., (121). However, problems can arise. The phosphorane (122) forms the ceph-2-em (123) rather than the expected ceph-3-em and, unlike the corresponding c/j-isomers, the phosphoranes (124) do not give penams (125), but rather thiazoles and oxazolines, presumably due to the instability of the initially formed penams. ... 

Synthesis has enabled, for better or worse, the production of compounds capable of producing powerful biological responses in living organisms. Early on, these were usually natural compounds or derivatives thereof. Notable examples are the myriad of folkloric agents, the P-lactam antibiotics (e.g., cephams and penamsX steroid hormones, and paclitaxel (see below). 

Hydrolysis of cephalosporin / -nitrobenzyl esters by microbial enzymes has been described. A convenient high-yield method for preparing benzhydryl esters of penicillins and cephalosporins has been described. Diphenyl-diazomethane is generated in situ in the presence of the antibiotic by oxidation with peroxyacetic acid of benzophenone hydrazone. Diazomethane has been found to add to 3-methyl-A -cephem sulphides, sulphoxides, and sulphones preferentially from the j3-side to give the respective pyrazolino-cephams (194 b). ... 

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