Cephalosporin derivatives hydrolysis

A number of interesting studies of lactam hydrolysis have been published. The metal(II)-catalyzed hydrolysis of some penicillin and cephalosporin derivatives displays saturation kinetics.410"412 A 1 1 complex is formed between the metal ion and penicillin which undergoes base hydrolysis up to 10s times faster than the free ligand. The catalytic activity follows the order Cu,>ZnII>NiII = Co11. Coordination of penicillin to copper(II) is believed to occur via the /3-lactam nitrogen and the carboxylate group (121)4l0-4n but other sites have been proposed.413... 

Although the C -amide cephalosporin derivatives showed increased stability as compared with the C -esters, they were still somewhat unstable. As an example, (16-7) had t,/2 values for hydrolysis at pH 8 (25°C) and for... 

There are a number of methods in use that directly detect the production of antimicrobial resistance in pathogens. /3 -Lactamase production can be detected rapidly and easily in the clinical laboratory with the use of nitrocephin disks. Nitrocephin is a chromogenic cephalosporin derivative that changes color on hydrolysis by /3-lactamase. Colonies from a growing bacterial culture can be touched to a disk, with /S-lactamase production noted within a few minutes. Although rapid and reliable, this method is limited to the assessment of strains of staphylococci, enterococci, H. influenzae, Moraxella catarrhalis, and N. gorwrrhoeae. The nitrocephin disk also cannot detect /3-lactam... 

The metallo-(3-lactamases hydrolyze a series of p-lactam antibiotics, such as penicillin and cephalosporin derivatives. making them harmless to pathogenetic bacteria. Thus, it is important to study the hydrolysis mechanism and prepare a clinically useful inhibitor. According to the three-dimensional structure of a zinc p-lactamase from Bacteroides fraglis, there are two zinc binding sites, where the two zinc ions, Znl and Zn2, are 3.5 A apart and bridged by one hydroxide group and Znl and... 

The effects of structural changes on the rates of alkaline hydrolysis of penicillin and cephalosporin derivatives are summarised in Table 4. 

Early work on the reactivity of the acetoxy grouping in (179) showed that displacement reactions occurred fairly readily with certain heterocyclic tertiary bases (139), while hydrolysis to deacetylcephalosporin C was readily effected using an acetyl esterase (140). The structure elucidation of this first cephalosporin derivative in 1961 has been followed by the discovery of a number of other natural metabolites produced by fungi and various actinomycete species. The various structures are listed in Table 6. Aspects of the history, chemistry and biology of the group are covered in the extensive review edited by Flynn (6). 

In these papers, the carboxylic acid to be protected was a stable, unsubstituted compound. Harsh conditions were acceptable for both formation and cleavage of the amide. Typically, a simple secondary amide is very difficult to cleave. As the pKa of the conjugate acid of an amide decreases, the rate of hydrolysis of amides derived from these amines increases. The dimethylamide of a cephalosporin was prepared as follows using 2,2 -dipyridyl disulfide. ... 

In some cases enzymes can increase the rate of reaction by up to lO times. Carnell and Roberts (1997) have briefly discussed the scope of biotransformations that are used to make pharmaceuticals like penicillins, cephalosporines, erythromycin, lovastatin, cyclosporin, etc., and for food additives like citric acid, L-glutamate, and L-lysine. A very successful transformation by Zeneca has been that of benzene reduction, with Pseudomonase Putida, to dihydrocatechol and catechol the dihydro derivative is used to produce (+/-) pinitol. Fluorobenzene has been converted to fluorodihydrocatechol, an intermediate for pharmaceuticals. The highly stereo selective Bayer-Villeger reaction has been carried out with genetically engineered S-cerevisvae. Hydrolases have allowed enantioselective, and in some cases regioselective, hydrolysis of racemic esters. 

Some cephalosporins can be both substrates and inhibitors of /3-lactamases. The acyl-enzyme intermediate can undergo either rapid deacylation (Fig. 5.4, Pathway a) or elimination of the leaving group at the 3 -position to yield a second acyl-enzyme derivative (Fig. 5.4, Pathway b), which hydrolyzes very slowly [35][53], Thus, cephalosporins inactivate /3-lactamases by a mechanism similar to that described above for class-II inhibitors. It has been hypothesized that differences in the rate of deacylation of the acyl-enzyme intermediates derive from their different abilities to form H-bonds. A H-bond to NH in Fig. 5.4, Pathway a, may be necessary to assure a catalytically essential conformation of the enzyme, whereas the presence of a H-bond acceptor in Fig. 5.4, Pathway b, may drive the enzyme to an unproductive conformation. The ratio between hydrolysis and elimination, and, consequently, the relative importance of substrate and inhibitor behaviors of cephalosporins, is determined by the nature of the leaving group at C(3 ). An appropriate substitution at C(3 ) of cephalosporins may, therefore, increase the /3-lactamase inhibitory properties and yield potentially better antibiotics [53]. 

Semi-synthetic penicillins are accessed from 6-aminopenicillanic acid, (6-APA), derived from fermented penicillin G. Starting materials for semi-synthetic cephalosporins are either 7-aminodesacetoxycephalosporanic acid (7-ADCA), which is also derived from penicillin G or 7-aminocephalosporanic acid (7-ACA), derived from fermented cephalosporin C (Scheme 1.10). These three key building blocks are produced in thousands of tonnes annually worldwide. The relatively labile nature of these molecules has encouraged the development of mild biocatalytic methods for selective hydrolysis and attachment of side chains. 

Chemical or enzymatic hydrolysis of this compound allows to obtain large quantities of 7-aminocephalosporanic acid. A number of semisynthetic beta-lactam cephalosporin antibiotics were created by acylating the amino group of the last with various acid derivatives (analogous to the semisynthetic penicillin series) and currently there are about 25,000 of them, of which about 100 are used in medicine. Unlike penicillins, semisynthetic cephalosporins are synthesized not only by expanding the spectrum of various acids by which 7-aminocephalosporanic acid is acylated, but also by internal modifications of aminocephalosporanic nucleus (Rj and Rj). 

The term / -lactamase denotes an enzyme which catalyzes the hydrolysis of the amide bond in the /3-lactam ring of 6-amino-penicillanic acid (6-APA) or 7-amino-cephalosporanic acid (7-ACA) and of their A-acyl derivatives (2). Such derivatives are commonly referred to as penicillins [Fig. 1 (I) and cephalosporins Fig. 1 (III), (V), and (VII)], respectively. There is no evidence that any bond other than the amide bond in the intact nucleus of penicillin or cephalosporin is broken by the... 

The different anhydride and thioanhydride derivatives may be regarded merely as intermediates useful for obtaining amides and esters. The penicillin anhydrides were synthesized long ago [105,106]. Some cephalosporin anhydrides too were described recently [106]. Cephalothin anhydride (72a) was reported to be effective against S. aureus Smith in a dose of 0.24 figlml. Assuming quantitative hydrolysis, the antimicrobial... 

Model studies for metallo- 3-lactamases have been performed using mononuclear zinc hydroxide complexes.99,129,130 The breadth of (3-lactam hydrolysis reactivity of hydro-tris(pyrazolyl)borate-ligated mononuclear zinc hydroxide complexes has been explored.129 Treatment of the mononuclear zinc hydroxide complex [(Tpph Mc)Zn OH] with simple 3-lactams ( 3-propiolactam, 4-phenyl-(3-propiolactam, Scheme 21) does not result in ring opening, but instead results in the formation of 3-lactamide complexes and water. Treatment of [(Tpph,Me)Zn-OH] with /V-alkyl or -aryl 3-lactam derivatives instead results in no reaction (Scheme 21). Use of natural derivatives of penicillin and cephalosporin (Scheme 22) did not yield 3-lactam hydrolysis, but instead coordination of the carboxylate moiety of the antibiotic derivatives to the mononuclear Zn(II) center and release of water. 

---