51818-85-0Relevant articles and documents
Modulation of the microenvironment surrounding the active site of penicillin g acylase immobilized on acrylic carriers improves the enzymatic synthesis of cephalosporins
Bonomi, Paolo,Bavaro, Teodora,Serra, Immacolata,Tagliani, Auro,Terreni, Marco,Ubiali, Daniela
, p. 14349 - 14365 (2014/01/06)
The catalytic properties of penicillin G acylase (PGA) from Escherichia coli in kinetically controlled synthesis of β-lactam antibiotics are negatively affected upon immobilization on hydrophobic acrylic carriers. Two strategies have been here pursued to improve the synthetic performance of PGA immobilized on epoxy-activated acrylic carriers. First, an aldehyde-based spacer was inserted on the carrier surface by glutaraldehyde activation (immobilization yield = 50%). The resulting 3-fold higher synthesis/hydrolysis ratio (vs/vh1 = 9.7 ± 0.7 and 10.9 ± 0.7 for Eupergit C and Sepabeads EC-EP, respectively) with respect to the unmodified support (vs/vh1 = 3.3 ± 0.4) was ascribed to a facilitated diffusion of substrates and products as a result of the increased distance between the enzyme and the carrier surface. A second series of catalysts was prepared by direct immobilization of PGA on epoxy-activated acrylic carriers (Eupergit C), followed by quenching of oxiranes not involved in the binding with the protein with different nucleophiles (amino acids, amines, amino alcohols, thiols and amino thiols). In most cases, this derivatization increased the synthesis/hydrolysis ratio with respect to the non derivatized carrier. Particularly, post-immobilization treatment with cysteine resulted in about 2.5-fold higher vs/vh1 compared to the untreated biocatalyst, although the immobilization yield decreased from 70% (untreated Eupergit C) to 20%. Glutaraldehydeand cysteine-treated Eupergit C catalyzed the synthesis of cefazolin in 88% (±0.9) and 87% (±1.6) conversion, respectively, whereas untreated Eupergit C afforded this antibiotic in 79% (±1.2) conversion.
Influence of substrate structure on PGA-catalyzed acylations. Evaluation of different approaches for the enzymatic synthesis of cefonicid
Terreni, Marco,Tchamkam, Joseph Gapesie,Sarnataro, Umberto,Rocchietti, Silvia,Fernandez-Lafuente, Roberto,Guisan, Jose M.
, p. 121 - 128 (2007/10/03)
The influence of the substrate structure on the catalytic properties of penicillin G acylase (PGA) from Escherichia coli in kinetically controlled acylations has been studied. In particular, the affinity of different β-lactam nuclei towards the active site has been evaluated considering the ratio between the rate of synthesis (vs) and the rate of hydrolysis of the acylating ester (vhl). 7-Aminocephalosporanic acid (7-ACA) and 7-amino-3-(1-sulfomethyl-1,2,3,4-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (7-SACA) showed a good affinity for the active centre of PGA. The enzymatic acylation of these nuclei with R-methyl mandelate has been studied in order to evaluate different approaches for the enzymatic synthesis of cefonicid. The best results have been obtained in the acylation of 7-SACA. Cefonicid (8) was recovered from the reaction mixture as the disodium salt in 65% yield and about 95% of purity. Furthermore, through acylation of 7-ACA, a "one-pot" chemo-enzymatic synthesis was carried out starting from cephalosporin C using three enzymes in sequence: D-amino acid oxidase (DAO), glutaryl acylase (GA) and PGA. Cefonicid disodium salt was obtained in three steps, avoiding any intermediate purification, in 35% overall yield and about 94% purity. This approach presents several advantages compared with the classical chemical processes.
Spirocyclic Side-chain Derivatives of Penicillin and Cephalosporin
Sammes, Peter G.,Smith, Steven,Ross, Barry C.
, p. 2117 - 2124 (2007/10/02)
A series of two spirocyclic oxazolidinone derivatives of penicillin and four derivatives of cephalosporin have been prepared, as well as a benzoxazine conjugate of cephalosporin, with the object of freezing the conformation of the 6(7)-amide side-chain bearing a pendant aromatic ring.The antibacterial properties of these derivatives are discussed.
