Gerardus J. Kemperman

Clathrate-Type Complexation of Cephalosporins withβ-Naphthol

The cephalosporin antibiotics cephalexin, cephradine, cefaclor, and cefadroxil form clathrate-type complexes with β-naphthol in the solid state (depicted here). The crystal structures and packing forces are unraveled.

In situ product removal during enzymatic cephalexin synthesis by complexation

In this paper, ‘complexation’ indicates the formation of clathrate type inclusion compounds of cephalexin with naphthalene derivatives. These inclusion compounds readily crystallise in solution, resulting in specific co-crystals of complexing agent and cephalexin with a set ratio between both components. Complexation is used for in situ product removal during enzymatic kinetic cephalexin synthesis to prevent undesired hydrolysis. In order to achieve this, beneficial reaction conditions have to be matched with conditions that are beneficial for complexation. In the work described here, a pH of 7.5 and a temperature of 293 K meet these requirements best. The results were compared to predictions obtained with a model originally developed for cephalexin synthesis and which is now extended with complexation. For 1,5-dihydroxy-naphthalene, the course of the reaction was predicted accurately. For 2-naphthol, this was not the case; synthesis was enhanced and hydrolysis reduced compared to the model predictions for immobilised enzyme. On the other hand, the course of reactions could be predicted accurately by the model for liquid enzyme. Apparently, the reduced reaction rate (30% residual activity) is such that mass transfer can keep up with it and diffusion limitation was lifted resulting in higher cephalexin concentrations. The effect of in situ complexation on productivity is discussed. It was found that complexation has a beneficial effect on overall cephalexin productivity and in most cases, hydrolysis is suppressed. The effects were most pronounced for liquid enzyme in combination with complexation with 1,5-dihydroxy-naphthalene for which, also experimentally, the highest cephalexin concentrations were measured.

Cavities, Layers, and Channels in the Hosting Framework of Molecular Complexes Derived From Cephradine

The cephalosporin-type antibiotics Cephradine, Cephalexin, and Cefaclor form clathrate-type complexes with a variety of naphthalene derivatives. The crystal structures of these complexes are isomorphous. Interestingly, the hosting framework formed by these cephalosporins can adapt to the guest molecule. This phenomenon of induced-fit appears to have a much larger potential, with the consequence that a series of smaller compounds (such as benzene derivatives) as well as bulkier compounds can also be hosted by Cephradine. When benzene derivatives were used as guests, pronounced deviations in the antibiotic framework were observed, and it is possible to induce deviations strikingly different from those found for the complexes with the naphthalene derivatives. Evidently, the hosting structure formed by Cephradine is highly flexible. Hosting frameworks containing layers, channels, and various other types of cavities can be obtained by selection of an appropriate guest molecule. Remarkably, a number of structural features and interactions remain unaffected in all these antibiotic frameworks. These persistent features seem to delineate the boundaries of framework formation for these antibiotics, thus defining the scope of complex formation.

Molecular challenges in modern chemometrics

Since the very beginning of the discipline, chemometrics has mainly focussed on analytical chemical problems such as calibration. With the growing importance of databases and applications in medicinal and computational chemistry, the domains of analytical chemistry and chemometrics have been enlarged significantly in recent years. Especially the relation between molecular structure and function has become of considerable interest. Despite the huge quantities of data that are available nowadays, it is often difficult to recognise and extract relevant chemical information for the problem at hand. One of the main obstacles is the definition of an appropriate representation of a molecule. Although a variety of different representations are used, none are generally applicable. This paper focuses on the challenges that arise in the chemometrical analysis of molecular structures, the relation between structure and function and the relation between molecular representation and chemometrical modelling. Exciting opportunities for further research are illustrated using an example concerning the prediction of co-crystallisation behaviour for small organic molecules with cephalosporin antibiotics. ©1999 Elsevier Science B.V. All rights reserved.

Complexants for the clathration mediated synthesis of the antibiotic cephradine

Enzymatic synthesis of cephalosporins is hampered by secondary hydrolysis and by complicated down-stream processing. Instantaneous removal of cephalosporin product by clathration, using an efficient and selective complexing agent, offers an attractive opportunity to tackle these problems. A series of benzene derivatives that form clathrate-type complexes with the cephalosporin antibiotics was subjected to efficiency measurements with Cephradine and enzyme inhibition studies. The best results for the antibiotic Cephradine were obtained with methyl 2-aminobenzoate, 2-hydroxybiphenyl and methyl 4-hydroxybenzoate. These three compounds are environmentally and toxicologically fully acceptable for application in a ‘green’ process.

Synthesis of Cephalosporin‐Type Antibiotics by Coupling of Their β‐Lactam Nucleus and Racemic Amino Acid Side Chains Using a Clathration‐Induced Asymmetric Transformation

The cephalosporin-type antibiotics Cephalexin, Cephradine and Cefadroxil have been prepared by coupling of their β-lactam nucleus and racemic amino acid side chain precursors. The initially obtained mixture of cephalosporin epimers is subjected to a clathration-induced asymmetric transformation which results in the epimerization of the epi-cephalosporin into the cephalosporin with the correct diastereomeric configuration.

Molecular Selectivity and Cooperativity in the Clathrate-Type Complexation of Cephradine

The cephalosporin antibiotic cephradine can form clathrate-type complexes with appropriate guest molecules. When a mixture of o- and p-disubstituted benzene derivatives is subjected to complexation with cephradine, a high preference and in some cases complete selectivity for one isomer is shown by the host molecule. It is demonstrated that clathration with cephradine is an effective method for the separation of o and p isomers. Another interesting feature is observed when a cocktail of appropriate guest molecules is used in the complexation with cephradine. The observed preference for inclusion of more than one type of complexing agent strongly points to a cooperative effect of guest molecules in the resulting complex. This cooperative effect, however, does not result in more efficient complexation − that is, a lower residual concentration of the antibiotic − which is desirable for industrial applications.

Efficiency of cephalosporin complexation with aromatic compounds

The cephalosporin antibiotics cephradine, cephalexin, cefaclor and cefadroxil form complexes with β-naphthol and several other naphthalene derivatives. In these clathrate-type complexes, the cephalosporins form the host lattice for the naphthalene derivatives. Complexation with β-naphthol analogues can be employed to withdraw cephalosporins selectively from an aqueous solution. In this process, the most important parameter is the complexation efficiency, which expresses the extent to which the cephalosporins can be withdrawn from a solution. The complexation efficiencies for a series of guest molecules are explained in terms of both the thermodynamics of the complexation reaction and the structural features of the cephalosporin complexes. In this manner, insight is gained into the subtle relationship between the molecular structure of naphthalene derivatives and the stability of their complexes with the antibiotics. It is shown which molecular properties of the guest molecules are the most important ones for an optimal complexation efficiency of cephalosporins.

Induced fit phenomena in clathrate structures of cephalosporins

The antibiotics cephalexin, cephradine, cefaclor and cefadroxil form clathrate type inclusion compounds with naphthalene derivatives that readily crystallize from an aqueous solution. In these clathrates the antibiotic molecules form the hosting lattice and the naphthalene derivatives are the guest molecules, whereby water serves as “cement”. A list of potential guest molecules was drawn up using the concept of molecular similarity. This list was extended by a series of compounds which are not supposed to fit. It was shown that a large variety of naphthalene derivatives can be hosted in clathrates with cephalexin, cephradine and cefaclor. Cefadroxil, however, is much more selective in accommodating guest molecules. Although cephalexin, cephradine and cefaclor form the principal hosting lattice and govern the overall crystal structure of the clathrates, the guest molecules are capable of inducing deviations in the framework of the host molecules, i.e. induced fit. Cefadroxil, however, lacks this adaptability due to the rigid three-dimensional hydrogen bonded structure of its hosting framework, and an exact fit of a guest molecule in the hosting framework of cefadroxil is thus required, i.e. lock and key concept. All four antibiotics have a limited adaptability by varying the number of water molecules in the clathrates. Certain guest molecules replace water in order to obtain the required space for inclusion, whereas other guest molecules cause incorporation of extra water, which is apparently beneficial for the crystal packing. However, the adaptability due to varying the water content cannot account for the remarkable flexibility in accommodating guest molecules exhibited by cephalexin, cephradine and cefaclor. The concept of induced fit is relevant for the understanding and design of clathrate type structures.

A computational model to predict clathration of molecules with cephradine

The prediction of inclusion of molecules in the hosting framework of the cephalosporin antibiotic cephradine has been investigated. For this purpose linear discriminant analysis has been applied on molecular similarity data. The way the molecular similarity is calculated appeared to be extremely important. The charge distribution similarity of two molecules calculated at optimal shape overlap, is most appropriate to derive a computational model. The predictive power of the model increases when the molecular similarity of a molecule with respect to only a limited number of guiding compounds is used. The ultimate outcome is that complexing behaviour of a molecule can be predicted using a simple equation containing the similarity indices of that molecule with respect to three guiding compounds only. The model eventually obtained can predict the complexing behaviour of independent test sets of molecules with an average score of 86%.