Macrocyclic glycopeptides Teicoplanin

The macrocyclic glycopeptide Teicoplanin has been used very successfully by Irv Wainer and his group at Georgetown University, to monitor the enantiomers of Albuterol in blood plasma. Albuterol (supplied under the names of Proventil and Ventolin) is used to dilate breathing passages and make breathing easier. It is often used to prevent bronchospasm in certain cases of lung diseases. 

Macrocyclic glycopeptides. The first of these CSPs - based on the cavity of the antibiotic vancomycin bound to silica - was introduced by Armstrong [25]. Two more polycyclic antibiotics teicoplanin and ristocetin A, were also demonstrated later. These selectors are quite rugged and operate adequately in both normal-phase and reversed-phase chromatographic modes. However, only a limited number of such selectors is available, and their cost is rather high. 

Fig. 2-1 Proposed structures of three macrocyclic glycopeptides. On teicoplanin, R = 8-methyl-nonanoic acid.

Berthod, A. et al.. Evaluation of the macrocyclic glycopeptide A-40,926 as a high-performance liquid chromatographic chiral selector and comparison with teicoplanin chiral stationary phase, J. Chromatogr. A, 897, 113, 2000. 

Two EPMEs based on macrocyclic glycopeptide antibiotics—vancomycin and teicoplanin—were designed for the assay of acetyl-L-carnitine [44]. The linear concentration ranges for the proposed electrodes were 10 5-10-2 mol/L for the vancomycin-based electrode and 10 4-10-2 mol/L for the teicoplanin-based electrode, with slopes of 58.1 and 55.0mV/p(acetyl-L-camitine), respectively. The enantioselectivity was determined over D-carnitine. 

Two EPMEs were proposed for the assay of R-baclofen. The electrodes were designed using macrocyclic glycopeptide antibiotic, teicoplanin [45]. Acetonitrile was added to the teicoplanin to design a modified teicoplanin-based electrode. The linear concentration ranges for the proposed enantioselective, membrane electrodes were 10 7-10 4mol/L for teicoplanin-based electrode and 10 6-10 4mol/L for the electrode based on teicoplanin modified with acetonitrile. The slopes of the electrodes were 60.0 and 57.2 mV/pR-baclofen for teicoplanin and teicoplanin modified with acetonitrile-based electrodes, respectively. The enantioselectivity was determined over S-baclofen. The proposed electrodes can be employed reliably for the assay of R-baclofen raw material and from its pharmaceutical formulation, Norton-Baclofen tablets. 

Three EPMEs based on macrocyclic glycopeptide antibiotics— vancomycin and teicoplanin (modified or not with acetonitrile)—were proposed for the determination of l- and D-enantiomers of methotrexate (Mtx) [48]. The linear concentration ranges for the proposed enantioselective membrane electrodes were between 10 6 and 10-3 mol/L for l- and D-Mtx. The slopes of the electrodes were 58.00 mV/pL-Mtx for vancomycin-based electrode, 57.60 mV/pD-Mtx for teicoplanin-based electrode and 55.40 mV/pD-Mtx for teicoplanin modified with acetonitrile-based electrode. The detection limits of the proposed electrodes were of 10 8 mol/L magnitude order. All proposed electrodes proved to be successful for the determination of the enantiopurity of Mtx as raw material and of its pharmaceutical formulations (tablets and injections). 

Figure 10.6. Structures of the macrocyclic glycopeptide chiral selectors vancomycin (A) and teicoplanin (B).

The antibiotics vancomycin (shown in Table 1), teicoplanin, and ristocetin A can be bonded to silica, giving a unique class of macrocyclic glycopeptide CSPs. They can be used in the normal-phase mode with a nonpolar eluent as well as in the reversed-phase mode with an aqueous eluent. They show unique selectivity for a large number of analytes. Figure 3 gives an example with the separation of the antidepressant citalopram and its metabolites on a vancomycin CSP. 

Figure 4.16 Chemical structures of the macrocyclic glycopeptide antibiotics (a) vancomycin, (b) teicoplanin, (c) avoparcin, (d) ristocetin A, that have been used as chiral selectors in CSPs for HPLC. Reproduced from Ward and Farris, J. Chromatogr. A 906 (2001), copyright (2001), with permission from Elsevier.

We performed this difficult study using the Supelco Chirobiotic0 CSPs based on macrocyclic glycopeptide selectors. The system parameters, e, s, a, b, and v, of the four different columns, namely ristocetin, vancomycin, teicoplanin, and teicoplanin aglycon, were obtained for six different normal heptane-ethanol mobile phases and ten different acetonitrile or methanol-water reversed mobile phases [47, 48]. The 44 achiral probe solutes contained aldehydes, ketones, amides, halogenated phenols, nitro-substituted benzenes, and nitro-alkanes. About 2,400 chromatograms were needed to obtain the 5 fl-v system parameters for the 4 CSP columns and the 16 mobile phases [47]. 

In recent years, the application of macrocyclic glycopeptide CSPs has been expanded to SFC, and teicoplanin aglycone phase (Chirobiotic TAG) was found to be the most effective closely followed by teicoplanin CSP (Chirobiotic T) [144, 184]. Because of a large number of polar groups available on the Chirobiotic CSPs, it is often required to work with considerable amount of polar additives in the mobile... 

This chapter will focus on chiral recognition mechanisms and molecular interactions. The commercialized macrocyclic glycopeptides ristocetin, R, vancomycin, V, teicoplanin, T and its aglycon form, teicoplanin aglycon, TAG will be the main subject of the study since a large database is available in the literature [3-7]. However, non-commercialized avoparcin, balhimycin, and the recently introduced eremomycin macrocyclic glycopeptides [8] are also included in the study for more information on possible mechanisms. 

The enantioselectivity and enantioresolution factors obtained on the ristocetin A selector are lower than the corresponding ones obtained on teicoplanin and TAG selectors. Eremomycin, a recently introduced macrocyclic glycopeptide very close... 

The picture is completely different when the carboxylic acid group is considered. As an absolute rule, any derivation of this group cancels the enantiomer separation of the amino acid derivatives on macrocyclic glycopeptide CSPs. This point is illustrated by the methyl esterification of phenylalanine and tryptophan canceling enantioselectivity on teicoplanin and TAG CSP (data not found on eremomycin). Similarly, the two phenylalanine amide enantiomers cannot be separated on any CSP (Table 2). 

The specificity of the amino acid charge-charge docking interaction must be pointed out. Non-amino acid enantiomers could still be separated by vancomycin and teicoplanin column in presence of copper ions clearly showing the multiple possible mechanisms of the macrocyclic glycopeptide selectors. The two enantiomers of tryptophan ethyl ester, a carboxylic acid blocked amino acid, could be separated on a ristocetin A chiral column in polar organic mode [16]. The separation did not involve the secondary amine on the macrocycle but other possible multiple interactions with the ristocetin A selector. 

Figure 1 selected the teicoplanin aglycon selector as the central molecular structure to clearly show the basket structure of the macrocyclic glycopeptide family. All naturally produced macrocyclic antibiotics bear several carbohydrate units whose primary role seems to be the enhancement of water solubility of the central... 

The macrocyclic glycopeptide chiral selectors are now a very important class of CSPs that must be part of the column set of any laboratory involved in enantiomeric separations. The variety of functionalities found in these relatively small molecules allow for many different interactions leading to successful enantioseparations [29]. The similarities between members of this class of chiral selectors produced the complementary separation property [14, 30, 31]. If a partial separation of an enantiomeric pair is observed on a macrocyclic selector, say vancomycin, a baseline separation may very likely be observed on a different selector, say teicoplanin. This interesting property in method development illustrates the large number of selector-selectand possible interactions. Such complementarities are due to the... 

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