Glycopeptide antibiotics ristocetins

Scheme 2.1 General synthetic schemes for the immobilization of macrocyclic antibiotics. (a) (i) 1,6-Diisocyanatohexane (ii) glycopeptide (TE, TAG, and A-40,926). (b) (i) Glycopeptide (eremomycin, ristocetin A, vancomycin), (c) (i) NaI04 (ii) glycopeptide (vancomycin, ristocetin A, MDL 63,246). (d) (i) 3-Isocyanatopropyl-silyl derivative of macrocyclic antibiotic (TE, rifamycin B, vancomycin, DMP-vancomycin, NVC).

The use of macrocyclic antibiotics as chiral selectors for HPLC was first proposed by Armstrong et al. [50] in 1994. The most successful of the CSPs are based on the glycopeptide antibiotics vancomycin, teicoplanin and ristocetin A and are commercially available through Advanced Separation Technologies Inc. (Astec Inc.) as Chirobiotic V , Chirobiotic 1 and Chirobiotic R , respectively. More recently, a number of other derivatives of these antibiotics have also been developed offering different stereoselectivities. A comprehensive handbook is now available from Astec Inc. [51 ] alongside a number of recent review articles... 

Figure 1.3 Chemical structures of glycopeptides antibiotics vancomycin (1) [1], eremomycin (2) [15a], ristocetin A (3) [15b], and teicoplanin (4) [15c],...

The SARs of glycopeptide antibiotics have mostly been studied with vancomycin and teicoplanin. Some other examples also comprise the glycopeptides eremomycin, baMmycin, ristocetin, and avoparcin. The reasons for the predominance of vancomycin and teicoplanin are that, particularly vancomycin (Vancomycin, Eli Lilly and Company) and teicoplanin (Targocid, Lepetit, Italy), are industrial large-scale fermentation products, and most of these studies were performed within research programs or with the participation of researchers from Eli Lilly and Lepetit. 

Glycopeptide antibiotics have been found to be very effective chiral selectors in the enantiomeric separation of racemic pharmaceutical compounds. Vancomycin, ristocetin A, rifamycins, teicoplanin, kanamycin, streptomycin, and avoparcin have been added to the running buffer to obtain enantioseparation (161,203— 207). A few technical modifications, such as coated capillaries and separation conditions in the reverse polarity mode (as opposed to normal polarity mode, where the flow is from anode to cathode) were found to improve sensitivity and increase efficiency (116,208). 

Biaryl structures are wide-spread in many of naturally occuring products including alkaloids, lignans, terpenes, flavonoids, tannins, as well as polyketides, coumarins, peptides, glycopeptides, etc. For example, vancomycin (1) is a basic structure of several related glycopeptide antibiotics [1] balhimycin, actinoidin A, ristocetin A, teicoplanin A2-2, complestatin, etc which are important in medicinal chemistry or as a HPLC chiral stationary phases (vancomycin) [2]. 

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.

Since first demonstration in 1994 of the potential use of macrocyclic antibiotics as chiral selectors in analysis, glycopeptide antibiotics have been successfully applied for enantiomer separations by liquid chromatography, as recognition components of chiral stationary phases, and by capillary electrophoresis (CE) as soluble chiral selec-tors. Four chiral stationary phases for chromatography with the selectors vancomycin, ristocetin, teicoplanin, and the teicoplanin aglycone are commercialized under the trade name Chirobiotic by Astec and Supelco. Various aspects of analytical applications of glycopeptide antibiotics have been extensively covered in the recent reviews cited above. As an example. Table 2 shows some representative results for CE enantioseparations with vancomycin, ristocetin A, and teicoplanin, which were taken from Ref. 39. 

Degradation of the avoparcin complex, a glycopeptide antibiotic mixture related to vancomycin and ristocetin, has yielded a variety... 

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. 

Non steroidal antiinflammatory drugs were among the first classes of chiral compounds investigated in the early stages of the application of macrocyclic antibiotics as chiral selectors therefore, they were screened on vancomycin [7], teicoplanin [30], ristocetin A [33] CSPs under RPmode systems, and on avoparcin CSP under NP mode systems [37]. The enantioresolution of a variety of pro fens was later reported on commercially available vancomycin CSPs [128, 168], and recently on a ME-TAG CSP [58]. Ibuprofen enantiomers were also separated on a CDP-1-containing CSP [55]. Glycopeptide A-40,926 CSP was successfully employed in the analytical and semipreparative separation of 2-arylpropionic acids [63]. 

In addition to the vancomycin and teicoplanin CSPs, ristocetin A (Chirobiotic R) [289] and recently avoparcin [280] have been evaluated as novel chiral SOs and CSPs. It turned out that within the large family of macrocyclic antibiotics complementarity of enantioselectivity exists for different glycopeptides. As a consequence, very often it is possible to obtain a complete resolution by switching to a congeneric antibiotic CSP, if after optimization no baseline, but partial. separation can be achieved on a certain macrocyclic antibiotic type CSP (see Fig. 9.22). It can be expected that the enantioselectivity potential of closely related antibiotics will be further exploited in the future leading to an increase in the number of macrocyclic antibiotic type CSPs. 

Tesarova and Bosakova [58] proposed an HPLC method for the enantio-selective separation of some phenothiazine and benzodiazepine derivatives on six different chiral stationary phases (CSPs). These selected CSPs, with respect to the structure of the separated compounds, were either based on b-CD chiral selectors (underivatized (J>-CD and hydroxypropyl ether (3-CD) or on macrocyclic antibiotics (vancomycin, teicoplanin, teicoplanin aglycon and ristocetin A). Measurements were carried out in a reversed-phase separation mode. The influence of mobile phase composition on retention and enantio-selective separation was studied. Enantioselective separation of phenothiazine derivatives, including levopromazine (LPZ), promethazine and thioridazine, was relatively difficult to achieve, but it was at least partly successful with both types of CSPs used in this work (CD-based and glycopeptide-based CSP), except for levomepromazine for which only the [CCD-based CSP was suitable. 

The first known structure within the glycopeptide family of antibiotics was vancomycin. Vancomycin, the clinically most important glycopeptide was discovered in 1956 however, its structure was disclosed only 25 years later, after correcting404,405 the previous X-ray structure of CDP-1406 by NMR.407 Since that time hundreds of related glycopeptides were discovered or prepared as semisynthetic compounds. More than 12 000 papers were published about the vancomycin topic within the last 20 years. Some recent reviews40 1 give in-depth accounts of the topic. Here we just summarize some basic structural features of the main representatives (vancomycin, eremomycin, teicoplanin, ristocetin-A) in Scheme 6. 

Fig. 7.15 Chemical structures of the glycopeptide-type antibiotics vancomycin, teicoplanin and ristocetin A. For teicoplanin the prevalent derivative (A2-2, 85%) of the teicoplanin complex is shown.

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