Current Medicinal Chemistry (v.24, #8)

Meet Our Editorial Board Member by Caterina Faggio (741-741).

Enantioselective high-performance liquid chromatography (eHPLC) using chiral stationary phases (CSPs) is surely the most used technique for the determination of the enantiomeric excess (e.e.) of chiral drugs, a fundamental parameter for reliable studies on the relationship between stereochemistry and pharmacological activity. A key aspect of this enantioseparation technique is the efficiency of the chiral selector, which can be optimized to obtain higher selectivity and a wider applicability. Thus, the determination of the mechanisms behind chiral recognition is very important to predict and improve the enantioselectivity of CSPs. The present review deals with the preparation and use of CSPs for eHPLC with human serum albumin (HSA) as chiral selector, with particular emphasis on the modulation of the chromatographic performance. HSA-based CSPs allow a relatively easy prediction of the binding sites involved in the retention of analytes and the possibility to improve the selectivity of enantioresolution by modulating the binding process, using either reversible or covalent modifications of the protein. Significant improvements of the chromatographic parameters, such as reduction of analysis time and increase of enantioselectivity, have been obtained for selected analytes by using competitors for a particular binding site of HSA dissolved in the mobile phase or by selectively modifying the protein structure at single amino acid residues.

(S)-Naproxen (Npx), an ?-aryl propionic acid derivative, belongs to the class of Non-Steroidal Anti-Inflammatory Drugs and is easily available in pure (S)-form. (S)-Npx has been used as a chiral selector for chromatographic separation of a variety of racemates, using both direct and indirect methods, and has been found to be useful and successful as a basic chiral moiety. This review article describes methods for enantioseparation of (RS)-Npx, development of chiral stationary phases based on (S)-Npx and preparation of novel chiral derivatizing reagents synthesized from (S)-Npx along with their application for enantioseparation of several pharmaceutically important racemates.

Application of Organic Monolithic Materials to Enantioseparation in Capillary Separation Techniques by Enrique Javier Carrasco-Correa, Ernesto Francisco Simo-Alfonso, Guillermo Ramis-Ramos, Jose Manuel Herero-Martinez (781-795).
This review article is primarily focused on the state-of-the-art of enantioseparations on organic monolithic materials. The article gives an overview of the chiral stationary phases and its application in capillary electrochromatography (CEC), and capillary- and nano-liquid chromatography (cLC and nLC). Since thousands of publications have been emerged from 2000's and citing all these papers would extend the scope of this review; then, recent developments from last 10 years (2006 to 2016) will be mentioned. Mostly, stationary phases based on copolymers obtained from chiral functional monomers and surface modifications of organic monoliths with chiral ligands will be discussed. The effective application of these chiral separation methodologies in several analysis areas will be also included.

Laboratory-Scale Preparative Enantioseparations of Pharmaceutically Relevant Compounds on Commercially Available Chiral Stationary Phases for HPLC by Roccaldo Sardella, Federica Ianni, Maura Marinozzi, Antonio Macchiarulo, Benedetto Natalini (796-817).
In response to the outburst of research in the field of synthetic medicinal chemistry, enantioselective chromatography methods based on the use of chiral stationary phases (CSPs) found immediate acceptance as the elective choice for the analytical determinations of the enantiomeric purity of synthetic compounds. In contrast to an initial scepticism, also the preparative-scale applications are gaining increasing recognition as a powerful alternative to enantioselective synthesis for the supply of pure enantiomers of bioactive compounds. The increasing success of liquid chromatography methods has been made possible thanks to the development of highly efficient CSPs allowing the enantioresolution of practically all the chemical classes of chiral compounds. However, only few CSPs are really suitable for preparative- scale applications, being the loading capacity is the major concern for preparativescale enantioseparations. The cellulose- and amylose-based CSPs present the highest loading capacity and enantiodiscrimination power, which makes these CSPs the most versatile and applicable for preparative-scale applications in all the applicable elution modes (reversedphase, normal-phase, and with polar-organic or polar-ionic eluents). However, also other types of CSPs have been successfully employed at this regard (brush-type phases, polyacrylamide and cross-linked di-allyltartardiamide phases as well as cyclodextrin, and glycopeptide containing phases).

Several instrumental methods exist for the determination of the absolute configuration of organic compounds in absence of known enantiopure reference standards. The most widely known are X-ray crystallography, followed by chirooptical methods [e.g., electronic and vibrational circular dichroism (ECD and VCD, respectively)] and nuclear magnetic resonance (NMR) spectroscopy.

All these aspects will be treated in the review.

It is well known for several decades that the two enantiomeric forms of a chiral compound can have very different effects on the human body. For this reason the synthesis or extraction from a natural source of a potential new drug, as well as its marketing, require a careful control of its optical purity. Chromatographic techniques can respond extremely well to this need, both in the analytical and in the preparative field.

Among the several methods developed for this purpose, one of the first and of the most effective is the Chiral Ligand-Exchange Chromatography, which is based on the stability difference between the metallic diastereomeric complexes containing one or the other of the two enantiomers to be separated and a suitable chiral selector. This method has been effectively used for resolving racemic mixtures of products of biomedical and/or pharmacological interest, such as ? - and ?-amino acids either proteinogenic or non-proteinogenic, oligopeptides, amino alcohols or ?-blockers. All these substances are linked together by their ability to bind metal ions, the most widely used of which is Cu(II). The chiral selector can be a component of either the mobile or the stationary phase, to which it can be either chemically bonded or dynamically adsorbed. The latter method has several advantages of convenience and, above all, cheapness. The preparation of dynamically-coated chiral stationary phases for Ligand-Exchange Chromatography has produced a large number of applications, the main of which, both in TLC and in HPLC, are reviewed below.

Oligosaccharide-based chiral stationary phases are frequently used for enantioselective separations by different chromatographic techniques, namely gas chromatography, high performance liquid chromatography, supercritical fluid chromatography or capillary electrochromatography. Their multimodal application potential (they are compatible with both polar and/or non-polar mobile phases) makes them suitable chiral selector candidates for separation of a wide variety of structurally diverse compounds. In this paper, separation systems utilizing cyclodextrin- or cyclofructan-based chiral stationary phases in analyses of pharmacologically active compounds are summarized. The review covers the period from 2000 to 2015. This review article can be helpful to analysts searching for an appropriate method for the separation/determination of pharmaceuticals of their interest.