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Free Radicals and Antioxidants
Published in Chuong Pham-Huy, Bruno Pham Huy, Food and Lifestyle in Health and Disease, 2022
Chuong Pham-Huy, Bruno Pham Huy
In pharmaceutical industries, 56% of the drugs currently in use are chiral products, and 88% of the chiral drugs are marketed as racemates consisting of an equimolar mixture of two enantiomers (isomers) such as β-blockers, calcium channel antagonists (verapamil, nicardipine, etc.), non-steroidal anti-inflammatory drugs (ibuprofen, ketoprofen, etc.), bronchodilators (salbutamol, salmeterol, terbutaline), analgesics (methadone), and so on (34). However, the majority of these racemic drugs only have one active isomer; the other isomer is pharmacologically inactive or toxic (34). The prolonged consumption of these racemic drugs may induce toxicity because the unnecessary energy used for the metabolism of the inactive isomer could engender free radicals leading to oxidative stress in the body. Therefore, the elimination of the inactive isomer in a racemic drug may be helpful for the sake of the patient’s health.
Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sergio González-Granda, Vicente Gotor-Fernández
Mandelic acid is a common scaffold for the synthesis of a wide range of chiral drugs, so the formation of optically active forms has been extensively described in the literature. One recent example consists of the resolution of mandelic acid methyl esters via O-acylation (Poterala et al., 2017). A series of mandelic acid derivatives bearing different substitutions in the aromatic ring have been efficiently resolved with either the Amano AK from Pseudomonas fluorescens lipase or different immobilised forms of PSL (Scheme 9.25). Best conditions were found using vinyl acetate and TMBE for the synthesis of the corresponding (S)-acetates and (R)-alcohols in good to excellent selectivities at room temperature using 3.5 of substrate. Taking advantage of one of this stereoselective processes, the chemoenzymatic preparation of enantiopure (R)-Pemoline was developed, which is a stimulant drug from the 4-oxazolidinone class. KR of racemic mandelic acid for the synthesis of the stimulant (R)-Pemoline.
Toxicology Through a Looking Glass: Stereochemical Questions and Some Answers
Published in Steven H. Y. Wong, Iraving Sunshine, Handbook of Analytical Therapeutic Drug Monitoring and Toxicology, 2017
The enantiomers of a chiral drug may also differ in their pharmacokinetics, metabolism and pharmacodynamic profiles. When this occurs, the administration of a racemic mixture creates potential problems particularly in the area of therapeutic drug monitoring. This is especially important when the desired pharmacological activity resides in only one of the stereoisomers.
Development and validation of LC/MS method for the determination of meclizine enantiomers in pharmaceutical formulations
Published in Drug Development and Industrial Pharmacy, 2021
Gowramma Byran, Senthil Kumar Ramachandran, Kaviarasan Lakshmanan, Kalirajan Rajagopal, Meyyanathan Subramania Nainar
Over the past decades, after the issuance of U.S. Food and Drug Administration (FDA) guidelines relating to the study and pharmaceutical development of individual enantiomers [1], the analysis and quantification of chiral drugs has become a necessity. This is due to the different pharmacological or toxicological effects that the two enantiomers of a chiral active pharmaceutical ingredient may have. Whereas one enantiomer can have the desired beneficial properties, the other can have none or the same or even adverse effects [2]. The separation of enantiomers has progressed since the early 1980s from an academic curiosity to an extraordinarily useful collection of related techniques. A great variety of technologies has been used for the separation of enantiomers on an analytical scale, such as high-performance liquid chromatography (HPLC), gas chromatography (GC), supercritical fluid chromatography (SFC), thin-layer chromatography (TLC), capillary electrophoresis (CE) and capillary electrochromatography (CEC) [3–5].
The problem of racemization in drug discovery and tools to predict it
Published in Expert Opinion on Drug Discovery, 2019
Andrew Ballard, Stefania Narduolo, Hiwa O. Ahmad, David A. Cosgrove, Andrew G. Leach, Niklaas J. Buurma
The impact of chirality on drug discovery has been reviewed previously and here we focus primarily on work that includes specific studies of the process of racemization. Relevant reviews include general surveys of chiral drugs, as well as those that describe the impact of chirality on toxicity and on synthesis [1–5]. Some studies of racemization have also been reviewed elsewhere [6,7]. In the context of dynamic kinetic resolution (DKR) for the preparation of highly enantio-enriched materials, a rapid racemization is often desirable [8]. Where an enzyme is the chiral catalyst in DKR, racemization must occur in conditions that are compatible with the enzyme. These conditions are likely to be similar to those in biological systems in general, and therefore also to be relevant to drug discovery.
Liquid chromatography coupled to mass spectrometry for metabolite profiling in the field of drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Javier Saurina, Sonia Sentellas
The study of chiral drugs and their metabolites has stirred up a tremendous interest in the last years owing to marked differences in the pharmacological activity among the optical isomers of some molecules. As a first approach, this issue was tackled on conventional stationary phases using chiral mobile phases that provided the required stereo-affinity. In the last years, however, chiral stationary phases have been designed such as those consisting of chitin or chitosan, tris(3,5-dimethylphenylcarbamate), tris(3,5-dichlorophenylcarbamate), etc. introduced as active points. A revision of LC methods for stereoselective metabolite profiling of herbal medicines is given elsewhere [49]. In another paper, Mesaros and Blair reviewed the determination of chiral bioactive metabolites of arachidonic acid using LC-MS [50]. Li and coworkers developed a new HPLC-UV/vis-MS method for the characterization of curcuminoid metabolites in feces and urine of male Wistar rats [51]. Various compounds with asymmetric centers were successfully resolved into the R- and S- enantiomers. Jones and coworkers studied the metabolism of racemin, D- and L-warfarin and related drugs to infer on the stereoselectivity of the processes using a vancomycin-based stationary phase [38].