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Pitfalls and Practical Solutions
Published in Joseph Chamberlain, The Analysis of Drugs in Biological Fluids, 2018
A particular type of artifact formation is in the racemization, or inversion of optically active compounds. Some drugs are considered to racemize so easily that it is accepted that nonchiral methods are adequate to measure their levels in biological fluids. However, where the racemate is dosed and it is desired to follow the true concentration of the separate enantiomers, then it is essential to ensure no artifactual racemization occurs, either in the extraction procedure or in the derivatization. Wright and Jamali1494 studied the potential of derivatization with ethylchlorformate for stereochemical conversion during the process of preparing diastereoisomers of several anti-inflammatory drugs with R-(+)-_-phenylethylamine or L-leucinamide. Although they concluded that conversion could occur, the degree of conversion was small enough in the assay conditions not to contribute a significant error to the results.
Introduction to Aspartic Acid Racemization
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Christian Thomas, Sara C. Zapico
Racemization is a spontaneous post-translational process, which eventually converts optically active compounds into a racemic mixture. Amino acids get converted from the native and common L-form to the relatively rare mirror image, D-form (McCudden and Kraus 2006). The L-amino acids found in living systems are the result of the stereochemical specificity of enzymes which use only L-enantiomeres (Helfman and Bada 1975). Racemization should take place in any metabolically stable protein, which has not turned over during the life-time of long lived organisms and as a consequence of racemization, these proteins will have altered conformations which would probably produce changes in their biological activities or chemical properties (Masters et al. 1977). The resultant alterations in the physicochemical properties of affected proteins may contribute to the progressive changes associated with the aging process (Helfman et al. 1977).
New Biological Targets for the Treatment of Leishmaniasis
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Fabrizio Carta, Andrea Angeli, Christian D.-T. Nielsen, Claudiu T. Supuran, Agostino Cilibrizzi
While there are numerous examples of successful repurposing, from acriscorin (i.e., antifungal to antimalarial) (Shahinas et al. 2010) to zafirlukast (i.e., asthma to NF-kB inhibitor) (Miller et al. 2010), perhaps the most telling is the case of thalidomide, universally taught in schools as it impresses upon students the importance of stereochemistry and the 3D nature of drug-biological target interactions. While one enantiomer indeed corrected the morning sickness of the patient mother, the other enantiomer led to severe birth defects in the child. Furthermore, the pitfalls of racemisation in vivo are revealed. What is perhaps less well documented is the revival of thalidomide. In a desperate attempt to sedate a critically ill patient suffering from erthyema nodosum leprosum (ENL, a painful complication of leprosy), Jacob Sheskin (a dermatologist working with leprosy patients) administered two pills of thalidomide (Sheskin 1975, Greenstone 2011). What followed after the patient’s night of sleep and remarkable recovery was a WHO sponsored follow up study in which 99% of patients enjoyed complete remission within two weeks. This in turn led to the general adoption of thalidomide as an effective medicine for ENL (Brynner and Stephens 2001, Silverman 2002, Ashburn and Thor 2004). Furthermore, thalidomide (rebranded as Thalidomid®) has additionally been shown to be an inhibitor of angiogenesis (D’Amato et al. 1994) and is currently used to treat myeloma. Its successors, namely Revlimid® (i.e., lenalidomide) and Pomalyst®(i.e., pomalidomide), made $6.97 billion for Celgene in 2015 (Kumar et al. 2014, Larocca et al. 2017, Büyükkaramikli et al. 2018).
Deamidation and isomerization liability analysis of 131 clinical-stage antibodies
Published in mAbs, 2019
Xiaojun Lu, R. Paul Nobrega, Heather Lynaugh, Tushar Jain, Kyle Barlow, Todd Boland, Arvind Sivasubramanian, Maximiliano Vásquez, Yingda Xu
In the Asp isomerization reaction, the Asu intermediate is first populated, with isomerization occurring because of subsequent hydrolysis of the cyclized intermediate. Because the Asu intermediate can be populated under either high or low pH, it is expected that isomerization-labile residues would be detected in the products of both treatments. However, agreement is not observed in 10 of 17 occurrences. Instead, in these 10 cases, an isomerization modification is detected only at the high pH condition without the corresponding observation at low pH (Fig S4B). Therefore, the observed retention time shift may be the result of a concurrent racemization reaction (Table S5B). It has been previously suggested that racemization is a product of proton abstraction from the Cα of amino acid residues,19 a reaction that will accelerate under high pH conditions. Our observation of this phenomenon in only the high pH stress is consistent with existing racemization data produced with alkaline treatment. The detection of racemization has been previously demonstrated via a shift in retention time using reverse-phase chromatography.19
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
Racemization is the process whereby a single enantiomer is converted into a mixture of both enantiomers. Thus, if a compound that tends to racemize is administered as a drug, the patient will over time very probably be exposed to both enantiomers even if the original preparation was a single enantiomer. Racemization is a particular concern to drug discovery because, as mentioned above, the two enantiomers are highly likely to have different biological properties, particularly in vivo. A process related to racemization is that of enantiomerization, which refers to one enantiomer being stereoselectively converted into the other and which can also lead towards a mixture of the two enantiomers.