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Magic Methyl“ Group - a Guide for Site-Selective Trideuteromethyl Incorporation and Labeling Using CD3-Reagents

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Magic Methyl“ Group - a Guide for Site-Selective Trideuteromethyl Incorporation and Labeling Using CD3-Reagents The Deuterated “Magic Methyl“ Group - A Guide for Site-selective Trideuteromethyl Incorporation and Labeling using CD3-reagents Item Type Article Authors Steverlynck, Joost Andre; Sitdikov, Ruzal; Rueping, Magnus Citation Steverlynck, J., Sitdikov, R., & Rueping, M. (2021). The Deuterated “Magic Methyl“ Group - A Guide for Site-selective Trideuteromethyl Incorporation and Labeling using CD3- reagents. Chemistry – A European Journal. doi:10.1002/ chem.202101179 Eprint version Post-print DOI 10.1002/chem.202101179 Publisher Wiley Journal Chemistry – A European Journal Rights Archived with thanks to Chemistry – A European Journal. © 2021 The Authors. Published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Download date 04/10/2021 08:07:29 Item License http://creativecommons.org/licenses/by-nc-nd/4.0/ Link to Item http://hdl.handle.net/10754/669361 Review Chemistry—A European Journal doi.org/10.1002/chem.202101179 The Deuterated “Magic Methyl” Group: A Guide to Site- Selective Trideuteromethyl Incorporation and Labeling by Using CD3 Reagents Joost Steverlynck,[a] Ruzal Sitdikov,[a] and Magnus Rueping*[a, b] Chem. Eur. J. 2021, 27, 11751–11772 11751 © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Mittwoch, 11.08.2021 2146 / 210161 [S. 11751/11772] 1 Review Chemistry—A European Journal doi.org/10.1002/chem.202101179 Abstract: In the field of medicinal chemistry, the precise the selective introduction of CD2H and CDH2 groups is also installation of a trideuteromethyl group is gaining ever- considered. For all methods, the corresponding mechanism increasing attention. Site-selective incorporation of the deu- and scope are discussed whenever reported. As such, this terated “magic methyl” group can provide profound pharma- review can be a starting point for synthetic chemists to cological benefits and can be considered an important tool further advance trideuteromethylation methodologies. At the for drug optimization and development. This review provides same time, this review aims to be a guide for medicinal a structured overview, according to trideuteromethylation chemists, offering them the available CÀ CD3 formation reagent, of currently established methods for site-selective strategies for the preparation of new or modified drugs. trideuteromethylation of carbon atoms. In addition to CD3, 1. Introduction stereoelectronics.[9] Apart from these stereoelectronic effects, also the solubility properties change upon methylation as a With around 80% of the top-selling drugs containing a methyl result of branching, which on its turn can improve the drug group, the importance of site-selective methylation in medicinal availability at the target location. Unlike the popular and [1] chemistry cannot be overestimated. This is not surprising as sterically analogous CF3 group, the lipophilicity of the molecule methylation is one of the most prevalent and important does not change much upon methylation, avoiding the chemical transformations in biology.[2] For example, just one Me formation of too greasy molecules and consequently a violation unit distinguishes thymine (DNA) from uracil (RNA). Five amino of the rules of Lipinsky.[10] acids just differ in number and position of methyl units, which A deeper understanding of these effects, provoked by ultimately will influence enzyme functionality.[3] Likewise, methylation, on the pharmacology of bioactive compounds is installation of a methyl unit can be a great tool to profoundly provided by the work of Lovering.[11] Here the increase of alter and optimize the pharmacological properties of drugs by saturation and the resulting three dimensionality of a com- inducing stereoelectronic and solubility effects.[4] Via stereo- pound (“escape from flatland”) is described to lead to higher electronic effects, methylation can change or improve the clinical success. At the same time, an increase in saturation affinity of a compound to a receptor with a minimal change in improves solubility. Not only in drug development but also in physical properties of the molecule.[5] As such, methylation can peptide chemistry, methylation is adopted as a well-established be a strategy to develop more selective and potent drugs.[6] strategy to achieve the desired pharmacological properties.[12] This effect can be dramatic in terms of both changes and When the hydrogen atoms of the methyl group are inter- improvements in the drug-bioreceptor interaction. For example, changed for deuterium atoms (the most conventional isosteric methylation has been demonstrated to change an antagonist replacement) additional benefits in terms of medicinal proper- into an agonist/allosteric modulator.[7] In the case of improved ties can be obtained. The CÀ D bond is stronger than the CÀ H drug-bioreceptor interaction, boosts in potency up to 507 fold bond due to the kinetic isotope effect, so replacing CÀ H bonds have been reported.[8] This very large potency increase resulting with CÀ D bonds can lead to drugs that are less prone to from a CÀ H to CÀ Me transformation is described as the “magic oxidative metabolization and, therefore, longer-acting.[13] Apart methyl effect”. This so-called “magic methyl effect” is attributed from optimizing the pharmacokinetics, site-selective deutera- to “the induction of profound conformational changes leading tion can also lead to reduced toxicity via “metabolic shunting”, to low energy conformers that better approximate the bound increased bio-activation, stabilization of unstable stereoisomers state”. In addition, the ease of enzymatic metabolization and and even a reduction in drug interactions.[13d] Only recently has thus half-life of the drug can be affected by methylation via there been increased interest in deuterated drugs, mainly due to extra costs and synthetic challenges. In 2017, deutetrabena- zine (Austedo) was approved by the FDA as the first deuterated [a] Dr. J. Steverlynck, Dr. R. Sitdikov, Prof. Dr. M. Rueping Kaust Catalysis Center (KCC) drug (Figure 1). Deutetrabenazine is, in fact, just an improve- King Abdullah University Science and Technology (KAUST) ment of a drug already on the market by so-called “deuterium Thuwal 23955-6900 (Saudi Arabia) switching”. Another strategy is deuterium incorporation during E-mail: [email protected] the early stage of drug development.[13d] A very extensive [b] Prof. Dr. M. Rueping review on deuterated drugs and their applications was Institute for Experimental Molecular Imaging [13d] RWTH Aachen University published in 2019 by Pirali et al. Forckenbeckstrasse 55, 52074 Aachen By installing a trideuteromethyl (CD3) group, the mentioned E-mail: [email protected] benefits of site-selective methylation and deuteration can be This manuscript is part of a special collection on Chemistry in Saudi Arabia. exploited in one chemical building block. There are currently © 2021 The Authors. Chemistry - A European Journal published by Wiley- multiple CD3-containing drugs in the clinical phase, and VCH GmbH. This is an open access article under the terms of the Creative deutetrabenazine, the first approved deuterated drug, contains Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, two OCD3 groups (Figure 1). the use is non-commercial and no modifications or adaptations are made. Chem. Eur. J. 2021, 27, 11751–11772 www.chemeurj.org 11752 © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Mittwoch, 11.08.2021 2146 / 210161 [S. 11752/11772] 1 Review Chemistry—A European Journal doi.org/10.1002/chem.202101179 In the following we discuss currently established methods for site-selective trideuteromethylation of carbon atoms accord- ing to the trideuteromethylation reagents and discuss the corresponding mechanisms and scope of the methodologies. Joost Steverlynck graduated in 2012 with an M.Sc. in chemistry from KU Leuven (Belgium). As a fellow of the Agency for Innovation by Science and Technology in Flanders (IWT) he ob- tained a PhD on the synthesis and self- assembly of conjugated polymers with nonlinear topologies under the super- vision of Prof. Guy Koeckelberghs. He continued as a postdoctoral research- er under the supervision of Prof. Thierry Verbiest, focusing on the syn- thesis of conjugated liquid-crystalline materials with high Faraday response. In 2019, he started to work in the group of Prof. Magnus Rueping at KAUST (Saudi Arabia). Figure 1. CD3-containing approved drug and drug candidates in clinical [16,13d] Ruzal Sitdikov studied at Kazan Univer- trials. sity (KFU, Russia) with a focus on supramolecular organic chemistry. He obtained his Ph.D. under Prof. Ivan Stoikov in 2015 on thiacalix[4]arene 2. [D4]Methanol receptors. In 2015 he worked on electro- active pillar[n]arenes at the KU Leuven, Deuterated methanol is one of the most accessible CD3 sources Belgium (Prof. Wim Dehaen’s group, that also can act as a reagent for CÀ CD3 bond formation. As a Erasmus Mundus grantee). Between trideuteromethylation reagent CD OD is especially interesting. 2016 and 2018, he performed research 3 in supramolecular glycochemistry at the It is an inexpensive, relatively low-toxic trideuteromethylation KTH, Sweden
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