Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct incorporation of an additional mass or radioactive tag into an organic molecule with almost no changes in its chemical structure, physical properties, or biological activity. Using deuterium-labelled isotopologues to study the unique mass-spectrometric patterns generated from mixtures of biologically relevant molecules drastically simplifies analysis. Such methods are now providing unprecedented levels of insight in a wide and continuously growing range of applications in the life sciences and beyond. Tritium ( H), in particular, has seen an increase in utilization, especially in pharmaceutical drug discovery. The efforts and costs associated with the synthesis of labelled compounds are more than compensated for by the enhanced molecular sensitivity during analysis and the high reliability of the data obtained. In this Review, advances in the application of hydrogen isotopes in the life sciences are described.

The various applications of hydrogen isotopes (deuterium, D, and tritium, T) in the physical and life sciences demand a range of methods for their installation in an array of molecular architectures. In this Review, we describe recent advances in synthetic C-H functionalisation for hydrogen isotope exchange.

The impact of covalent binding on PROTAC-mediated degradation of BTK was investigated through the preparation of both covalent binding and reversible binding PROTACs derived from the covalent BTK inhibitor ibrutinib. It was determined that a covalent binding PROTAC inhibited BTK degradation despite evidence of target engagement, while BTK degradation was observed with a reversible binding PROTAC. These observations were consistently found when PROTACs were employed that were able to recruit either IAP or cereblon E3 ligases. Proteomics analysis determined that use of a covalently bound PROTAC did not result in the degradation of covalently bound targets, whilst degradation was observed for some reversibly bound targets. This observation highlights the importance of catalysis on successful PROTAC-mediated degradation, and highlights a potential caveat for the use of covalent target binders in PROTAC design.Protein degrading bifunctional molecules are emerging as a novel drug discovery strategy with the potential to offer pharmacologic control of biology that is not currently achievable with existing small molecule medicines. 1-3 Mechanistic hallmarks of proteolysis-targeting chimeras (PROTACs) include high cellular degradation potency (DC50, the concentration at which 50% of substrate is degraded) high target selectivity, and extended pharmacodynamic duration of action that is dependent upon both drug pharmacokinetics and target protein resynthesis rate. 4, 5 The targeted protein degradation paradigm is driven by the ability of PROTACs to catalytically promote the degradation of a desired protein in an event-driven process. This contrasts with occupancy-driven pharmacology that is characteristic of traditional small molecule inhibitors. 3

Iridium-catalyzed C−H activation and orthohydrogen isotope exchange is an important technology for allowing access to labeled organic substrates and aromatic drug molecules and for the development of further C−H activation processes in organic synthesis. The use of [(COD)Ir(NHC)Cl] complexes (NHC = N-heterocyclic carbene) in the orthodeuteration of primary sulfonamides under ambient conditions is reported. This methodology has been applied to the deuteration of a series of substrates, including the COX-2 inhibitors Celecoxib and Mavacoxib, demonstrating selective complexation of the primary sulfonamide over a competing pyrazole moiety. The observed chemoselectivity can be reversed by employing more encumbered catalyst derivatives of the type [(COD)Ir(NHC)(PPh 3 )]PF 6 . Computational studies have revealed that, although C−H activation is rate-determining, substrate complexation or subsequent C−H activation can be product-determining depending on the catalyst employed.

This version is available at https://strathprints.strath.ac.uk/49161/ Strathprints is designed to allow users to access the research output of the University of Strathclyde. Unless otherwise explicitly stated on the manuscript, Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Please check the manuscript for details of any other licences that may have been applied. You may not engage in further distribution of the material for any profitmaking activities or any commercial gain. You may freely distribute both the url (https://strathprints.strath.ac.uk/) and the content of this paper for research or private study, educational, or not-for-profit purposes without prior permission or charge.Any correspondence concerning this service should be sent to the Abstract. : A series of robust iridium(I) complexes bearing a sterically encumbered N-heterocyclic carbene ligand, alongside a phosphine ligand, has been synthesised and investigated in hydrogen isotope exchange processes. These complexes have allowed isotope incorporation over a range of substrates with the use of practically convenient deuterium and tritium gas. Moreover, these active catalysts are capable of isotope incorporation to particularly high levels, whilst employing low catalyst loadings and in short reaction times. In addition to this, these new catalyst species have shown flexible levels of chemoselectivity, which can be altered by simple manipulation of preparative approaches.Furthermore, a number of industrially-relevant drug molecules have also been labelled, including the sulfonamide containing drug, Celecoxib. Alongside detailed NMR experiments, initial mechanistic investigations have also been performed, providing insight into both substrate binding energies, and, more importantly, relative energies of key steps in the mechanistic cycle as part of the overall exchange process.

Practically convenient methods have been developed for the preparation of new iridium complexes, possessing bulky N-heterocyclic carbene and phosphine ligands; these routinely handled complexes are highly active catalysts within directed hydrogen isotope exchange processes.

R. K. (2020). Structure-based design of a bromodomain and extraterminal domain (BET) inhibitor selective for the N-terminal bromodomains that retains an anti-inflammatory and antiproliferative phenotype. Journal of Medicinal Chemistry.

Impurity profiling of seized methamphetamine can provide very useful information in criminal investigations and, specifically, on drug trafficking routes, sources of supply, and relationships between seizures. Particularly important is the identification of “route specific” impurities or those which indicate the synthetic method used for manufacture in illicit laboratories. Previous researchers have suggested impurities which are characteristic of the Leuckart and reductive amination (Al/Hg) methods of preparation. However, to date and importantly, these two synthetic methods have not been compared in a single study utilizing methamphetamine hydrochloride synthesized in-house and, therefore, of known synthetic origin. Using the same starting material, 1-phenyl-2-propanone (P2P), 40 batches of methamphetamine hydrochloride were synthesized by the Leuckart and reductive amination methods (20 batches per method). Both basic and acidic impurities were extracted separately and analyzed by GC/MS. From this controlled study, two route specific impurities for the Leuckart method and one route specific impurity for the reductive amination method are reported. The intra- and inter-batch variation of these route specific impurities was assessed. Also, the variation of the “target impurities” recently recommended for methamphetamine profiling is discussed in relation to their variation within and between production batches synthesized using the Leuckart and reductive amination routes.