Triantennary GalNAc Molecular Imaging Probes for Monitoring Hepatocyte Function in a Rat Model of Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease that can lead to irreversible liver cirrhosis and cancer. Early diagnosis of NASH is vital to detect disease before it becomes life-threatening, yet noninvasively differentiating NASH from simple steatosis is challenging. Herein, bifunctional probes have been developed that target the hepatocyte-specific asialoglycoprotein receptor (ASGPR), the expression of which decreases during NASH progression.

Carbon-13 synthesis and NMR spectroscopic geometric isomer evaluation to support the filing of teriflunomide.

The two isotopomers of teriflunomide were synthesized starting from isotopically stable-labeled stocks of [ C]potassium cyanide and [1- C]ethyl bromoacetate. The two C-labeled compounds 1a, b were applied in several NMR studies to study the E/Z ratio in different matrices. In a solution, such as dimethyl sulfoxide (DMSO), a dynamic equilibrium between E/Z-isomers (ratio of 8:92) was determined by initial C-carbon NMR experiments.

NHC-Stabilized Iridium Nanoparticles as Catalysts in Hydrogen Isotope Exchange Reactions of Anilines.

The preparation of N-heterocyclic carbene-stabilized iridium nanoparticles and their application in hydrogen isotope exchange reactions is reported. These air-stable and easy-to-handle iridium nanoparticles showed a unique catalytic activity, allowing selective and efficient hydrogen isotope incorporation on anilines using D or T as isotopic source. The usefulness of this transformation has been demonstrated by the deuterium and tritium labeling of diverse complex pharmaceuticals.

Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites.

For fasiglifam (TAK875) and its metabolites the substance-specific mechanisms of liver toxicity were studied. Metabolism studies were run to identify a putatively reactive acyl glucuronide metabolite. In vitro cytotoxicity and caspase 3/7 activation were assessed in primary human and dog hepatocytes in 2D and 3D cell culture.

Directed Iridium-Catalyzed Hydrogen Isotope Exchange Reactions of Phenylacetic Acid Esters and Amides.

For the first time, a catalytic protocol for a highly selective hydrogen isotope exchange (HIE) of phenylacetic acid esters and amides under very mild reaction conditions is reported. Using a homogeneous iridium catalyst supported by a bidentate phosphine-imidazolin-2-imine P,N ligand, the HIE reaction on a series of phenylacetic acid derivatives proceeds with high yields, high selectivity, and with deuterium incorporation up to 99 %. The method is fully adaptable to the specific requirements of tritium chemistry, and its effectiveness was demonstrated by direct tritium labeling of the fungicide benalaxyl and the drug camylofine.

Tritiation of azido-labeled diiodo cabazitaxel (Jevtana) and docetaxel (Taxotere) derivatives to generate H-photoaffinity probes.

Radiolabelled azidophenyl analogues can make powerful photoaffinity probes for the identification of molecular targets. We describe our efforts to prepare tritiated azidophenyl analogues of the taxols cabazitaxel and docetaxel. Late-stage tritiation by isotope exchange with diiodo precursors resulted in reduction of the azide moiety, which could only be overcome by addition of high excess of a sacrificial azide.

Highly Selective Directed Iridium-Catalyzed Hydrogen Isotope Exchange Reactions of Aliphatic Amides.

For the first time, we describe highly selective homogeneous iridium-catalyzed hydrogen isotope exchange (HIE) of unactivated C(sp ) centers in aliphatic amides. When using the commercially available Kerr catalyst, the HIE with a series of common antibody-drug conjugate (ADC) linker side chains proceeds with high yields, high regioselectivity, and with deuterium incorporation up to 99 %. The method is fully translatable to the specific requirements of tritium chemistry and its effectiveness was demonstrated by direct tritium labelling of a maytansinoid.

Cabazitaxel is more active than first-generation taxanes in ABCB1(+) cell lines due to its reduced affinity for P-glycoprotein.

Purpose: The primary aim of this study was to determine cabazitaxel's affinity for the ABCB1/P-glycoprotein (P-gp) transporter compared to first-generation taxanes.

Methods: We determined the kinetics of drug accumulation and retention using [C]-labeled taxanes in multidrug-resistant (MDR) cells. In addition, membrane-enriched fractions isolated from doxorubicin-selected MES-SA/Dx5 cells were used to determine sodium orthovanadate-sensitive ATPase stimulation after exposure to taxanes.

Evaluation of a P,N-ligated iridium(I) catalyst in hydrogen isotope exchange reactions of aryl and heteroaryl compounds.

We have developed a novel and efficient iridium-catalyzed hydrogen isotope exchange reaction method with secondary and tertiary sulfonamides at ambient temperatures. Furthermore N-oxides and phosphonamides have been successfully applied in hydrogen isotope exchange reactions with moderate to excellent deuterium introduction.

C-H Functionalisation for Hydrogen Isotope Exchange.

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.

Deuterium- and Tritium-Labelled Compounds: Applications in the Life Sciences.

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.

Burgess iridium(I)-catalyst for selective hydrogen isotope exchange.

We have evaluated the commercially available Burgess catalyst in hydrogen isotope exchange reactions with several substrates bearing different directing group functionalities and have obtained moderate to high (50%-97%D) deuterium incorporations. The broad applicability in hydrogen isotope exchange reactions makes the Burgess catalyst a possible alternative compared to other commercially available iridium(I)-catalysts.

Conception, realization and qualification of a radioactive clean room lab facility dedicated to the synthesis of radiolabeled API for human ADME studies.

The human absorption, distribution, metabolism and elimination study administering radiolabeled drugs to human volunteers is an important clinical study in the development program of new drug candidates. The manufacture of radiolabeled Active Pharmaceutical Ingredients is covered by national drug laws and may come within the scope of regulatory GMP requirements. Additionally, authorities may request an appropriate environmental zoning to minimize the risk of microbiological contaminations particularly during the synthesis of radiolabeled Active Pharmaceutical Ingredients intended for parenteral application.

Iridium-catalysed ortho-H/D and -H/T exchange under basic conditions: C-H activation of unprotected tetrazoles.

The first examples of selective ortho-directed C-H activation with unprotected 2-aryltetrazoles are described. A new base-assisted protocol for iridium(i) hydrogen isotope exchange catalysis allows access to ortho-deuterated and tritiated tetrazoles, including the tetrazole-containing pharmaceutical, Valsartan. Preliminary mechanistic studies are also presented.

One-pot synthesis of human metabolites of SAR548304 by fungal peroxygenases.

Unspecific peroxygenases (UPOs, EC 1.11.2.

Effect of deuteration on metabolism and clearance of Nerispirdine (HP184) and AVE5638.

Replacing hydrogen with deuterium as a means of altering ADME properties of drug molecules has recently enjoyed a renaissance, such that at least two deuterated chemical entities are currently in clinical development. Although most research in this area aims to increase the metabolic stability, and hence half-life of the active species, experience has shown that prediction of the in vivo behaviour of deuterated molecules is difficult and depends on multiple factors including the complexity of the metabolic scheme, the enzymes involved and hence the mechanism of the rate-determining step in the biotransformation. In an effort to elucidate some of these factors we examined the metabolic behaviour of two molecules from the Sanofi portfolio in a range of in vitro and in vivo systems.

Preparation of labeled human drug metabolites and drug-drug interaction-probes with fungal peroxygenases.

Enzymatic conversion of a drug can be an efficient alternative for the preparation of a complex metabolite compared with a multi-step chemical synthesis approach. Limitations exist for chemical methods for direct oxygen incorporation into organic molecules often suffering from low yields and unspecific oxidation and also for alternative whole-cell biotransformation processes, which require specific fermentation know-how. Stable oxygen-transferring biocatalysts such as unspecific peroxygenases (UPOs) could be an alternative for the synthesis of human drug metabolites and related stable isotope-labeled analogues.

Selected scientific topics of the 11th International Isotope Symposium on the Synthesis and Applications of Isotopes and Isotopically Labeled Compounds.

This micro-review describes hot topics and new trends in isotope science discussed at the 11th International Isotope Symposium on the Synthesis and Applications of Isotopes and Isotopically Labeled Compounds from a personal perspective.

Ruthenium-catalyzed selective α,β-deuteration of bioactive amines.

A novel and convenient protocol for the catalytic hydrogen-deuterium exchange of biologically active tertiary amines utilizing the borrowing hydrogen methodology has been developed. In the presence of the readily available Shvo catalyst, excellent chemoselectivity toward α- and β-protons with respect to the nitrogen atom as well as high degree of deuterium incorporation and functional group tolerance is achieved. This allowed for the deuteration of complex pharmaceutically interesting substrates, including examples for actual marketed drug compounds.

Hydrogen-deuterium exchange reactions of aromatic compounds and heterocycles by NaBD4-activated rhodium, platinum and palladium catalysts.

Conventional thermal and microwave conditions were compared for hydrogen-deuterium (H/D) exchange reactions of aminobenzoic acids catalysed by NaBD(4)-activated Pd/C or RhCl(3) with D(2)O as the deuterium source. We also investigated different NaBD(4)-activated metal catalysts (including Pd/C, RhCl(3) and Pt/C) under microwave conditions for an efficient H/D exchange of aromatic and heterocyclic compounds. Even higher deuterium incorporations were obtained for Pd/C and Pt/C catalyst mixtures due to the previously observed synergistic effect.

The renaissance of H/D exchange.

The increasing demand for stable isotopically labeled compounds has led to an increased interest in H/D-exchange reactions at carbon centers. Today deuterium-labeled compounds are used as internal standards in mass spectrometry or to help elucidate mechanistic theories. Access to these deuterated compounds takes place significantly more efficiently and more cost effectively by exchange of hydrogen by deuterium in the target molecule than by classical synthesis.