Magneto-Luminescence Correlation in the Textbook Dysprosium(III) Nitrate Single-Ion Magnet

Multifunctional Single-Molecule Magnets (SMMs) or Single-Ion Magnets (SIMs) are intriguing molecule-based materials presenting an association of the slow magnetic relaxation with other physical properties. In this article, we present an example of a very simple molecule based on Dy3+ ion exhibiting a field induced SIM property and a characteristic Dy3+ based emission. The [Dy(NO3)(3)(H2O)(4)]center dot 2H(2)O (1) complex is characterized by the means of single crystal X-Ray diffraction and their magnetic and photo-luminescent properties are investigated. We demonstrate here that it is possible to correlate the magnetic and luminescent properties and to obtain the Orbach barrier from the low temperature emission spectra, which is often difficult to properly extract from the magnetic measurements, especially in the case of field induced SIMs

19F-NMR based determination of the absorption, metabolism and excretion of the oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor leniolisib (CDZ173) in healthy volunteers

1. Leniolisib is a novel oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor, currently in clinical development for the treatment of inflammatory and autoimmune diseases. 2. We investigated the absorption, metabolism, and excretion of leniolisib in healthy subjects after a single oral 400 mg dose as part of a first-in-human clinical study. The parent drug and metabolites were quantified by 19F-NMR in plasma, urine and faeces after liquid chromatography separation, and structures were determined by liquid chromatography coupled to tandem mass spectrometry. 3. Drug related material was mainly excreted as oxidative metabolites in urine and faeces, providing evidence that elimination occurs mainly by metabolism. No metabolites were abundant in plasma relative to the parent drug. An average mass balance of 66% was obtained, demonstrating that relatively extensive elimination/excretion data can be obtained by 19F-NMR in a first in human clinical study without use of a radiolabeled drug

Comparison of 19F-NMR and 14C measurements for the assessment of ADME of BYL719 (Alpelisib) in humans

The human mass balance study is the definitive study for the assessment of absorption, distribution, metabolism and excretion (ADME) properties of a new chemical entity (NCE) in humans. Traditionally this has been carried out by the administration of radiolabeled drug substances, typically 14C or occasionally 3H, as detection methods for these isotopes allow the absolute quantification of drug related material (DRM) in blood, plasma and excreta. Coupled with the use of analytical techniques such as liquid chromatography-mass spectrometry, a picture of the metabolic fate of a compound can be elucidated. In this study we demonstrate the capabilities of 19F-nuclear magnetic resonance (NMR) spectroscopy, applied as an alternative to radiolabeling, for the determination of mass balance and for metabolite profiling of an orally administered fluorinated drug. To demonstrate the capabilities of NMR, the study was conducted on remaining samples from a 14C human mass balance study conducted on Alpelisib (BYL719), a compound in late stage development at Novartis for the treatment of solid tumors. Quantitative 14C data was used to cross-validate the data obtained by NMR. The data show that, using 19F-NMR, comparable data can be obtained for key human ADME endpoints including mass balance, total DRM determination in plasma and metabolite profiling and identification in plasma and excreta. Potential scenarios where NMR could be employed as an alternative to radiolabeling for the conduct of an early human ADME study are discusse

Novel Concept for Super-Soft Topical Drugs: Deactivation by an Enzyme-Induced Switch into an Inactive Conformation

We present a novel concept for the design of soft topical drugs. Enzymatic cleavage of the carbonate ester of the potent pan Janus kinase (JAK) inhibitor 2 releases hydroxypyridine 3. Due to hydroxypyridine-pyridone tautomerism, 3 undergoes a rapid conformational change preventing the compound to assume the bioactive conformation required for binding to JAK kinases. We demonstrate that the hydrolysis in human blood and the subsequent shape change lead to the deactivation of 2

Mapping the Magnetic Anisotropy inside a Ni4 Cubane Spin Cluster Using Polarized Neutron Diffraction

International audienceIn this publication, we report on the study of the magnetic anisotropy of the cubane type tetranuclear cluster of Ni(II), [Ni4(L)4(MeOH)4] (H2L = salicylidene-2-ethanolamine; MeOH = methanol), by the means of angular-resolved magnetometry and polarized neutron diffraction (PND). We show that better than other usual characterization techniques—such as electron paramagnetic resonance spectroscopy (EPR) or SQUID magnetometry—only PND enables the full determination of the local magnetic susceptibility tensor of the tetranuclear cluster and those of the individual Ni(II) ions and the antiferromagnetic pairs they form. This allows highlighting that, among the two antiferromagnetic pairs in the cluster, one has a stronger easy-axis type anisotropy. This distinctive feature can only be revealed by PND measurements, stressing the remarkable insights that they can bring to the understanding of the magnetic properties of transition metals cluster

Micropreparative isolation and NMR structure elucidation of metabolites of a drug candidate from rat bile and urine

LC-MS based drug metabolism studies are effective in the optimization stage of drug discovery for rapid partial structure identification of metabolites. However, these studies usually do not provide unambiguous structural characterization of all metabolites, due to the limitations of MS-based structure identification. LC-MS-SPE-NMR is a more powerful approach that allows complete structure identification of compounds from mixtures. LC-MS-SPE-NMR of compounds in complex in vivo samples (such as bile samples from drug metabolism studies) is difficult due to the presence of high concentrations of interfering endogenous components, and potentially also dosage vehicle components (e.g. polyethylene glycols). Here, we describe the isolation and structure characterization of seven metabolites of a drug development candidate in bile and urine samples from a routine low dose bile-duct cannulated rat metabolism study. The structure of all seven compounds could be determined, resulting in much higher information content than common LC-MS structure characterization studies

High-throughput synthesis provides data for predicting molecular properties and reaction success.

The generation of attractive scaffolds for drug discovery efforts requires the expeditious synthesis of diverse analogues from readily available building blocks. This endeavor necessitates a trade-off between diversity and ease of access and is further complicated by uncertainty about the synthesizability and pharmacokinetic properties of the resulting compounds. Here, we document a platform that leverages photocatalytic N-heterocycle synthesis, high-throughput experimentation, automated purification, and physicochemical assays on 1152 discrete reactions. Together, the data generated allow rational predictions of the synthesizability of stereochemically diverse C-substituted N-saturated heterocycles with deep learning and reveal unexpected trends on the relationship between structure and properties. This study exemplifies how organic chemists can exploit state-of-the-art technologies to markedly increase throughput and confidence in the preparation of drug-like molecules

KAE609 (Cipargamin), a new spiroindolone agent for the treatment of malaria: Evaluation of the Absorption, Distribution, Metabolism and Excretion of a single oral 300 mg dose of [14C]KAE609 in healthy male subjects

KAE609 is a potent, fast-acting, schizonticidal agent in clinical development for the treatment of malaria. The absorption, distribution, metabolism and excretion of KAE609 was investigated after oral administration of [14C]KAE609 in healthy subjects. Following oral administration , KAE609 was the major radioactive component in plasma, ( ~76% of the total radioactivity ); M23 was the major circulating oxidative metabolite, (~12% of the total radioactivity ). Several minor oxidative metabolites (M14, M16, M18, and M23.5B) were also identified, each accounting for ~3-8% of the total radioactivity in plasma. KAE609 was well absorbed and extensively metabolized such that KAE609 accounted for ~32% of the dose in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways. M23 was the major metabolite in feces. Subjects reported yellowish semen discoloration after dosing in prior studies; therefore semen samples were collected once from each subject to further investigate this clinical observation. Radioactivity excreted in semen was negligible, but the major component in semen was M23, supporting the conclusion that this yellow colored metabolite was the main source of semen discoloration. In this study, a new metabolite, M16, was identified in all biological matrices albeit at low levels. All 19 recombinant human CYP enzymes were capable of catalyzing the hydroxylation of M23 to form M16 even though the extent of turnover was very low. Thus, electrochemistry was utilized to generate sufficient quantity of M16 for structural elucidation. Metabolic pathways of KAE609 in human are summarized herein and M23 is the major metabolite in plasma and excreta

High-throughput synthesis provides data for predicting molecular properties and reaction success

Data and code to accompany the publication. Data S1 through S3 are described in the supplementary materials. The virtual library is contained in virtual_library.tar, a tar-archive containing bzip2-compressed CSV files each holding a chunk of 10,000 records for a total of 17,482,092 records. Each record has a unique identifier "mol_number". For each chunk, two files are provided: VL_chunk_xxxx_smiles.csv contains only the identifier and the respective SMILES string. The second file, VL_chunk_xxxx.csv additionally contains the predictions made for the library members. In addition to the identifier and SMILES string, the columns of VL_chunk_xxxx.csv are: - MoKa calculations: [number_of_ionizable_centers, center1_acidorbase, center1_pKa, center1_atom_number, center1_prediction_quality, center2_acidorbase, center2_pKa, center2_atom_number, center2_prediction_quality, center3_acidorbase, center3_pKa, center3_atom_number, center3_prediction_quality, center4_acidorbase, center4_pKa, center4_atom_number, center4_prediction_quality, center5_acidorbase, center5_pKa, center5_atom_number, center5_prediction_quality, center6_acidorbase, center6_pKa, center6_atom_number, center6_prediction_quality, center7_acidorbase, center7_pKa, center7_atom_number, center7_prediction_quality, center8_acidorbase, center8_pKa, center8_atom_number] - Property predictions using Novartis' model: [predicted_logD_pH7.4, predicted_logSolubility_pH6.8_(mM), predicted_ionization_constant] - Property predictions using Schrödinger: [QPlogPo/w, QPlogS]. These are calculated for the all-cis diastereomer. - Reaction outcome predictions for up to two possible reactions leading to the product: [rxn1_smiles, rxn1_predictions, rxn1_confidence, rxn2_smiles, rxn2_predictions, rxn2_confidence