A common biological basis of obesity and nicotine addiction

J. Kaprio ja J. Tuomilehto työryhmien jäseniä (yht. 281).Peer reviewe

Ro-vibrational Spectrum of Linear Dialuminum Monoxide (Al₂O) at 10 μm

Dialuminum monoxide, Al2O, has been investigated in the laboratory at mid-IR wavelengths around 10 μm at high spectral resolution. The molecule was produced by laser ablation of an aluminum target with the addition of gaseous nitrous oxide, N2O. Subsequent adiabatic cooling of the gas in a supersonic beam expansion led to rotationally cold spectra. In total, 848 ro-vibrational transitions have been assigned to the fundamental asymmetric stretching mode ν3 and to five of its hot bands, originating from excited levels of the ν1 symmetric stretching mode and the ν2 bending mode. The measurements encompass 11 vibrational energy states (v1 v2l v3). The ro-vibrational transitions show spin statistical line intensity alternation of 7:5, which is caused by two identical aluminum nuclei of spin I = 5/2 at both ends of the centrosymmetric molecule of structure Al–O–Al. The less effective cooling of vibrational states in the supersonic beam expansion allowed measurement of transitions in excited vibrational states at energies of 1000 cm–1 and higher, while rotational levels within vibrational modes exhibited thermal population, with rotational temperatures around Trot = 115 K. Molecular parameters for 11 vibrational states were derived, including rotation and centrifugal distortion constants and l-type doubling constants for the states (v1 v2l v3) = (0 11 0) and (0 11 1) and an l-type resonance between the states (0 20 0) - (0 22 0) and (0 20 1) - (0 22 1). From the experimental results, rotational correction terms and the equilibrium bond length re were derived. The measurements were supported and guided by high-level quantum-chemical calculations that agree well with the derived experimental results

Development, Optimization, and Structure–Activity Relationships of Covalent-Reversible JAK3 Inhibitors Based on a Tricyclic Imidazo[5,4‑<i>d</i>]pyrrolo[2,3‑<i>b</i>]pyridine Scaffold

Janus kinases are major drivers of immune signaling and have been the focus of anti-inflammatory drug discovery for more than a decade. Because of the invariable colocalization of JAK1 and JAK3 at cytokine receptors, the question if selective JAK3 inhibition is sufficient to effectively block downstream signaling has been highly controversial. Recently, we discovered the covalent-reversible JAK3 inhibitor FM-381 (<b>23</b>) featuring high isoform and kinome selectivity. Crystallography revealed that this inhibitor induces an unprecedented binding pocket by interactions of a nitrile substituent with arginine residues in JAK3. Herein, we describe detailed structure–activity relationships necessary for induction of the arginine pocket and the impact of this structural change on potency, isoform selectivity, and efficacy in cellular models. Furthermore, we evaluated the stability of this novel inhibitor class in <i>in vitro</i> metabolic assays and were able to demonstrate an adequate stability of key compound <b>23</b> for <i>in vivo</i> use

Development, Optimization, and Structure–Activity Relationships of Covalent-Reversible JAK3 Inhibitors Based on a Tricyclic Imidazo[5,4‑<i>d</i>]pyrrolo[2,3‑<i>b</i>]pyridine Scaffold

Janus kinases are major drivers of immune signaling and have been the focus of anti-inflammatory drug discovery for more than a decade. Because of the invariable colocalization of JAK1 and JAK3 at cytokine receptors, the question if selective JAK3 inhibition is sufficient to effectively block downstream signaling has been highly controversial. Recently, we discovered the covalent-reversible JAK3 inhibitor FM-381 (<b>23</b>) featuring high isoform and kinome selectivity. Crystallography revealed that this inhibitor induces an unprecedented binding pocket by interactions of a nitrile substituent with arginine residues in JAK3. Herein, we describe detailed structure–activity relationships necessary for induction of the arginine pocket and the impact of this structural change on potency, isoform selectivity, and efficacy in cellular models. Furthermore, we evaluated the stability of this novel inhibitor class in <i>in vitro</i> metabolic assays and were able to demonstrate an adequate stability of key compound <b>23</b> for <i>in vivo</i> use

NANPDB: A Resource for Natural Products from Northern African Sources

Natural products (NPs) are often regarded as sources of drugs or drug leads or simply as a “source of inspiration” for the discovery of novel drugs. We have built the Northern African Natural Products Database (NANPDB) by collecting information on ∼4500 NPs, covering literature data for the period from 1962 to 2016. The data cover compounds isolated mainly from plants, with contributions from some endophyte, animal (e.g., coral), fungal, and bacterial sources. The compounds were identified from 617 source species, belonging to 146 families. Computed physicochemical properties, often used to predict drug metabolism and pharmacokinetics, as well as predicted toxicity information, have been included for each compound in the data set. This is the largest collection of annotated natural compounds produced by native organisms from Northern Africa. While the database includes well-known drugs and drug leads, the medical potential of a majority of the molecules is yet to be investigated. The database could be useful for drug discovery efforts, analysis of the bioactivity of selected compounds, or the discovery of synthesis routes toward secondary metabolites. The current version of NANPDB is available at http://african-compounds.org/nanpdb/

<i>Tetra</i>-Substituted Pyridinylimidazoles As Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and c‑Jun <i>N</i>‑Terminal Kinase 3 for Potential Treatment of Neurodegenerative Diseases

<i>Tetra</i>-substituted imidazoles were designed as dual inhibitors of c-Jun <i>N</i>-terminal kinase (JNK) 3 and p38α mitogen-activated protein (MAP) kinase. A library of 45 derivatives was prepared and evaluated in a kinase activity assay for their ability to inhibit both kinases, JNK3 and p38α MAP kinase. Dual inhibitors with IC₅₀ values down to the low double-digit nanomolar range at both enzymes were identified. The best balanced dual JNK3/p38α MAP kinase inhibitors are <b>6m</b> (IC₅₀: JNK3, 18 nM; p38α, 30 nM) and <b>14d</b> (IC₅₀: JNK3, 26 nM; p38α, 34 nM) featuring both excellent solubility and metabolic stability. They may serve as useful tool compounds for preclinical proof-of-principle studies in order to validate the synergistic role of both kinases in the progression of Huntington’s disease

Design, Synthesis, and Biological Evaluation of Novel Type I¹/₂ p38α MAP Kinase Inhibitors with Excellent Selectivity, High Potency, and Prolonged Target Residence Time by Interfering with the R‑Spine

We recently reported <b>1a</b> (skepinone-L) as a type I p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, as a type I inhibitor, it is entirely ATP-competitive and shows just a moderate residence time. Thus, the scope was to develop a new class of advanced compounds maintaining the structural binding features of skepinone-L scaffold like inducing a glycine flip at the hinge region and occupying both hydrophobic regions I and II. Extending this scaffold with suitable residues resulted in an interference with the kinase’s R-Spine. By synthesizing 69 compounds, we could significantly prolong the target residence time with one example to 3663 s, along with an excellent selectivity score of 0.006 and an outstanding potency of 1.0 nM. This new binding mode was validated by cocrystallization, showing all binding interactions typifying type I¹/₂ binding. Moreover, microsomal studies showed convenient metabolic stability of the most potent, herein reported representatives