Åsmund Kaupang

α-Bromodiazoacetamides – a new class of diazo compounds for catalyst-free, ambient temperature intramolecular C–H insertion reactions

Summary In this work, we introduce a new class of halodiazocarbonyl compounds, α-halodiazoacetamides, which through a metal-free, ambient-temperature thermolysis perform intramolecular C–H insertions to produce α-halo-β-lactams. When carried out with α-bromodiazoacetamides bearing cyclic side chains, the thermolysis reaction affords bicyclic α-halo-β-lactams, in some cases in excellent yields, depending on the ring size and substitution pattern of the cyclic amide side chains.

tert-Butyl 4-(2-diazo-acet-yl)piperazine-1-carboxyl-ate.

The title crystal structure, C11H18N4O3, is the first diazoacetamide in which the diazoacetyl group is attached to an N atom. The piperazine ring is in a chair form and hence the molecule has an extended conformation. Both ring N atoms are bonded in an essentially planar configuration with the sum of the C—N—C angles being 359.8 (2) and 357.7 (2)°. In the crystal structure, the O atom of the diazoacetyl group accepts two H atoms from C—H donors, thus generating chains of weak hydrogen-bonded R 2 1(7) rings.

Synthesis, biological evaluation and molecular modeling studies of the PPARβ/δ antagonist CC618

Herein, we describe the synthesis, biological evaluation and molecular docking of the selective PPARβ/δ antagonist (4-methyl-2-(4-(trifluoromethyl)phenyl)-N-(2-(5-(trifluoromethyl)-pyridin-2-ylsulfonyl)ethyl)thiazole-5-carboxamide)), CC618. Results from in vitro luciferase reporter gene assays against the three known human PPAR subtypes revealed that CC618 selectively antagonizes agonist-induced PPARβ/δ activity with an IC50 = 10.0 μM. As observed by LC-MS/MS analysis of tryptic digests, the treatment of PPARβ/δ with CC618 leads to a covalent modification of Cys249, located centrally in the PPARβ/δ ligand binding pocket, corresponding to the conversion of its thiol moiety to a 5-trifluoromethyl-2-pyridylthioether. Finally, molecular docking is employed to shed light on the mode of action of the antagonist and its structural consequences for the PPARβ/δ ligand binding pocket.

Synthesis of 5-trifluoromethyl-2-sulfonylpyridine PPARβ/δ antagonists: Effects on the affinity and selectivity towards PPARβ/δ.

The covalent modification of peroxisome-proliferator activated receptor β/δ (PPARβ/δ) is part of the mode of action of 5-trifluoromethyl-2-sulfonylpyridine PPARβ/δ antagonists such as GSK3787 and CC618. Herein, the synthesis and in vitro biological evaluation of a range of structural analogues of the two antagonists are reported. The new ligands demonstrate that an improvement in the selectivity of 5-trifluoromethyl-2-sulfonylpyridine antagonists towards PPARβ/δ is achievable at the expense of their immediate affinity for PPARβ/δ. However, their putatively covalent and irreversible mode of action may ensure their efficacy over time, as observed in time-resolved fluorescence resonance energy transfer (TR-FRET)-based ligand displacement assays.

Structural review of PPARγ in complex with ligands: Cartesian- and dihedral angle principal component analyses of X-ray crystallographic data

Two decades of research into the ligand‐dependent modulation of the activity of the peroxisome proliferator‐activated receptor γ (PPARγ) have demonstrated the heterogeneous modes of action of PPARγ ligands, in terms of their interaction surfaces in the ligand‐binding pocket, binding stoichiometry and ability to interact with functionally important parts of the receptor, through both direct and allosteric mechanisms. These findings signal the complex mechanistic bases of the distinct biological effects of different classes of PPARγ ligands. Today, the development of PPARγ ligands focuses on partial‐ and non‐agonists as opposed to classical agonists, due to the severe side effects observed with PPARγ classical agonists as therapeutic agents. To aid this development, we performed principal component analyses of the atomic (Cartesian) coordinates (cPCA) and dihedral angles (dPCA) of the structures of human PPARγ from X‐ray crystallography, available in the public domain, seeking to reveal ligand‐induced trends. In the cPCA, projections of the structures along the principal components (PCs) demonstrated a moderate correlation between cPC1 and structural parameters related to the stabilization of helix 12, which is central to the transcriptional activation by PPARγ classical agonists. Consequently, the presented cPCA mapping of the PPARγ‐ligand complexes may guide in silico drug discovery programs seeking to avoid stabilization of helix 12 in their development of partial‐ and non‐agonistic PPARγ ligands. Notably, while the dPCA could identify key regions of dihedral fluctuation in the structural ensemble, the distributions along dPC1 – 2 could not be classified according to the same parameters as the distribution along cPC1. Proteins 2017; 85:1684–1698.

A solid-state oxidation of 1,1,3,3-tetramethylguanidinium 4-methylbenzenesulfinate to 1,1,3,3-tetramethylguanidinium 4-methylbenzenesulfonate.

The organic acid-base complex 1,1,3,3-tetramethylguanidinium 4-methylbenzenesulfonate, C5H14N3(+)·C7H7O3S(-), was obtained from the corresponding 1,1,3,3-tetramethylguanidinium 4-methylbenzenesulfinate complex, C5H14N3(+)·C7H7O2S(-), by solid-state oxidation in air. Comparison of the two crystal structures reveals similar packing arrangements in the monoclinic space group P2(1)/c, with centrosymmetric 2:2 tetramers being connected by four strong N-H···O=S hydrogen bonds between the imine N atoms of two 1,1,3,3-tetramethylguanidinium bases and the O atoms of two acid molecules.

Involvement of covalent interactions in the mode of action of PPARβ/δ antagonists

A broad range of chemical structures modulate the inductive and repressive transcriptional regulation of the peroxisome proliferator-activated receptor β/δ (PPARβ/δ). In order to shed light on mechanistic differences in the modes of action of three classes of the reported PPARβ/δ antagonists, an investigation into their in vitro biological and chemical reactivities, with particular focus on covalent reactivity, was undertaken. The results reported here, substantiate the covalent modification of Cys249 as a part of the mode of action of the 5-trifluoromethyl-2-sulfonylpyridine class of antagonists. In contrast, GSK0660 does not appear to be a covalently binding antagonistic ligand. Additionally, we demonstrate the electrophilic nature of the recently published antagonist DG172 towards thiolates, although a covalent adduct with PPARβ/δ is not detected in our experiments.

2-Diazo-1-(1,1-dioxothio-morpholin-4-yl)ethanone.

In the molecule of the title compound, C6H9N3O3S, at 105 K, the six-membered ring is predominantly found in the chair conformation, with 1.89 (14)% in the boat conformation. In the crystal structure, there are five intermolecular C—H⋯O=C and C—H⋯O=S contacts less than 2.6 Å, as well as a weak C—H⋯N=N interaction to the diazo group.

1,4-Bis(2-diazo­acet­yl)piperazine

The asymmetric unit of the title compound, C8H10N6O2, contains one-half molecule, which is completed by a crystallographic center of symmetry. The piperazine ring adopts a chair conformation. In the crystal, weak C—H⋯O interactions link the molecules into layers parallel to the bc plane. The crystal packing also exhibits short N⋯N contacts of 3.0467 (16) Å between the terminal diazo N atoms from neighbouring molecules.

(2SR,3RS)-Benz­yl[4-chloro-1-(4-chloro­phen­yl)-1-methoxy­carbon­yl-2-but­yl]­ammonium chloride

In the racemic hydrochloride salt of the title ester, C19H22Cl2NO2 +·Cl−, the pentanoic acid chain shows a mixture of trans and gauche orientations to give an overall helical conformation. The dihedral angle between the two aromatic rings is 26.11 (10)°. The charged secondary amine function participates in two N—H⋯Cl hydrogen bonds.