Expedite synthesis of [3H]NF608 – a new subtype selective GluK1 radioligand.

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A new type of galactose mimetics has been synthesized following a straightforward synthetic approach based on cyclohexene olefin aziridination reactions directed by hydroxyl substituents. These enantiomerically pure galacto-configured N-aminoaziridines are potent irreversible inhibitors of Aspergillus oryzae and Escherichia coliβ-galactosidases.

Development of pharmacological tools for the ionotropic glutamate receptors (iGluRs) is imperative for the study and understanding of the role and function of these receptors in the central nervous system. We report the synthesis of 18 analogues of (2S,3R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explores the effect of introducing a substituent on the ε-carbon (3c−q). A new synthetic method was developed for the efficient synthesis of racemic 3a and applied to give expedited access to 13 racemic analogues of 3a. Pharmacological characterization was carried out at native iGluRs, cloned homomeric kainate receptors (GluK1−3), NMDA receptors (GluN1/ GluN2A-D), and excitatory amino acid transporters (EAAT1−3). From the structure−activity relationship studies, several new ligands emerged, exemplified by triazole 3p-d1, GluK3preferring (GluK1/GluK3 K i ratio of 15), and the structurally closely related tetrazole 3q-s3−4 that displayed 4.4−100-fold preference as an antagonist for the GluN1/GluN2A receptor (K i = 0.61 μM) over GluN1/GluN2B-D (K i = 2.7−62 μM).

A library of sphingolipid analogues is designed and tested as inhibitors against mammalian and fungal sphingolipid enzymes. The synthesis of sphingolipid analogues is based on the nucleophilic ring-opening reactions of N-activated aziridine derivatives with thiols, β-thioglycosyl thiols, phosphorothioates, phosphates, and amines to afford compounds having different lipid backbones and substituents representative of the naturally occurring sphingolipid families. The screening on mammalian sphingomyelin synthase (SMS) and glucosylceramide synthase (GCS) and yeast inositol phosphorylceramide synthase (IPCS) enzymes identified several inhibitors of GCS and IPCS, but no inhibition of SMS was observed among the tested compounds.

Natural Killer T (NKT) cells play an important role in the immune response and can be activated by glycolipids presented by CD1d protein. We present MCS‐0208, an unprecedented arylthioether‐phytoceramide able to induce potent invariant NKT (iNKT) cell activation, notably when tested in human iNKT cells. This arylsphingolipid analog has a simple phenyl group containing a single hydroxyl substituent as a surrogate of the sugar ring. The phenylthioether structure contrasts with α‐galactosylceramide (1), the prototypical glycolipid used to induce iNKT cell stimulation, where the galactose 2’‐OH and 3’‐OH substituents are accepted as the minimal footprint and considered critical for NKT T cell receptor (TCR) recognition. A computational study supports the recognition of aromatic compound by the CD1d and TCR proteins as radically new structures for NKT cell stimulation.

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