Michael Pätzel

Inhibition of calcineurin‐NFAT signaling by the pyrazolopyrimidine compound NCI3

Dephosphorylation of NFAT by the Ca2+‐calmodulin‐dependent Ser/Thr protein phosphatase calcineurin is a bottleneck of T cell receptor‐dependent activation of T cells. In dimeric complexes with immunophilins, the immunosuppressants cyclosporine A (CsA) and tacrolimus (FK506) block this process by inhibition of the enzymatic activity of calcineurin. We have identified the pyrazolopyrimidine compound NCI3 as a novel inhibitor of calcineurin‐NFAT signaling. Similar to CsA and FK506, NCI3 inhibits dephosphorylation and nuclear translocation of NFAT, IL‐2 production and proliferation of stimulated human primary T cells with IC50 values from 2 to 4.5 µM. However, contrary to CsA and FK506, NCI3 neither blocks calcineurin`s phosphatase activity nor requires immunophilins for inhibiting NFAT activation. Our data suggest that NCI3 binds to calcineurin and causes an allosteric change interfering with NFAT dephosphorylation in vivo but not in vitro. NCI3 acts not only on the endogenous calcineurin but also on a C‐terminally truncated, constitutively active version of calcineurin. The novel inhibitor described herein will be useful in better defining the cellular regulation of calcineurin activation and may serve as a lead for the development of a new type of immunosuppressants acting not by direct inhibition of the calcineurin phosphatase activity.

Chiral dienes from enantiomerically pure enones. Highly stereoselective intramolecular Diels–Alder reaction involving ethenesulfonates

Chiral dienes 2, easily prepared from α,β-unsaturated γ-alkoxy ketones, are subjected to inter- and intramolecular Diels–Alder reactions. Intermolecular cycloadditions of dienes 2 with 4-phenyl-1,2,4-triazole-3,5(2H)-dione 3 are found to be diastereoselective. Thermal or high pressure-induced intramolecular cycloadditions of trienes 8, featuring a sulfonate moiety connecting a diene and a dienophile, are found to proceed with high diastereoselectivity to give sultones 11 and 12. An interesting domino process is observed when enone 5 is reacted with sodium hydride. In this reaction sequence, the decahydropyrano[2,3,4-de]chromene derivative 15 was formed. NMR spectroscopic studies allowed the assignments of the configurations of the bi- and tri-cyclic products.

SYNTHESES OF S,N-HETEROCYCLES FROM N-THIOACYLLACTAMIMINES

Abstract Nitrile imines undergo cycloadditions to the thiocarbonyl group of N-thioacyllactamimines 1 giving 1,3,4-thiadiazolines 2. Depending on the substituents oxidation of N-thioacyllactamimines 1 leads to different products, such as condensed 5-amino-1,2,4-thiadiazolium bromides 5, 3,5-diaryl-1,2,4-dithiazolium salts 6, 3,5-diaryl-1,2,4-thiadiazoles 7 or 2-benzothiazolyliminopyrrolidine 8.

Ring-Chain Transformations of Semicyclic 3-Chloropropeniminium Salts to w-Aminoalkyl-1,2-oxazoles Using Hydroxylamine

Semicyclic 3-chloropropeniminium salts (2) or (8) react with hydroxyl- amine giving either ω-aminoalkyl-1,2-oxazoles (4, 6, 10) by ring chain transformation or chlorovinyloximes (7) by ring opening