One-pot synthesis of a chromeno[4,3,2-de]-1,6-naphthyridine derivative from 4-chlorocoumarin-3-carbaldehyde

In the reaction of 4-chlorocoumarin-3-carbaldehyde with malononitrile in the presence of piperidine a crystalline piperidinium salt of a novel tetracyclic chromeno[4,3,2-de]-1,6-naphthyridine-2-carboxylic acid was isolated instead of the expected product of the "tert-amino effect". The structure of this piperidinium salt and its corresponding acidic form was characterized through spectral methods (IR, NMR, MS) and elemental analysis. In addition, the structure was established by means of X-ray crystallographic analysis. A theoretical multistep mechanism for this one-pot synthesis is discussed

Heterogeneous Hydrogenations in Continuous Flow

Catalytic heterogeneous hydrogenation processes arguably belong to the most valuable synthetic transformations known. [...

PKC-dependent coupling of calcium permeation through transient receptor potential canonical 3 (TRPC3) to calcineurin signaling in HL-1 myocytes

Cardiac transient receptor potential canonical (TRPC) channels are crucial upstream components of Ca2+/calcineurin/nuclear factor of activated T cells (NFAT) signaling, thereby controlling cardiac transcriptional programs. The linkage between TRPC-mediated Ca2+ signals and NFAT activity is still incompletely understood. TRPC conductances may govern calcineurin activity and NFAT translocation by supplying Ca2+ either directly through the TRPC pore into a regulatory microdomain or indirectly via promotion of voltage-dependent Ca2+ entry. Here, we show that a point mutation in the TRPC3 selectivity filter (E630Q), which disrupts Ca2+ permeability but preserves monovalent permeation, abrogates agonist-induced NFAT signaling in HEK293 cells as well as in murine HL-1 atrial myocytes. The E630Q mutation fully retains the ability to convert phospholipase C-linked stimuli into L-type (CaV1.2) channel-mediated Ca2+ entry in HL-1 cells, thereby generating a dihydropyridine-sensitive Ca2+ signal that is isolated from the NFAT pathway. Prevention of PKC-dependent modulation of TRPC3 by either inhibition of cellular kinase activity or mutation of a critical phosphorylation site in TRPC3 (T573A), which disrupts targeting of calcineurin into the channel complex, converts cardiac TRPC3-mediated Ca2+ signaling into a transcriptionally silent mode. Thus, we demonstrate a dichotomy of TRPC-mediated Ca2+ signaling in the heart constituting two distinct pathways that are differentially linked to gene transcription. Coupling of TRPC3 activity to NFAT translocation requires microdomain Ca2+ signaling by PKC-modified TRPC3 complexes. Our results identify TRPC3 as a pivotal signaling gateway in Ca2+-dependent control of cardiac gene expression