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Various aromatic ketones were first functionalized next to the carbonyl function by deprotolithiation in the presence of a zinc salt followed by iodolysis. The outcome of the reactions was analyzed, and in particular their regioselectivity in the light of the calculated pKa values. Various halogenated ketones were next involved in copper-catalyzed twofold C-N bond formation to obtain fused systems based on 2-aminopyrimidines. Besides a potential antibacterial effect, 2-aminobenzothiopyrano[4,3,2-de]quinazoline was shown to inhibit PIM1 (IC50: 0.61 μM) and CDK2/cyclin A (IC50: 2.0 μM) kinases. [ABSTRACT FROM AUTHOR]

Necroptosis is a regulated form of cell death involved in several disease models including in particular liver diseases. Receptor-interacting protein kinases, RIPK1 and RIPK3, are the main serine/threonine kinases driving this cell death pathway. We screened a noncommercial, kinase-focused chemical library which allowed us to identify Sibiriline as a new inhibitor of necroptosis induced by tumor necrosis factor ( TNF) in Fas-associated protein with death domain ( FADD)-deficient Jurkat cells. Moreover, Sib inhibits necroptotic cell death induced by various death ligands in human or mouse cells while not protecting from caspase-dependent apoptosis. By using competition binding assay and recombinant kinase assays, we demonstrated that Sib is a rather specific competitive RIPK1 inhibitor. Molecular docking analysis shows that Sib is trapped closed to human RIPK1 adenosine triphosphate-binding site in a relatively hydrophobic pocket locking RIPK1 in an inactive conformation. In agreement with its RIPK1 inhibitory property, Sib inhibits both TNF-induced RIPK1-dependent necroptosis and RIPK1-dependent apoptosis. Finally, Sib protects mice from concanavalin A-induced hepatitis. These results reveal the small-molecule Sib as a new RIPK1 inhibitor potentially of interest for the treatment of immune-dependent hepatitis. [ABSTRACT FROM AUTHOR]

SUMMARY The horizontal semicircular canal of the inner ear is a unique feature of gnathostomes and is predated by the two vertical semicircular canals, which are already present in lampreys and some fossil, armored jawless vertebrates regarded as close relatives of gnathostomes. Inactivation in mice of the orthodenticle-related gene Otx1 results in the absence of this structure. In bony fishes and tetrapods (osteichthyans), this gene belongs to a small multigene family comprising at least two orthology classes, Otx1 and Otx2. We report that, as in the mouse, xenopus and zebrafish, Otx1- and Otx2-related genes are present in a chondrichthyan, the dogfish Scyliorhinus canicula, with an Otx1 expression domain in the otocyst very similar to those observed in osteichthyans. A strong correlation is thus observed in extant vertebrates between the distribution of the horizontal semicircular canal and the presence of an Otx1 ortholog expressed in the inner ear, which supports the hypothesis that the absence of this characteristic in Otx1-/- mice may correspond to an atavism. The same conclusion applies to two other gnathostome-specific characteristics also deleted in Otx1-/- mice, the utriculosaccular duct and the ciliary process. Together with functional analyses of Otx1 and Otx2 genes in mice and comparative analyses of the Otx gene families characterized in chordates, these discoveries lead to the hypothesis that some of the anatomic characteristics of gnathostomes have appeared quite suddenly and almost simultaneously in vertebrate evolution, possibly as a consequence of gene functional diversifications following duplications of an ancestral chordate gene. [ABSTRACT FROM AUTHOR]

Immunocytochemical studies have shown that peptides like Phe-Met-Arg-Phe-NH2 (FMRFamide) are widely distributed throughout the nervous system of three Nereidae. In Nereis diversicolor we have isolated these peptides from an extract of total worms by affinity chromatography and two steps of reversed-phase high-performance liquid chromatography. The sequences of the purified peptides have been determined by amino acid sequencing and on the basis of their reactivity with an anti-FMRFamide serum specific for the determinant Arg-Phe-NH2. Two primary structures have been established: Phe-Thr-Arg-Phe-NH2 (FTRFamide) and Phe-Met-Arg-Phe-NH2 (FMRFamide). Furthermore a methionine sulfoxide derivative of the FMRFamide has been identified. We have synthesized the FTRFamide peptide and in all cases, the native peptides were indistinguishable from the synthetic counterparts. The structure of the two native peptides and of the methionyl sulfoxide derivate have been confirmed by fast-atom-bombardment and tandem mass spectrometry. [ABSTRACT FROM AUTHOR]