Generation of Functionalized Azepinone Derivatives via a (4 + 3)-Cycloaddition of Vinyl Ketenes and α-Imino Carbenes Derived from N-Sulfonyl-triazoles.

An intermolecular RhII-catalyzed, formal (4 + 3)-cycloaddition between vinyl ketenes and N-sulfonyl-1,2,3-triazoles for the construction of azepinone products is described. Employing vinyl ketenes as a 1,4-dipolar surrogate, instead of the more commonly used dienyl moieties, allows for the intermolecular and selective formation of azepinone products over a potential (3 + 2)-cycloadduct under mild reaction conditions allows for the generation of azepinone products in up to 98% yield.

Rational Design and Identification of Harmine-Inspired, N-Heterocyclic DYRK1A Inhibitors Employing a Functional Genomic In Vivo Drosophila Model System.

Deregulation of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) plays a significant role in developmental brain defects, early-onset neurodegeneration, neuronal cell loss, dementia, and several types of cancer. Herein, we report the discovery of three new classes of N-heterocyclic DYRK1A inhibitors based on the potent, yet toxic kinase inhibitors, harmine and harmol. An initial in vitro evaluation of the small molecule library assembled revealed that the core heterocyclic motifs benzofuranones, oxindoles, and pyrrolones, showed statistically significant DYRK1A inhibition. Further, the utilization of a low cost, high-throughput functional genomic in vivo model system to identify small molecule inhibitors that normalize DYRK1A overexpression phenotypes is described. This in vivo assay substantiated the in vitro results, and the resulting correspondence validates generated classes as architectural motifs that serve as potential DYRK1A inhibitors. Further expansion and analysis of these core compound structures will allow discovery of safe, more effective chemical inhibitors of DYRK1A to ameliorate phenotypes caused by DYRK1A overexpression.

Diastereoselective Synthesis of Terminal Bromo-Substituted Propargylamines via Generation of Lithium Bromoacetylide and Addition to Chiral N-tert-Butanesulfinyl Aldimines.

The stereoselective synthesis of terminal bromo-substituted propargylamines via in situ generation of lithium bromoacetylide from 1,2-dibromoethene and addition to Ellman chiral N-tert-butanesulfinyl aldimines is reported. Modest to good yields (43-85%) and diastereoselectivity (dr = 3:1 to >20:1) were achieved for a range of aryl, heteroaryl, alkyl, and α,ß-unsaturated substrates. Terminal bromo-substituted propargylamines prepared via this method can be directly used in the frequently employed Cadiot-Chodkiewicz coupling to produce functionalized diynes. The method reported here increases the structural diversity of chiral terminal bromo-substituted propargylamines that can be readily synthesized as previous methods for the stereoselective synthesis of these compounds rely on amino acid precursors from the chiral pool.

Diverting ß-Hydride Elimination of a π-Allyl PdII Carbene Complex for the Assembly of Disubstituted Indolines via a Highly Diastereoselective (4 + 1)-Cycloaddition.

A Pd0-catalyzed formal (4 + 1)-cycloaddition approach to 2,3-disubstituted dihydroindoles is described. The diastereoselective formation of dihydroindoles that is highlighted by a carbene migratory insertion/reductive elimination sequence proceeding via a π-allyl PdII-species compliments existing methods of indoline assembly.

Evaluation of 1,2,3-Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX-770 and VX-809.

The 1,2,3-triazole has been successfully utilized as an amide bioisostere in multiple therapeutic contexts. Based on this precedent, triazole analogues derived from VX-809 and VX-770, prominent amide-containing modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), were synthesized and evaluated for CFTR modulation. Triazole 11, derived from VX-809, displayed markedly reduced efficacy in F508del-CFTR correction in cellular TECC assays in comparison to VX-809. Surprisingly, triazole analogues derived from potentiator VX-770 displayed no potentiation of F508del, G551D, or WT-CFTR in cellular Ussing chamber assays. However, patch clamp analysis revealed that triazole 60 potentiates WT-CFTR similarly to VX-770. The efficacy of 60 in the cell-free patch clamp experiment suggests that the loss of activity in the cellular assay could be due to the inability of VX-770 triazole derivatives to reach the CFTR binding site. Moreover, in addition to the negative impact on biological activity, triazoles in both structural classes displayed decreased metabolic stability in human microsomes relative to the analogous amides. In contrast to the many studies that demonstrate the advantages of using the 1,2,3-triazole, these findings highlight the negative impacts that can arise from replacement of the amide with the triazole and suggest that caution is warranted when considering use of the 1,2,3-triazole as an amide bioisostere.