ABSTRACT
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 inâ 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 inâ vivo model system to identify small molecule inhibitors that normalize DYRK1A overexpression phenotypes is described. This inâ vivo assay substantiated the inâ 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.
Subject(s)
Drosophila Proteins/antagonists & inhibitors , Harmine/analogs & derivatives , Harmine/pharmacology , Heterocyclic Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Dose-Response Relationship, Drug , Drosophila , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drug Design , Harmine/chemical synthesis , Harmine/chemistry , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Humans , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship , Dyrk KinasesABSTRACT
An efficient and convergent (4+1)-cycloaddition strategy toward the construction of spirooxindole benzofurans that involves the intermediacy of an isatin-derived oxyphosphonium enolate is presented. Mechanistic investigations employing inâ situ NMR analysis of the reaction mixture revealed a correlation between phosphonium enolate structure and product distribution that was heavily influenced by the solvent and reaction temperature.
Subject(s)
Benzofurans , Isatin , Carboxylic Acids , Cycloaddition ReactionABSTRACT
The synthesis and crystal structures of two tris-(tri-alkyl-sil-yl)silyl bromide compounds, C9H27BrSi4 (I, HypSiBr) and C27H63BrSi4 (II, TipSiBr), are described. Compound I was prepared in 85% yield by free-radical bromination of 1,1,1,3,3,3-hexa-methyl-2-(tri-methyl-sil-yl)tris-ilane using bromo-butane and 2,2'-azobis(2-methyl-propio-nitrile) as a radical initiator at 333â K. The mol-ecule possesses threefold rotational symmetry, with the central Si atom and the Br atom being located on the threefold rotation axis. The Si-Br bond distance is 2.2990â (12)â Å and the Si-Si bond lengths are 2.3477â (8)â Å. The Br-Si-Si bond angles are 104.83â (3)° and the Si-Si-Si bond angles are 113.69â (2)°, reflecting the steric hindrance inherent in the three tri-methyl-silyl groups attached to the central Si atom. Compound II was prepared in 55% yield by free-radical bromination of 1,1,1,3,3,3-hexa-isopropyl-2-(triiso-propyl-sil-yl)tris-ilane using N-bromo-succinimide and 2,2'-azobis(2-methyl-propio-nitrile) as a radical initiator at 353â K. Here the Si-Br bond length is 2.3185â (7)â Å and the Si-Si bond lengths range from 2.443â (1) to 2.4628â (9)â Å. The Br-Si-Si bond angles range from 98.44â (3) to 103.77â (3)°, indicating steric hindrance between the three triiso-propyl-silyl groups.
