ABSTRACT
Enantioenriched allenylsilanes are used in three-component propargylation reactions with aldehydes and silyl ethers to form syn-homopropargylic ethers that contain an imbedded azide. These materials then undergo thermally induced intramolecular 1,3-dipolar cycloaddition reactions, resulting in unique fused ring systems containing 1,2,3-triazoles. The ability to modify all three components of the reaction allows for expedient access to compounds containing significant structural and stereochemical variation.
Subject(s)
Alkynes/chemical synthesis , Azides/chemical synthesis , Aldehydes/chemistry , Alkynes/chemistry , Azides/chemistry , Cyclization , Ethers/chemistry , Molecular Conformation , StereoisomerismABSTRACT
A series of inhibitors of Pim-2 kinase identified by high-throughput screening is described. Details of the hit validation and lead generation process and structure-activity relationship (SAR) studies are presented. Disclosure of an unconventional binding mode for 1, as revealed by X-ray crystallography using the highly homologous Pim-1 protein, is also presented, and observed binding features are shown to correlate with the Pim-2 SAR. While highly selective within the kinase family, the series shows similar potency for both Pim-1 and Pim-2, which was expected on the basis of homology, but unusual in light of reports in the literature documenting a bias for Pim-1. A rationale for these observations based on Pim-1 and Pim-2 K(M(ATP)) values is suggested. Some interesting cross reactivity with casein kinase-2 was also identified, and structural features which may contribute to the association are discussed.
Subject(s)
Azepines/chemistry , Models, Molecular , Phenylpropionates/chemistry , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Proto-Oncogene Proteins c-pim-1/chemistry , Azepines/chemical synthesis , Binding Sites , Casein Kinase II/antagonists & inhibitors , Casein Kinase II/chemistry , Crystallography, X-Ray , Phenylpropionates/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Porphyromonas gingivalis, a recognized periodontal pathogen, is a source of sphinganine bases, fatty acids, free ceramides as well as complex lipids that potentiate interleukin-1b-mediated secretory responses in gingival fibroblasts. The purpose of this study is the structural verification of the sphinganine bases and fatty acids that had been proposed as major components of the complex lipids found in P. gingivalis. The putative C17, C18, and C19 sphinganine bases were prepared from Garner's aldehyde (1) or from a protected serine Weinreb's amide (2). We confirmed that isobranched sphinganine bases are the major structural feature of the ceramides observed from P. gingivalis. We also prepared a C17 unsaturated fatty acid, along with an isobranched C17 3-hydroxy fatty acid, and determined that the major component of the active lipids was the latter.
