Kaname Kimura

Protein kinase C modulators bearing dicarba-closo-dodecaborane as a hydrophobic pharmacophore

The size and position of a hydrophobic moiety on a benzolactam skeleton, which reproduces the active conformation and biological activity of teleocidins, play an important role in the appearance of the activity. We have designed and synthesized benzolactams bearing dicarba-closo-dodecaborane. These compounds showed potent binding affinity to protein kinase C, providing a further example of the application of carborane as the hydrophobic pharmacophore of biologically active molecules.

Effects of ortho-substituent groups of sulochrin on inhibitory activity to eosinophil degranulation.

Sulochrin, a metabolite of fungi, has been shown to have an inhibitory activity to eosinophil degranulation. A series of sulochrin derivatives substituted at ortho-positions to the 10-carbonyl group was examined the activity. The importance of alkylester at C-6 position and several chemical properties of substituted groups at ortho-positions to exhibit activity are described.

Synthesis, computer modeling and biological evaluation of novel protein kinase C agonists based on a 7-membered lactam moiety

4-Hydroxymethyl-5a-methyl-1,3,4,5,5a beta,6,7,8,9,9a alpha-decahydro-2H-benz[d]azepin-2-ones (4-12), which were designed to mimic the biologically active conformation of teleocidins and benzolactams, were synthesized and evaluated for the ability to compete with [3H]phorbol 12,13-dibutyrate in a PKC delta binding assay. Among the compounds, 10-12 showed potent binding affinity, with inhibition constants (Ki) of low nanomolar order. Computational docking simulation also indicates that the relative positions of the hydrogen-bonding sites and hydrophobic regions of the compounds are well matched to the PKC delta binding site.

Synthesis and Evaluation of [2-(4-Quinolyloxy)phenyl]methanone Derivatives: Novel Selective Inhibitors of Transforming Growth Factor-β Kinase

We synthesized and evaluated various [2-(4-quinolyloxy)phenyl]methanone derivatives. These compounds had novel chemical structures that were distinct from those of previously reported inhibitors. Biological data suggested that these compounds inhibited transforming growth factor-beta signaling by interacting with the ATP-binding pocket of the transforming growth factor-beta type I receptor kinase domain. Here, we report on the synthesis and structure-activity relationships of the compounds in this series.