Triorganogermanes as non-toxic reagents in radical reactions

Tributyltin hydride (TBTH) has proven to be an extremely useful synthetic reagent which has been widely used for generating free radicals, is largely responsible for the large increase in the use of free radicals in organic synthesis and is the reagent of choice for many researchers. However, the tin residues are highly toxic and difficult to separate from reaction mixtures which precludes the use of tributyltin hydride in the pharmaceutical industry. In this project, triorganogermanium compounds have been investigated as possible alternatives to tin-based radical mediators. [Continues.

Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition

PI3Kδ is a lipid kinase and a member of a larger family of enzymes, PI3K class IA­(α, β, δ) and IB (γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3Kδ inhibitors and describe a structural hypothesis for isoform (α, β, γ) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization