Modular Synthesis of Radicicol A and Related Resorcylic Acid Lactones, Potent Kinase Inhibitors

Abstract

Short and sweet: A concise and modular synthesis of radicicol A and related resorcylic acid lactones using fluorous isolation technology and immobilized reagents is reported (see scheme, RF=C3H6C6F13, TMSE=2-(trimethylsilyl)ethyl). The compounds are found to be potent (low-nanomolar) inhibitors of selected kinases. Despite their irreversible inactivation of kinases, they show good selectivity amongst a panel of 127 kinases

The Resorcylic Acid Lactone Hypothemycin Selectively Inhibits the Mitogen-Activated Protein Kinase Kinase-Extracellular Signal-Regulated Kinase Pathway in Cells

“…2,[5][6][7][8]14,15) Because the inhibition was time dependent and irreversible, these compounds were speculated to bind reversibly to targets and then form Michael addition products with protein thiols. Schirmer et al recognized that a cysteine residue adjacent the catalytically important DFG-motif is the cis-enone RAL binding site.…”

“…2,[5][6][7][8]14,15) Whether these compounds differ in selectivity has not been thoroughly investigated. The K i of hypothemycin for reversible binding to protein kinases varied as much as 10000-fold.…”

“…[2][3][4] Hypothemycin and other closely related cis-enone RALs gained attention as compounds that irreversibly inhibit certain protein kinases such as mitogen-activated protein kinase kinase (MEK), extracellular signalf-regulated kinase (ERK) and TAK1, but not RAF, protein kinase C (PKC) or protein kinase A (PKA). [5][6][7][8] From their structures and irreversible mode of action, cis-enone RALs were predicted to form stable Michael addition products with cysteine residues of protein kinases. Bioinformatics studies revealed that a cysteine residue that immediately precedes the highly conserved Asp-Phe-Gly (DFG) motif is the cis-enone RAL binding site.…”

Fluorous Linker Units

“…[58] Cross-metathesis of the linker with the vinyl borolane afforded trans-vinyl borolane 53. Treatment of 53 with t-BuLi followed by the addition of a tert-butyldiphenylsilyl (TBDPS) protected aldehyde led to the formation of product 54.…”

Polyubiquitination of Transforming Growth Factor β (TGFβ)-associated Kinase 1 Mediates Nuclear Factor-κB Activation in Response to Different Inflammatory Stimuli

“…Inhibitors-The TAK1 inhibitor chloro-radicicol A, compound 31, was prepared according to the previously reported procedure (17). Chloro-radicicol A was dissolved in dimethyl sulfoxide as a 10 mM stock solution and further diluted into buffer.…”