New thalidomide analogues derived through Sonogashira or Suzuki reactions and their TNF expression inhibition profiles

A library of new thalidomide C4/5 analogues containing either a phenyl or alkyne tether were synthesized using Sonogashira or Suzuki cross coupling reactions from their aryl halogenated precursors. All thalidomide analogues were tested for their ability to inhibit the expression of the proinflammatory cytokine Tumor Necrosis Factor (TNF). More explicitly the use of a novel reporter system utilizing the promoter region of the TNF gene in a human T-cell line provided a rapid and effective measure of NFκB transcriptional activity. Several compounds either containing either an aryl-isobutyl or aryl-isopropoxy group were the most effective in inhibiting TNF expression, and were several times more active than thalidomide itself. Five of the more active derivatives indicated an apoptotic response while one of these compounds, containing an aldehyde tether, showed possible influence of cell cycling effects.

Thalidomide analogues containing either a phenyl or alkyne tether were prepared using cross coupling reactions. Several analogues were far more efficient in the inhibition of the expression of the Tumour Necrosis Factor (TNF) monitored through a novel reporter system. Several derivatives showed increased cytotoxicity due to induction of an apoptotic response.Figure optionsDownload as PowerPoint slide