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 NFkappaB 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.
Stewart
Scott G
SG
The School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia Crawley, WA 6009, Australia. sgs@cyllene.uwa.edu.au
Braun
Carlos J
CJ
Ng
Sze-Ling
SL
Polomska
Marta E
ME
Karimi
Mahdad
M
Abraham
Lawrence J
LJ
D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D006801:Humans; D015394:Molecular Structure; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide