Unit:
Τομέας ΦΑΡΜΑΚΟΓΝΩΣΙΑΣ ΚΑΙ ΧΗΜΕΙΑΣ ΦΥΣΙΚΩΝ ΠΡΟΪΟΝΤΩΝLibrary of the School of Science
Supervisors info:
Αλέξιος- Λέανδρος Σκαλτσούνης Καθηγητής
Original Title:
Σύνθεση νέων αναλόγων ιντιρουμπίνης και αξιολόγηση τους ως αναστολείς της 5-LOX
Translated title:
Synthesis of new indirubins and their evaluation as 5-lox inhibitors
Summary:
Recent studies used indirubins to innovatively target 5-LOX at the ATP-binding
site. Finally 6BIO was identified as a potent, direct and reversible 5-LOX
inhibitor (IC50=1.5 μΜ).
The assessement of all the information described before led to the principal
aim of this master thesis: we synthesized 30 new indirubin derivatives, which
structurally can be separated in three categories: 1) 6BIO analogs with 5’
-substirution 2) benzo[g]indole derivatives and 3) isoprene derivatives of
indirubin.
The first results concerning the inhibitory 5-LOX activity of the derivatives
showed that:
• The prenylation decreased the activity on the isolated enzyme and in
the PMNLs.
• Geranylation could increase the activity.
• Modifications on 5’ position do not seem to affect the activity in the
ATP-binding pocket but they decrease the activity in the position where the
arachidonate binds.
• In addition the prenyl-group seems to be too bulky for the
ATP-binding-pocket and too sort to mimic the arachidonic acid and interact with
its binding pocket. Analogs that were only ATP-competitive (without isoprene
cains at all) and analogs more similar to the arachidonic acid (with long
isoprene chains such as geranyl and farnesyl), proved to be active.
Keywords:
Indirubin, 5-LOX, Enzyme, Leukotrienes, Inflammation
