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Fatema Yasser Al-Farhoud

Cytokine modulation by aminoacetylenic
isoindoline-1,3-dione compounds
by
Fatema Yasser Al-Farhoud
A Thesis Submitted in
Partial Fulfillment of the
Requirements for the Degree of
Master of Science
in Pharmaceutical Sciences
at
Petra University
Faculty of Pharmacy
Amman – Jordan
January, 2012
 
Cytokine modulation by aminoacetylenic
isoindoline-1,3-dione compounds
Under the supervision of Prof. Zuhair Muhi-Eldeen, and Prof. Khalid Matalka
 
Abstract
Aminoacetylenic isoindoline-1,3-dione derivative were synthesized from the reaction of potassium phthalimide with propargyl bromide to generate 2-(prop-2-yn-1-yl)-isoindoline-1,3-dione (ZM1). Treatment of 2-(prop-2-yn-1-yl)-isoindoline-1,3-dione with appropriate cyclic amines through Mannich reaction yielded the desired aminoacetylenic isoindoline-1,3-diones (ZM2, ZM3, ZM4, and ZM5). Since it was observed that these latter compounds have COX-1 and COX-2 inhibitory activities and reduce carrageenan-induced inflammation in rat paws, such results promoted us to investigate the effect of these compounds on pro-inflammatory and anti-inflammatory cytokines production in different conditions. The long goal, however, is to examine the potential effects of these synthetic compounds in treating or managing inflammatory diseases. It was found that these isoindoline-1,3-dione derivatives suppressed significantly spleen IL-17 in carrageenan and lipopolysaccharide (LPS)-stimulated mice; IL-12 and TNF-α in LPS-stimulated mice; and increased TGF-β in carrageenan and LPS-stimulated mice. In vitro studies, however, showed that ZM4 and ZM5 compounds and in dose-dependent manner increased significantly TGF-β and suppressed significantly TNF-α production from spleen cells stimulated with LPS+PMA (protein kinase C activator) more than LPS-stimulated spleen cells. On the other hand, no significant effect of either ZM compounds on IL-12 and IL-10 production from LPS or LPS+PMA stimulated  spleen cells.
 
Dedication
I would like to dedicate the fruit of this hard work to the soul of my late father who did not live to this moment to witness the success of his daughter. A special dedication with the greatest love and appreciation goes to my uncle, Hatem Al-Khawam, the leader and mentor of our family, who has always believed in my abilities and followed up my successes from the early stages of my life. I also dedicate this achievement to my caring and loving mother who taught me that success starts with one step and who gave me full support to reach this point. A special dedication goes to my special husband, Hussein Al-Mousawi, who gave me his full tolerance and never put obstacles in the way of my studies. I will never forget my brothers and sisters who stood on my side in hard times and difficult situations. Last but not least, I would like to dedicate this work to my son, Hashim, whose smile gave me the encouragement I always needed and effaced the fatigues of long hours of hard work.