Dissertation committee:
ΚΟΚΟΤΟΣ ΓΕΩΡΓΙΟΣ, Καθηγητής ΕΚΠΑ
ΜΟΥΤΕΒΕΛΗ – ΜΗΝΑΚΑΚΗ ΠΑΝΑΓΙΩΤΑ, Καθηγήτρια ΕΚΠΑ
ΓΕΩΡΓΙΑΔΗΣ ΔΗΜΗΤΡΙΟΣ, Αναπλ. Καθηγητής ΕΚΠΑ
ΜΑΓΚΡΙΩΤΗ ΒΙΚΤΩΡΙΑ, Επικ.. Καθηγήτρια ΕΚΠΑ
ΒΑΣΙΛΕΙΟΥ ΣΤΑΜΑΤΙΑ, Επικ. Καθηγήτρια ΕΚΠΑ
ΤΣΟΤΙΝΗΣ ΑΝΔΡΕΑΣ, Καθηγητής ΕΚΠΑ
ΧΙΟΥ ΑΝΤΩΝΙΑ, Αναπλ. Καθηγήτρια ΧΠ
Summary:
Phospholipases A2 are a superfamily of hydrolytic enzymes that catalyze the hydrolysis of the sn-2 ester bond of the membrane phospholipids. The result of this hydrolysis is the release of fatty acids, including arachidonic acid (AA). Arachidonic acid through various enzymes is converted into a number of eicosanoids, such as prostaglandins, that are key mediators of inflammation, as well as other pathophysiological conditions such as autoimmune diseases, multiple sclerosis and cancer. Therefore, potent inhibitors of phospholipases A2 may be new agents to treat inflammation and pain.
Prostaglandins are a class of lipids that participate in both physiological (protection of the digestive and cardiovascular systems) and pathological conditions. They are produced by AA after the action of various enzymes, most notably the microsomal synthase-1 of prostaglandin E2 (mPGES-1). In particular, mPGES-1 is significantly increased in inflammatory tissues, and overexpressed in tumors. It is therefore considered a key enzyme for treating inflammatory conditions such as arthritis, atherosclerosis, stroke and cancer. For this reason, inhibitors of mPGES-1 may be new therapeutic agents for acute and chronic inflammatory conditions without the side effects of non-steroidal anti-inflammatory drugs.
In this thesis, the design and synthesis of compounds with inhibitory activity towards certain phospholipases A2, in particular GIVA cPLA2 and GVIA iPLA2, are described. 2-Oxoamides incorporating a sulfur atom in the β-position to the activated carbonyl were synthesized and studied in vitro for their inhibitory potency. Also, new 2-oxoesters and analogues were synthesized exhibiting potent inhibitory activity against GIVA cPLA2 and their metabolic stability was investigated. Subsequently, and in attempting to develop new compounds capable of inhibiting PGE2 production at cellular level, α-keto-benzothiazole compounds and their analogs were synthesized and studied. Among them, compounds able to inhibit the formation of PGE2 in mesangial cells at a submicromolar level were identified.
Keywords:
Anti-inflammatory, inhibitors, prostaglandin E2, synthesis, phospholipases A2
