Supervisors info:
Γεώργιος Κόκοτος Καθηγητής ΕΚΠΑ (επιβλέπων), Μαρία Κουφάκη Διευθύντρια Ερευνών ΕΙΕ, Βικτώρια Μαγκριώτη ΕΚΠΑ
Summary:
The goal of the present study was the design and synthesis of novel inhibitors
of sPLA2 possessing antioxidant and anti-inflammatory activity. The new
compounds combine in one molecular scaffold an antioxidant moiety and the amide
or oxoamide characteristic pharmacophores of sPLA2 inhibitors.
Specifically, amide derivatives encompass the unnatural amino acid γ-norleucine
connected with an antioxidant moiety through a chain of 7-8 carbon atoms. Thus
starting from the appropriate antioxidant (phenol, lipoic and caffeic acid and
vitamin E analogue) an aliphatic chain bearing a carboxylic acid functionality
was built. These intermediate acids were activated and then coupled with the
ethyl ester of γ-norleucine. Hydrolysis of the terminal esters afforded the
corresponding carboxylic acids which will be sent for biological evaluation.
Additionally, a 2-oxo-amide derivative, the
(8-(4-methoxy-phenyl)-2-oxo-octanoylamino)-acetic acid methyl ester, a phenolic
derivative with an aliphatic chain of 13 atoms was synthesized. As starting
material, 4-methoxybenzaldehyde was used and the chain length was then
increased by a Wittig reaction. Subsequent hydrogenation and conversion to
hydroxyl-carboxylic acid and coupling with glycine methyl ester followed by
oxidation afforded the final oxoamide. Moreover, we endeavoured to develop a
new method for the synthesis of 2-oxo-amide derivatives. The advantages of this
method over the previous one, are that the antioxidant compound will be coupled
to the oxoamide moiety at the final synthetic step, avoiding the harsh
conditions necessary for the formation of the oxoamide in the presence of
strong acid/base sensitive antioxidants.
Keywords:
Inhibitors of secreted phospholipase A2 (sPLA2), Oxidative stress, Lipoic acid , Vitamin E, Phenolic analogues
