Unit:
ΠΜΣ με ειδίκευση ΣΥΝΘΕΤΙΚΗ ΦΑΡΜΑΚΕΥΤΙΚΗ ΧΗΜΕΙΑLibrary of the School of Science
Supervisors info:
Κουρουνάκη Αγγελική Αναπλ. Καθηγήτρια
Original Title:
Δομικές τροποποιήσεις αντιοξειδωτικών μορίων προς ενίσχυση της in vitrο/in vivo αντιοξειδωτικής, αντιφλεγμονώδους ή/και αντιυπερλιπιδαιμικής τους δράσης
Summary:
Cardiovascular diseases are the leading cause of death in most developed
countries. They are mainly caused by atherosclerosis, a chronic vascular
disorder which is characterized by three main processes: inflammation,
oxidative stress and hypercholesterolaemia-hyperlipidaemia. Both prevention and
treatment are challenging due to the multifactorial nature of atherosclerosis.
So far there are several therapeutic strategies, among which treatment with
multifunctional molecules, i.e. one molecule combining multiple activities, has
several advantages.
The purpose of this study is the design and development of derivatives which
combine antioxidant, antiinflammatory and/or antihyperlipidemic activity. Nine
new derivatives were designed by combining structural features of known
molecules with respective activities in order to enhance/extend their
pharmacological profile. Specifically, three new morpholine derivatives, one
thiomorpholine and five new ester derivatives of known antioxidants and/or
anti-inflammatory molecules were synthesized and their structures verified by
1H and 13C NMR spectroscopy.
The new molecules were pharmacologically evaluated in vitro, in four separate
assays; from their interaction with the free radical of DPPH they exhibited
EC50 values between 24 to 240 mM while their inhibition of lipid peroxidation
of rat microsomal membranes was determinded with IC50 values between 0.6 μΜ to
70 μΜ, for the most active molecules. One of the derivatives was tested for its
cytoprotective effect in a fibroblast cells (primary culture) after UV
radiation, resulting in an increase in cell viability. Finally,
anti-inflammatory activity was evaluated in vitro via their inhibition of
lipoxygenase. Interestingly, all new compounds exhibited significant inhibition
of the enzyme with IC50 ranging from 0.09 to 194 μM.
The in vivo pharmacological activity of the derivatives was evaluated in two
different protocols: a hypercholesterolaemia mouse model and an inflammation
mouse model. In the first protocol, compounds reduced after 24h plasma total
cholesterol up to 42% and triglycerides levels up to 70%. They also increased
the plasma total antioxidant capacity up to 75%. In the second, inflammation
expressed as mouse paw edema was reduced up to 60%.
The results point to structure activity relationships that are discussed, and
confirm the successful enhancement of the pharmacological activity profile of
the designed new derivatives. Thus, they may be considered as potentially
interesting agents for the treatment of multifactorial diseases such as
atherosclerosis, type II diabetes and/or neurodegeneration.
Keywords:
Atherosclerosis, Antioxidant, Antihyperlipidaemic, Antiinflammantory, Morpholine derivatives
File:
File access is restricted.
document.pdf
3 MB
File access is restricted.
