Dissertation committee:
Σκαλτσούνης Αλέξιος-Λέανδρος (Επιβλέπων, Καθηγητής, Φαρμακευτική, ΕΚΠΑ)
Μητάκου Σοφία (Συμβουλευτική και Εξεταστική επιτροπή, Καθηγήτρια, Φαρμακευτική, ΕΚΠΑ)
Κωστάκης Ιωάννης (Συμβουλευτική και Εξεταστική επιτροπή, Αν. Καθηγητής, Φαρμακευτική, ΕΚΠΑ)
Χαλαμπαλάκη Μαρία (Εξεταστική επιτροπή, Αν. Καθηγήτρια, Φαρμακευτική, ΕΚΠΑ)
Μικρός Εμμανουήλ (Εξεταστική επιτροπή, Καθηγητής, Φαρμακευτική, ΕΚΠΑ)
B. Smith III Amos (Εξεταστική επιτροπή, Professor, University of Pennsylvania School of Arts & Sciences
Department of Chemistry)
Oberlies Nicholas (Εξεταστική επιτροπή, Professor, University of North Carolina at Greensboro
Department of Chemistry and Biochemistry)
Summary:
The strong relationship between Mediterranean diet and health has been reported by several epidemiological studies. Its effects are possibly linked to olive and olive oil, the foremost source of fat in the Mediterranean area. Olive products are characterized by the presence of bioactive phenolic compounds with the most typical being oleuropein, ligstroside, hydroxytyrosol, tyrosol, oleacein and oleocanthal, which all present bioactive potential. The latter has attracted the scientific and pharmaceutical industry interest. However, just a few of them can be extracted in a large amount from the natural matrix and there is an apparent high-cost efficiency of the process. Additionally, their application as preventive agents or drugs is limited by their low membrane permeability. Therefore, there is a need to develop efficient synthetic ways to reach natural and non-natural olive bioactive compounds derivatives. The semi-synthetic procedures stand for efficient and economical options for the synthesis of the phenolic derivatives compared to total synthesis. Thus, combining extraction methods with specific synthetic conversions can lead to new or already known olive active compounds. In our study, we developed an efficient, five-step, three-pot procedure for the semi-synthesis of oleuropein and oleocanthal analogues. The synthesis has been performed by a convenient biomimetic approach for the preparation of oleoside from oleuropein. The diacid of oleoside was transformed efficiently into the mixed anhydride by treatment with acetic anhydride in the presence of pyridine. The method was stereo controlled and provided an efficient approach to the synthesis of various analogues with remarkable good yields. During this thesis, 47 semi-synthetic analogues were synthetized. Moreover, we examined the biological activity (antioxidant, antimutagenic, anti-inflammatory and cytotoxic activities) of these analogues in vitro, using human and mouse cell lines (i.e., HepG2, HeLa, MCF-7, MDA-MB-231, BT-474, MKN45, EA.hy926, MiaPaca-2, PANC-1, and C2C12) and radical assays (i.e., ABTS•+, DPPH•, O2•−, and OH•). Our main purpose was to extract outcomes regarding the structure-activity relationships and understand their potential mechanism of action. The results revealed that several compounds presented increased biological activity compared to the parental molecule (oleuropein), and cell line specificity. Finally, in a parallel experiment we aimed to examine the composition of olive leaves, fruits, and stones of different cultivars. For this purpose, the composition was studied qualitatively and quantitatively in 22 cultivars, grown in the same grove, under the same agronomical and environmental conditions. This orthogonal approach, combining data from three olive organs, provided valuable and unique information, regarding the impact of olive cultivar and determined possible varietal markers. Moreover, the outcome of this study was to track down the cultivar with the most noteworthy oleuropein level to be utilized for the semi-synthesis of analogues.
Keywords:
Olea europaea L. leaves, Oleuropein, Oleacein, Oleocanthal, Olive, Potential anticancer agents, Semi-synthetic analogues
