Dissertation committee:
Αθανάσιος Γκιμήσης Αναπλ. Καθηγητής ΕΚΠΑ (επιβλέπων), Κωνσταντίνα Γιαννακοπούλου Ερευνήτρια Α' ΕΚΕΦΕ «Δημόκριτος», Παναγιώτα Μουτεβελή-Μηνακάκη Αναπλ. Καθηγήτρια ΕΚΠΑ
Summary:
Cyclodextrins (CDs) are cyclic hollow oligosaccharide molecules that form water
soluble host-guest systems, with many applications in drug formulation and
delivery. CD oligomers have been previously studied due to the interest towards
smart hosts with enhanced molecular recognition and binding capacity as
sensors, catalysts, enzyme mimics, photoreactive systems, etc. The aim of this
dissertation was to prepare βCD oligomers for drug inclusion and transport with
criteria: (i) ease of preparation, in aqueous media, in short steps, under mild
conditions and in good yields, (ii) to obtain oligomers with satisfactory
aqueous solubility and full availability of the CD cavities (iv) to achieve
multiple binding with strengths better or comparable to those of parent βCD.
The copper catalyzed azide-alkyne cyclization (CuAAC) reaction was utilized to
prepare a new water soluble cyclodextrin trimer very efficiently. The trimer
engulfed three molecules of a model guest and satisfactorily solubilized the
chemotherapeutic tamoxifen citrate and its active metabolite, N
-desmethyltamoxifen, increasing their solubility by >1 order of magnitude.
Moreover, for the first time the bioorthogonal Staudinger Ligation was applied
to prepare βCD-dimers. For this purpose, a doubly active linker was
specifically developed that enabled dimer preparation in a single step, in
aqueous/organic media, under mild conditions and with high yields. The above
prepared products were studied in detail by NMR spectroscopy and were found to
adopt, by self-inclusion, a closed conformation in aqueous solution, which
completely opened up in the presence of a suitable guest, leaving the cavities
fully available to form the corresponding inclusion complexes. Titration and
DOSY NMR experiments confirmed the above and showed that the dimeric species
form slowly diffusing aggregates in water, that in the presence of the guest
partially disperse. The Staudinger Ligation could thus become the method of
choice for preparing CD dimers. Solubilization of practically insoluble N
-desmethyl-tamoxifen was also achieved to 0.3 mM. Moreover, CD dimers prepared
via amide bond formation were less efficient and required harsh conditions.
Finally, SNO-βCD derivatives were prepared and characterized as bimodal NO and
drug carrier systems.
Keywords:
Cyclodextrins, Oligomers, Staudinger Ligation, [3+2] Cycloaddition, Complexation
