Unit:
Department of ChemistryLibrary of the School of Science
Author:
Kokkala Paraskevi
Dissertation committee:
Δημήτριος Γεωργιάδης, Αναπληρωτής Καθηγητής ΕΚΠΑ
Ευστράτιος Στρατίκος, Ερευνητής Α΄, Ε.Κ.Ε.Φ.Ε. «Δημόκριτος»
Βικτωρία Μαγκριώτη, Επίκουρη Καθηγήτρια ΕΚΠΑ
Παναγιώτα Μουτεβελή-Μηνακάκη, Καθηγήτρια ΕΚΠΑ
Γεώργιος Κόκοτος, Καθηγητής ΕΚΠΑ
Διονύσιος Βουρλούμης, Ερευνητής Α΄, Ε.Κ.Ε.Φ.Ε. «Δημόκριτος»
Χριστόφορος Κόκοτος, Επίκουρος Καθηγητής ΕΚΠΑ
Original Title:
Σχεδιασμός και Σύνθεση Νέων Αναστολέων των Αμινοπεπτιδασών του Ενδοπλασματικού Δικτύου
Translated title:
Design and Synthesis of New Inhibitors of the Aminopeptidases of the Endoplasmic Reticulum
Summary:
The oxytocinase subfamily of M1 aminopeptidases (ERAP1, ERAP2 and IRAP) located in the Endoplasmic Reticulum has a critical role in the production of antigenic peptides and indirectly regulates human adaptive immune responses. We have previously demonstrated that phosphinic pseudotripeptides can be potent inhibitors of these enzymes. The object of this thesis is:
• The use of late-stage differentiation approaches for the stereoselective synthesis of phosphinic pseudotripeptides with various modifications at P1΄ position, aiming to find inhibitors with improved selectivity and in vivo activity profiles, conducting an extensive SAR study. In vitro enzymatic evaluation of the synthesized compounds revealed several potent nM inhibitors for all ERAPs and selective inhibitors mainly for ERAP2 and IRAP. These results are encouraging for further preclinical development of these inhibitors as regulators of adaptive immune responses.
• Τhe development of a novel, mild P-C bond forming reaction for the synthesis of phosphinic pseudodipeptides is presented in order to differentiate their N-terminus (P1 position), a key position in driving selectivity. At the next step the scope of the reaction was investigated, using a large variety of different substrates. In addition, a new mechanistic reaction pathway is formulated in conjunction with DFT calculations, which includes the formation of an active cyclic intermediate in the case of Η-phosphinic diacids. Finally, the final phosphinic dipeptides were evaluated as inhibitors of ERAPs
Main subject category:
Science
Keywords:
Organic Synthesis, Inhibitor, phosphinic acid, Amidoalkylation, Aminopeptidases
Number of index pages:
13
Number of references:
214
