Department of Chemistry
Library of the School of Science

2021-06-28

2021

Mavreas Konstantinos-Fioravantes

Αθανάσιος Γκιμήσης, Καθηγητής, Tμήμα Χημείας, ΕΚΠΑ
Θωμάς Μαυρομούστακος, Kαθηγητής, Tμήμα Χημείας, ΕΚΠΑ
Μιχαήλ Ράλλης, Aν. Καθηγητής, Τμήμα Φαρμακευτικής, ΕΚΠΑ
Σταματία Βασιλείου, Αν. Καθηγήτρια, Τμήμα Χημείας, ΕΚΠΑ
Δημήτρης Γεωργιάδης, Καθηγητής, Τμήμα Χημείας, EKΠA
Αλέξανδρος Κουμπής, Καθηγητής, Τμήμα Χημείας, ΑΠΘ
Παναγιώτα Παπαζαφείρη, Αν. Καθηγήτρια, Τμήμα Βιολογίας, ΕΚΠΑ

Σύνθεση και μελέτη C-γλυκοπυρανοζιτών με πιθανή φαρμακολογική δράση

Greek

Synthesis and study of C-glucopyranosides with potential pharmaceutical action

Τhe main target of the present doctoral thesis was the synthesis of new, metabolically stable inhibitors of glycogen phosphorylase (GP), a central enzyme in the homeostasis of glucose, dysregulation of which has been implicated in pathological conditions, with type 2 diabetes mellitus and cancer being two prominent examples. For this purpose, synthetic methods were developed that led to two new families of inhibitors.
The new compounds are analogues of potent inhibitors with the structure of N2-aryl-substituted β-D-glucopyranosylcytosines, previously synthesized in our group, in which the chemically labile acetal glycosidic linkage has been replaced. More specifically, in the first part, C-β-D-glucopyranosyl analogues of the lead compounds were synthesized, including 5-(β-D-glucopyranosyl)- derivatives of uracil, isocytosine and 2-methylthiopyrimidin 4(3H)-one and N2-substituted with acrid-9-on-2-yl-, acrid-9-on-2-yl-1-methyl- and 1,3-dihydrobenzo[d]imidazole-2-on-5-yl- derivatives of 5-β-D-glucopyranosylisocytosine. The synthetic protocol included an organometallic coupling of appropriately protected D-glucono-δ-lactone and functionalized pyrimidine moieties, followed by reduction of the intermediate by trialkylsilanes in the presence of Lewis acids and consecutive substitution by arylamines, under acidic conditions, after a suitable trans-protection. In the second part, carbacyclic inositolyl-analogues of the lead compounds were synthesized, including 2-deoxy-scyllo-inositol-2-yl- and 6-deoxy-DL-chiro-inositol- derivatives of uracil and N4-substituted with acrid-9-on-2-yl-, and 1,3-dihydrobenzo[d]imidazole-2-on-5-yl- derivatives of 6-deoxy- DL-chiro-inositolylcytosine.
The synthesis was based on the coupling of suitably protected and functionalized inositols with pyrimidines, followed by a similar with above substitution by arylamines, under acidic conditions. The new compounds were subjected to in vitro kinetic assays and were found to act as GP inhibitors. By comparison with the lead compounds and utilization of a theoretical conformation study, an initial structure-activity relationship analysis was performed. The strongest inhibitors of each new class were subjected to a cell viability assay and, for the first time, a cytostatic effect was observed for inhibitors acting at the catalytic site of GP.

Science

C-glycosides, pyrimidine, glycogen phosphorylase inhibitors, cytostatic activity

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Yes

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https://pergamos.lib.uoa.gr/uoa/dl/object/2948059