Κατεύθυνση Οργανική Χημεία
Library of the School of Science

2016-07-11

2016

Κοντομάρκος Δημήτριος

Αθανάσιος Γκιμήσης, Aναπληρωτής Kαθηγητής

Σύνθεση του άγλυκου και παραγώγων γνωστών αναστολέων της φωσφορυλάσης του γλυκογόνου: Μελέτη της επίδρασης στην σταθερά αναστολής

Greek

Aglycon and derivatives synthesis of glycogen phosphorylase inhibitors: Study of the effect on inhibition constants

Glycogen phosphorylase (GP) is an enzyme involved in glycogen degradation and
control of glucose levels in blood. This makes it a target for the development
of hypoglycemic drugs for the treatment of type 2 diabetes, a disease with a
great socio-economic impact. From previous studies, it has been known that β-
D-glucose and its derivatives bind in the catalytic site of GP, inhibiting its
action. This has led to the development of new strong catalytic site inhibitors
of GP. In our lab, a general synthetic scheme has been developed for accessing
β-D-glucopyranosylcytidines. Using this methodology, β-D-glucose has been
derivatized to compounds containing aromatic heterocycles at the anomeric
position and their inhibition constant has been found up to 104 times stronger
than that of glucose. In this thesis, we put forth the question whether the
aglycons of these strong inhibitors maintain part of the inhibition, in the
absence of sugar, or in the presence of a modified sugar. The synthetic targets
were aromatic heterocycles that proved useful intermediates for the synthesis
of new arylamines leading to novel potent inhibitors. Extension of the current
methodology led to the synthesis of new modified pyranosyl nucleosides, in
order to determine the effect to the inhibition constant of certain
modifications on the sugar or base. In total, 10 new compounds, parts or
derivatives of known strong inhibitors, were synthesized. For the successful
development of the chemistry required, a new selective substitution reaction of
2,4-dichloropyrimidine was developed and the products were hydrolyzed to the
corresponding pyrimidinones. The kinetic and crystallographic study of the new
inhibitors will provide new clues on the factors favoring binding within the
catalytic site and probably shed light on the binding reaction mechanism.

Glycogen phosphrylase , Inhibitors, β-D-glycopyranosylcytidines, Arylamines

Yes

13-19

Yes

56

161

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https://pergamos.lib.uoa.gr/uoa/dl/object/1320115