ΠΜΣ με ειδίκευση ΣΥΝΘΕΤΙΚΗ ΦΑΡΜΑΚΕΥΤΙΚΗ ΧΗΜΕΙΑ
Library of the School of Science

2015-01-20

2015

Γρηγορίου Στυλιανός

Ε. Μικρός Καθηγητής (Επιβλέπων), Α. Λ. Σκαλτσούνης Καθηγητής, Π. Μαράκος Καθηγητής

Ανάπτυξη Εκλεκτικού Αναστολέα Πυραζολικού Υποστρώματος για τον Επιγενετικό Στόχο PB1(5)

Greek

Development of Selective Inhibitor Based on a Pyrazole Scaffold for the Epigenetic Target PB1(5)

Bromodomains are protein reader modules of the lysine acetylation state and are
involved in the epigenetic regulation of gene expression. Recently, a number of
landmark reports have revealed that the bromodomains are potential therapeutic
targets and their inhibitors act as anticancer, antiflammatory or antiviral
agents. In recent studies, conducted by our laboratory, a pyrazolocoumarin
derivative was identified to have binding affinity towards the fifth
bromodomain of PB1 protein, a subunit of the SWI/SNF-B remodeling complex.
X-ray crystallography revealed the interactions between the ligand and the
protein. In this study, based on those structure-activity relationships a
number of analogues were designed, synthesized and then tested. The rational
design was based on the use of SZMAP algorithm along with the Free Perturbation
Energy which suggested possible substitutions on the hit compound. Then, a
flexible synthetic approach resulted in the formation of new derivatives.
Starting with homophthalic acid, which is commercially available and cheap, and
thionyl chloride we synthesized the homophthalic anhydride. Subsequently, the
introduction of an a-keto side chain was achieved with the use of the
appropriate anhydride and the formation of the pyrazole ring was performed via
the use of monohydrate hydrazine. Moreover, substitution on the free
amino-group of our scaffold was achieved by using sodium hydride and an
appropriate nucleophilic. Moreover, in vitro evaluations and x-ray
crystallography of the new analogues justified the suggested approach since the
extended aliphatic chain improved the potency, of which the highest was 1.4μΜ,
by displacing a channel of water molecules inside the cavity

Epigenetic, Bromodomain, PB1(5), Inhibitor, Pyrazole

No

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Yes

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https://pergamos.lib.uoa.gr/uoa/dl/object/1315861