Design, synthesis and pharmacological evaluation of 4,7 disubstituted pyrimido[4,5-d]pyrimidines as potent inhibitors of EGF and VEGF-2 receptors in Glioblastoma Multiforme’s treatment

Postgraduate Thesis uoadl:2864702 280 Read counter

Unit:
Κατεύθυνση Σχεδιασμός και Ανάπτυξη νέων Φαρμακευτικών Ενώσεων - Φαρμακευτική Χημεία
Library of the School of Science
Deposit date:
2019-03-05
Year:
2019
Author:
Christopoulou Kalliopi
Supervisors info:
Κωστάκης Ιωάννης, Επίκουρος Καθηγητής του Τομέα Φαρμακευτικής Χημείας, Τμήμα Φαρμακευτικής, Σχολή Θετικών Επιστημών, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Original Title:
Σχεδιασμός, σύνθεση και φαρμακολογική αξιολόγηση 4,7 δισυποκατεστημένων πυριμιδο[4,5-d]πυριμιδινών ως πιθανών αναστολέων των υποδοχέων EGF και VEGF-2 στη θεραπεία του Πολύμορφου Γλοιοβλαστώματος.
Languages:
Greek
Translated title:
Design, synthesis and pharmacological evaluation of 4,7 disubstituted pyrimido[4,5-d]pyrimidines as potent inhibitors of EGF and VEGF-2 receptors in Glioblastoma Multiforme’s treatment
Summary:
Glioblastoma Multiforme (GBM) is the most common and aggressive type of primary malignant brain tumors, constitutes approximately 50% of gliomas and 20% of all the brain tumors. It grows aggressively within weeks and has an overall survival of 14 months. Thus the development of novel therapeutic modalities is essential for improving the poor prognosis of patients with GBM.
The lack of specificity and limited efficacy of the existing therapies has shifted the research to the rational design and development of innovative targeted molecular therapies. Recent studies are based on the synthesis of low molecular weight compounds which inhibit tyrosine kinases (Tyrosine Kinase Inhibitors-TKI’s) which are related to the disease’s evolution.
The present thesis refers to the design, synthesis and pharmacological evaluation of two generic analogs of 4,7 disubstituted pyrimido[4,5-d]pyrimidines which are potent inhibitors of the EGF and VEGF-2 receptors. General formula I refers to diphenylurea substituted compounds at the 4-aniline site of the basic scaffold of pyrimidopyrimidine, whereas general formula II, relates to molecules having aromatic substitution at the 4-anilinal site.
The design of the compounds was carried out through docking studies, at crystallized protein kinases EGFR (PDB code: 2YTI) and VEGFR-2 (PDB code: 2OH4). The selectivity of the derivatives towards the active site of each protein (EGFR and VEGFR-2) increases, while changing the 4-anilinal substitution.
The synthesis of the final molecules was carried out through the reaction of appropriate aniline substituted molecules and the basic imine backbone in acetic acid.
Finally the pharmacological evaluation was performed on some selected compounds of type I and II in GOS-3, T98G and 1321N1 Glioblastoma Multiforme cell lines through the XTT assay.
The first results estimate the pyrimidopyrimidine analogs with the diphenyurea substitution on the 4-aniline site of the compounds, having the greatest cytotoxicity. However the results are encouraging for further investigation.
Main subject category:
Science
Other subject categories:
Health Sciences
Keywords:
protein kinases, Glioblastoma Multiforme, EGFR, VEGFR-2, kinase inhibitors
Index:
Yes
Number of index pages:
1
Contains images:
Yes
Number of references:
177
Number of pages:
95
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