Dissertation committee:
1. Ιωάννη Κ. Κωστάκη, Αν. Καθηγητής, Τμήμα Φαρμακευτικής, ΕΚΠΑ
2. Εμμανουήλ Μικρό Καθηγητής, Τμήμα Φαρμακευτικής, ΕΚΠΑ
3. Αλέξιο-Λέανδρο Σκαλτσούνη, Καθηγητής, Τμήμα Φαρμακευτικής, ΕΚΠΑ
4. Νικολαίς Πουλή, Καθηγήτρια Τμήμα Φαρμακευτικής, ΕΚΠΑ
5. Ουρανία Τσιτσιλώνη Καθηγήτρια, Τμήμα Βιολογίας, ΕΚΠΑ.
6. Ανδρέα Τσοτίνη, Καθηγητής, Τμήμα Φαρμακευτικής, ΕΚΠΑ
7. Stefan Knapp, Professor, Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Germany
Summary:
The last years, there has been an increasing need to discover new drugs for various diseases such as cancer, COVID-19, Influenza A, and hepatitis. The rising number of patients and fatalities has made the need for effective and selective treatments imperative. Staurosporine1,2-Rutaecarpine3 and Meridianin4,5-Meriolin6,7, are well-known bioactive compounds that exhibit high potency against various targets. A wide range of natural and synthetic analogs of these compounds, possessing unique physicochemical and biological properties, have gained the interest due to their interference with complex biological pathways and pathologies in cancerous, viral and microbial infections. However, the clinical use of these drugs and their analogs is limited due to toxicity, poor bioavailability, pharmacokinetic issues and lack of selectivity. Therefore, there is an indispensable need to synthesize new drugs with intended anticancer and antiviral activity.
In this research work, the aforementioned multitargeted inhibitors were utilized as lead compounds for the design and synthesis of 4 novel scaffolds based on pyrazole and indole rings. These two heterocyclic moieties have been widely studied in drug discovery since the early stages of drug development. Numerous indole- and pyrazole-based bioactive compounds have been found to interfere with essential biological processes, such as cell proliferation and cell cycle regulation, which are implicated in cancer, inflammation or viral infections, when dysregulated.8–13 In my Ph.D., a vast number of 3-(pyrazol-4-yl)indole based compounds, have been designed and synthesized, in order to understand their implication in malignant and viral diseases. The new compounds were screened against a panel of 110 protein targets, particularly kinases and bromodomains, to discover the targets of interest (NAK kinases, IV family BDs, GSK3b, CLK1, etc.) and to highlight the important for the activity structural characteristics. The preliminary results indicated that the activity and selectivity of the new inhibitors is controlled by the substitutions of the 3-(pyrazol-4-yl)indole moiety and that both indole and pyrazole contribute to the binding to their targets.
The goal of my research work is the establishment of a model for the design and synthesis of novel high added value and selective 3-(pyrazol-4-yl)indole-based inhibitors against dysregulated protein kinases and bromodomains, that play a crucial role in the initiation and progression of various diseases. Through state-of-the-art research and experimental procedures, this work aims to assist in the investigation and understanding of the complex biological pathways and mechanisms involved in various types of tumors and viral infections. Additionally, it will identify and highlight promising novel compounds that can be considered for in vivo trials and future clinical use. This project will deepen our knowledge and expertise in the field of anticancer and antiviral research, and the dissemination of its results will provide valuable research tools to the drug discovery community.
