Unit:
Κατεύθυνση Φαρμακευτική ΧημείαLibrary of the School of Science
Author:
Zografistou Marianthi
Supervisors info:
Πουλή Νικολαΐς, Καθηγήτρια, Τμήμα Φαρμακευτικής, ΕΚΠΑ
Μαράκος Παναγιώτης, Καθηγητής, Τμήμα Φαρμακευτικής, ΕΚΠΑ
Λουγιάκης Νικόλαος, Επίκουρος Καθηγητής, Τμήμα Φαρμακευτικής, ΕΚΠΑ
Original Title:
Σχεδιασμός, σύνθεση και μελέτη της κυτταροτοξικής δράσης νέων 3-ακυλο-7-αρυλαμινο παραγώγων της πυρρολο[2,3-c]πυριδίνης
Translated title:
Design, synthesis and cytotoxic activity evaluation of new 3-acyl-7-arylaminopyrrolo[2,3-c]pyridines
Summary:
Cancer is a multifactorial disease and its treatment is being studied intensively in order to improve the effectiveness and increase the survival rate of patients. It is characterised by genetic changes that affect the functioning of the cell cycle, causing uncontrolled cell proliferation. Anticancer drugs are classified into several categories, depending on their mechanism of action at the molecular level.
It has been found that cancer cells often exhibit mutations in protein kinases, enzymes that catalyse protein phosphorylation, which is the transfer of phosphate groups from ATP to another protein in the signaling pathway, ultimately leading to the regulation of transcription factors. This triggered the development of protein kinase inhibitors, small molecular weight drugs that compete with ATP at its binding site in the active site of the enzyme. As kinases are overexpressed in many cancers, protein kinase inhibitors suppress signaling pathways associated with uncontrolled cell proliferation.
Among the compounds that exert significant anticancer activity, or are being developed as inhibitors of protein kinases, a substantial amount are suitably substituted azaindole derivatives, which are structural analogs to biologically active purines. Several 7-azaindole derivatives have shown potent anticancer activity and are being clinically evaluated, and one of them has received marketing approval against metastatic melanoma.
Our research team has advanced in the discovery of new cytotoxic compounds bearing structural similarity to biologically active purine derivatives. The central bicyclic azaheterocycle is usually a pyrazolo- or pyrrolopyridine, bearing suitable substitution patterns. Several compounds were found to be endowed with interesting antiproliferative activity, and among them certain compounds exhibit low IC50 values concerning inhibition of protein kinases. Structure-activity relationships have been derived from this research and have been taken under consideration in the present work in the design of the basic skeleton, as well as to the nature and position of the ring substituents.
In this thesis we have chosen to use 6-azaindole (pyrrolo[2,3-c]pyridine) as the basic heterocyclic core. We substituted position 3 with aminoacetyl- or carboxamido- substituents, and position 7 with arylamino-substituents. The aim is to study the impact on cytotoxic activity of the presence of an amine aliphatic substitution on a carbonyl group directly linked to position 3 of the aromatic system, while maintaining the activity-favourable 7-arylamino substitution.
A total of nineteen (19) new 7-arylamino derivatives of 6-azaindole were synthesized, among them, seven (7) bear 3-aminoacetyl substitution, seven (7) bear 3-carboxamido substitution and five (5) bear 3-acetyl substitution. The new molecules have been synthesized using three synthetic pathways and a total of eleven (11) intermediates have been synthesized, while six (6) of them are novel compounds. Classic synthetic methods were used, while the possibility of using microwave irradiation for the shared final reaction of the synthetic pathways was also explored, which improved the yield of the reaction.
The cytotoxic activity of the novel compounds was tested using the MTT method and their ability to inhibit cell proliferation of human cancer cells was evaluated, while their effect against normal cells was also studied.
It became apparent that the carboxamide derivatives do not show interesting activity against both cancer cell lines tested and also lack toxicity against the normal cell line. The most remarkable results concern the aminoacetyl derivatives, several of which show activity at the low micromolar level against one or both cancer cell lines, while having low toxicity against the normal cell line, thus highlighting their potential for further exploration. Finally, among the 3-acetyl substituted derivatives, one showed satisfactory activity comparable to the aminoacetyl analogues and one retained activity in one of the cancer cell lines.
Main subject category:
Science
Other subject categories:
Health Sciences
Keywords:
Cancer, anticancer activity, purine analogues, MTT, 6-azaindole, toxicity, microwave irradiation
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