Projektowanie i synteza nowych inhibitorów kinaz tyrozynowych

Abstract

Powerful and safe pharmacological anti-cancer approach is the link in-between classical chemotherapy and gene-based therapy. Each type of cancer displays multiple intercellular signaling pathways, which may function independently or parallel and may couple each other. They may thus promote uncontrolled cell proliferation in different ways. Thus, the knowledge how to design new active molecules come from better understanding of relations and mechanism of action of the kinases participating in cancer progression. That objective may be pursued by means of biological assays of multitargeted inhibitors. In this regards the inhibitors of tyrosine kinases are well accepted drugs. For many years academia and the industry has been conducting extensive research in this field. Presented dissertation was aimed to verify how valuable is styrylquinazoline core (2-[(E)-2-phenylethenyl]quinazoline) as a framework of multi – selective kinase inhibitors. The work is focused around ligand design which should reveal selective antiproliferative effect toward cancer cells. Furthermore, author devoted his attention to the method of their multi-step synthesis. Nearly a hundred compounds were obtained including 4-amino and 4-sulfanyl derivatives. Their preparation process was initiated by condensation of styrylquinazolinones with aromatic aldehydes. In the next step the precursors were transformed into reactive benzenesulfonates, followed by amino or sulfanyl nucleophiles. Biological testing in vitro showed that obtained molecules are good kinase ligands and suppress proliferation of cancer cell lines. Particularly interesting are compounds which displayed compelling antiproliferative effect to multi-drug resistant lung cancer cell lines. These results made them more effective than clinical drug dasatinib.