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Digital archive of theses discussed at the University of Pisa


Thesis etd-02262012-221220

Thesis type
Tesi di dottorato di ricerca
Thesis title
Synthesis of new polycyclic systems with potential antitumor activity and Angiogenic biological studies
Academic discipline
Course of study
tutor Prof. Marini, Anna Maria
tutor Prof. D'Ocon Navaza, Maria Pilar
  • Angiogenesis
  • Cancer
  • DNA Topoisomerases
  • Tyrosine kinase inhibitors
Graduation session start date
DNA and the nucleus still represent the main target of the traditional “cytotoxic chemotherapy” for the treatment of cancer. A particular interest has been awarded to the DNA Topoisomerases (topos), essential enzymes that regulate the topological state of DNA during cellular processes such as replication, transcription, recombination, and chromatin remodeling. The ability to interfere with these enzymes or generate enzyme-mediated damage is an effective strategy for cancer therapy and DNA topos (I and II) proved to be excellent targets of clinically significant classes of anticancer drugs. In this connection, I performed the synthesis of a series of benzo- and pyrido-thiopyrano indoles, characterized by a planar mojety and pendant protonable dialkylaminoalkyl side chains, as new potential DNA intercalators and Topoisomerases inhibitors. The antiproliferative activity of the novel derivatives, as well as their ability to intercalate into the DNA and eventually inhibit the Topoisomerases were evaluated along the course of the thesis by a research group of the Faculty of Pharmacy of the University of Padua. A more recent and alternative strategy for the treatment of cancer is represented by the so called “biological therapy”, which is based on the disproportion of the signaling pathways controlling growth and differentiation, between normal and cancer cells. In particular, the molecular basis of tumour angiogenesis, the process of new vessel formation, has been extensively studied, and the Vascular Endothelial Growth Factor (VEGF) pathway has emerged as one of the most important positive modulators of this process. The founding that expression of VEGF and of its receptors correlates with the degree of vascularization of many experimental and clinical tumours led to the rational design and development of agents targeting this pathway, both selectively and with a multi-target action involving other tyrosine kinases responsible for tumour pathogenesis. In this regard I synthesized a series of benzo- and pyrido-thiopyrano-fused pyrimidines as new potential VEGFR inhibitors. Then the ability of the novel derivatives to inhibit the kinase activity of the VEGFR-2, as well as their cytotoxic effect were determined by the research group of the University of Padua. Moreover, as a part of the collaboration with the University of Valencia, I tested the anti-angiogenic activity of selected compounds in the ex-vivo “rat aortic ring assay”. My collaboration with the University of Valencia also regarded the partecipation to an extensive project on the study of the mechanism of action of Carvedilol and the Vasodilating Beta-Blockers. In particular I focused my studies on the evaluation of the relationship between adrenoceptors and angiogenic growth, through the “rat aortic ring assay”, on the analysis of the changes in the ARs gene expression induced by Carvedilol and/or by other α/β ARs agonists, by RT-PCR, and finally on the analysis of intracellular signals coupled to α/β ARs (ERK 1/2 activation), by western blotting.