Neoplastic diseases have become one of the most important causes of death in the world. In USA, cancer is the second cause of death after the cardiovascular diseases. Therefore, the research, the discovery and the development of new compounds with antitumoral activity have become one of the most important goals in medicinal chemistry, also trying to make a selective toxicity towards the diseased or cancer cells, thus not involving the healthy cells. Many therapeutic approaches are available for the treatment of cancer in clinical use: surgery, radiotherapy are used for localized cancer; chemotherapy, hormone-therapy and immunotherapy are considered useful, as systemic treatments, for leukemia and metastatic tumours. In the chemotherapy a high number of molecules interacts with nucleic acids like groove binders, alkylating and intercalator compounds. The molecules that belong to the latter class, interact with DNA by intercalation in the base pairs through van der Waals interactions, hydrogen bonds, hydrophobic and/or charge transfer forces. Therefore, these molecules have attracted, during their development, particular attention as chemotherapeutic agents in medicinal chemistry because the consequences of DNA intercalation by exogenous molecules lead to a significant modification of the DNA structure and may result in a hindered or suppressed function of the nucleic acid in physiological processes. But the clinic application of these compounds has shown some problems such as multidrug resistance (MDR), and secondary and/or collateral effects. These shortcomings have motivated the search of new compounds to be used either in place of, or in conjunction with, the existing molecules.
Condensed poly(hetero)aromatic compounds are usually regarded as representative DNA intercalators, especially if they contain electron-deficient or charged aromatic cores in the structure. Measurement of the binding constant and biological activity of DNA-intercalator complexes and QSAR studies lead to the conclusion that there should exist a relationship between cytotoxic activity and binding force. Otherwise, cytotoxicity is not only dependent on the ability to interact with DNA, since there are many DNA intercalators that are incapable of working as cytotoxic agents: to be effective, a drug must first overcome many barriers, including metabolic pathways, cytoplasmatic and nuclear membranes. Cytotoxicity could be also a consequence of the poisoning of topoisomerases, enzymes that are directly involved in DNA recognition and that regulate DNA topology. They induce cytotoxicity when they act as poisons towards the enzymes by stabilizing the ternary DNA-intercalator-topoisomerase complex in such a way that the enzymatic process cannot continue forward or backward. This complex is detected by the cell as a damaged portion, which triggers a series of events such as cell apoptosis.
Some compounds, called photonucleases, which induce DNA damage after UV-VIS-irradiation, have become interesting; while the association of cationic dyes to DNA is a reversible process, the DNA damage, which frequently occurs on irradiation of ligand-DNA complexes, is often irreversible. The latter DNA damage may lead to cell death or mutation, and must be avoided in healthy systems. However, this photoinduced DNA-damage may be applied in photochemotherapy to remove unwanted cells.
Among the compounds investigated along these lines, the quinolizinium derivatives, such as coralyne and the related molecules, have attracted particular attention. They are arenes containing quaternary bridgehead nitrogen atom and have been shown to bind to DNA and may be employed as a central unit in DNA-targeting drugs. During the studies of the influence of the substituition pattern of quinolizinum derivatives on their intercalation with DNA, it has been shown that the chemical structure of the tetracyclic naphtho[1,2-b]quinolizinium bromide 2 has interesting properties with respect to the binding to nucleic acids. In particular, these intercalators may exhibit a stronger interaction with nucleic acids as compared with the tricyclic benzo[b]quinolizinium 1: the additional benzene moiety extends the surface of the planar chromophore and increases the stacking between the dye and the DNA bases, resulting in higher binding constants. Other important aspects are represented by the photobiological properties: it was shown that an efficient DNA-strand cleavage is photoinduced by the naphtho[1,2-b]quinolizinium bromide 2.
The compounds synthesized and analyzed in this project were 3-aryl-substituted-naphtho[1,2-b]quinolizinium derivatives; then studies about the DNA-binding properties and cytotoxic activity were carried out. The investigation of these compound allows to evaluate the effects of the extension of system, by the introduction of fourth aromatic ring, and the effects of the substituent in position 3. This position was chosen for structural analogy with some tricyclic benzo[b]quinolizinium 1, with better biological activity with respect to the not-substituted compound. After these, experiments in comparison to the naphtho[1,2-b]quinolizinum bromide 2, without substituents in position 3, to investigate preliminary molecular target (topoisomerase I and II), to attempt a structure-relactionship-activity and finally photobiological tests will be carried out
