New quinolizinium derivatives: design, synthesis and study on biological and photobiological activity

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