Exploring new strategies of controlling DNA binding

Licentiatavhandling, 2009

Abstract Due to the increasing knowledge about DNA structure and function, as well as the fact that the sequence of the human genome is now known, DNA becomes more and more interesting as a drug target, especially for treatment of genetic diseases and cancer, but also for treatment of diseases caused by pathogens. However, one of the major challenges is to achieve specificity - in the case of genetic diseases to uniquely target a specific gene and in the case of the cancer and pathogens to target specific cells. The work in this thesis is based on two different strategies to control DNA binding: light controlled DNA binding of a photochromic spiropyran and the kinetic selectivity towards AT-rich DNA of binuclear ruthenium complexes. We have shown that due to the dramatically different DNA-binding properties of the two isomeric forms of a nitro-substituted photochromic spiropyran, binding of the spiropyran indeed can be controlled by light illumination, a strategy that potentially can be used to selectively activate DNA binding in specific cells. The closed spiro form shows no indication of interaction with DNA in absorption and linear dichroism experiments, while the open merocyanine form, obtained by illumination by UV light, has been shown to intercalate DNA. The process is fully reversible as the corresponding dissociation process is induced by visible light. Also, we have investigated the effect of structural changes to the bridging ligand of threading intercalating binuclear ruthenium complexes and found that the length and flexibility of the bridging ligand as well as the size of the intercalated aromatic ring system are factors that definitely affect threading ability. In addition to the known [bidppz(phen)4Ru2]4+ we have found a new threading intercalating complex, [dppzip(phen)4Ru2]4+, which appears to be a weaker threading intercalator than the parent compound but even more selective towards AT-DNA. Both ruthenium complexes may be interesting as model compounds for antimalaria drugs, since the genome of the malaria parasite P. Falciparum contains more than 80 % AT-DNA.