Structural Requirements for Selective DNA Binding - Studies on Mono- and Binuclear Ruthenium Complexes
Doktorsavhandling, 2012

Ever since the discovery of the role of DNA as the template for protein synthesis, efforts have been made to develop DNA targeted drugs. One of the major challenges in the design of DNA binding drugs is to achieve selective binding to specific DNA sequences, which is crucial to avoid side effects. In this thesis, the relationship between molecular structure and DNA binding properties for a group of ruthenium complexes is investigated with focus on sequence selectivity and binding affinity. In particular, threading intercalation, an unusual DNA binding mode sometimes observed for dumbbell shaped molecules, is examined. The study is motivated by the fact that threading intercalating binuclear ruthenium complexes previously have been shown to bind selectively to long stretches of AT-base pairs, which potentially can be used to target parasites with high AT-content in their genomes. The dissociation from DNA is also very slow, which is a property thought to be important for biological activity. In this thesis, it is demonstrated by spectroscopic DNA binding studies on four new binuclear complexes that threading intercalating ability is very sensitive to bridging ligand structure. The presence of a dppz-moiety is important for threading to occur and increased flexibility is not beneficial for this type of binding. Shortening of the bridging ligand increases the AT-selectivity but reduces the binding constant. Further, it is demonstrated that the enantioselectivity is different for the two DNA grooves. A new mononuclear threading intercalating complex with aryl substituents on the dppz-ligand is presented, for which it is shown that reduced complex charge can be compensated for by structural variations to maintain slow dissociation. Altogether, three new threading intercalators have been developed. From calorimetric studies on non-threading mononuclear complexes it is evident that cooperativity effects have large influence on binding to AT-DNA. Those effects are probably present also for threading intercalating binuclear complexes and may explain some of the observations made for such complexes. Finally, cell studies show that threading intercalation is possible also in the intracellular milieu and that binuclear complexes are internalized in live CHO-K1 cells, though endosomal escape may be a potential problem for biological applications.

ruthenium

enantioselectivity

sequence selectivity

spectroscopy

threading intercalation

calorimetry

kinetics

DNA

cell studies

KA-salen, Kemigården 4, Chalmers tekniska högskola
Opponent: Prof. Yitzhak Tor, Department of Chemistry & Biochemistry, University of California, La Jolla, USA

Författare

Johanna Andersson

Chalmers, Kemi- och bioteknik

Slow Threading Intercalation of Monomeric Ru(II) Complexes with 10,13-Diarylsubstituted dppz Ligands

Journal of Physical Chemistry B,; Vol. 115(2011)p. 7923-7931

Artikel i vetenskaplig tidskrift

Stereoselectivity for DNA Threading Intercalation of Short Binuclear Ruthenium Complexes

Journal of Physical Chemistry B,; Vol. 115(2011)p. 14768-14775

Artikel i vetenskaplig tidskrift

AT-Specific DNA Binding of Binuclear Ruthenium Complexes at the Border of Threading Intercalation

Chemistry - A European Journal,; Vol. 16(2010)p. 11037-11046

Artikel i vetenskaplig tidskrift

Styrkeområden

Nanovetenskap och nanoteknik

Livsvetenskaper och teknik

Ämneskategorier

Kemi

ISBN

978-91-7385-632-4

Doktorsavhandlingar vid Chalmers tekniska högskola. Ny serie: 3313

KA-salen, Kemigården 4, Chalmers tekniska högskola

Opponent: Prof. Yitzhak Tor, Department of Chemistry & Biochemistry, University of California, La Jolla, USA

Mer information

Skapat

2017-10-06