click on the pictures at right for other research projects in the Burgmayer Research group

Moco icon...Ru icon

molybdenum cofactor modeling-- --ruthenium interactions with DNA

metal pterin icon .....Tri icon

metals & pteridines--- --molybdenum tris-dithiolenes--


 

Ruthenium Pteridine Interactions with DNA

Molecules can bind to DNA through several types of interactions. Electrostatic interaction of positively charged molecules with the negatively charged DNA surface occurs within major and minor grooves. Intercalation interactions typically involve a planar molecular or portion of a molecule that can slip between the planes of GC and AT base pairs (shown at right). Intercalators frequnetly are designed to have an aromatic, heterocyclic ring structure which is particularly effective in inserting between the base pairs of a DNA helix. Intercalation interactions are stronger tthan electrostatic binding, but is most often studied because of its effect on DNA structure. Intercalative binding of a molecule forces the base pairs apart and distorts the helical shape of DNA where DNA distortions include bending, lengthening, and stiffening. An important consequence of DNA distortions is that they can prevent replication enzymes such as polymerase, helicase, and topoisomerase from recognizing their specific binding sites, thus inhibiting replication. For this reason, intercalators have substantial pharmaceutical applications and warrant extensive study.

The structural relationship of pteridines to the nucleic acids of DNA made us curious as to the effect of pteridine substitution on known intercalating complexes. The pteridine match to the purines and pyrimidines of DNA (shown at right, below) might be envisioned to disrupt base paring or to form triplex-like interactions, as well as allow for intercalation.

Ruthenium tris-chelate complexes, such as [Ru(II)(bpy)2DPPZ]2+, are known intercalators which have been extensively studied. Such ruthenium complexes have inherent photochemical stability, as well as redox and photophysical properties, that make it possible to utilize multiple physical techniques to study their interactions with DNA. We hypothesized that pteridine extensions onto a robust di-imine ligand might introduce new aspects into Ru complex binding studies. To this end wehave synthesized four new Ru(II)(bpy)2 complexes chelated by a phenanthroline ligand extended with dimethylalloxazine (phen-DMA), alloxazine (phen-alloxazine), diaminopteridine (phen-diaminopteridine) and pterin (phen-pterin). The resulting complexes are shown below.

The results of fluorescence titrations, viscometry, circular dichroism, plasmid unwinding and thermal denaturation studies on DNA in the presence of four pteridinyl complexes of Ru(II) can differentiate between electrostatic and intercalative binding mechanisms. While all four of the new complexes shown DNA interactions by fluorescence and absorbance titrations, viscometry, CD spectroscopy, DNA melting and plasmid unwinding experiments give evidence that only three complexes, [Ru(bpy)2(phen-dimethylalloxazine)]2+, [Ru Ru(bpy)2(phen-alloxazine)] 2+, and [Ru(bpy)2(phen-diaminopteridine)]2+ intercalate to calf thymus (CT) DNA. All five methods point to the same interpretation: three complexes— [Ru(bpy)2phen-alloxazine]2+,
[Ru(bpy)2phen-dimethylalloxazine]2+, and [Ru(bpy)2phen-diaminopteridine] 2+— can intercalate DNA nearly as well as ethidium bromide or [Ru(bpy)2DPPZ]2+, while [Ru(bpy)2phen-pterin]2+ shows little ability to disrupt the DNA structure and hence, no intercalation.

   
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