Sequence specific recognition and photocleavage of DNA by phenanthrenequinone diimine complexes of rhodium(III)

Citation

Sitlani, Ayesha (1993) Sequence specific recognition and photocleavage of DNA by phenanthrenequinone diimine complexes of rhodium(III). Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/phhk-4s21. https://resolver.caltech.edu/CaltechTHESIS:01102013-100729852

Abstract

Sequence-specific recognition and photocleavage of DNA by a series of 9,10- phenanthrenequinone diimine (phi) complexes of rhodium(III) was studied. [Rh(phi)]^(3+) complexes bind to DNA via intercalation of their phi ligand and upon photoactivation promote strand scission. The DNA degradation products formed are consistent with photoreaction of [Rh(phi)]^(3+) intercalated in the major groove of DNA, via abstraction of the C3'-H atom of the deoxyribose. For the complex [Rh(phen)2phi]^(3+) and its derivatives [Rh(X)2phi]^(3+), the primary products are 5' and 3' phosphate termini and nucleic acid bases. For the complex [Rh(phi)2bpy]^(3+) and its derivatives [Rh(phi)2X]^(3+), additional products, dependent on dioxygen concentrations, are characterized as base propenoic acids and 3'-phosphoglycaldehyde termini. The partitioning between the oxygen dependent and oxygen independent pathways correlates best with how the shapes of these complexes limit access of dioxygen to the C3' deoxyribose position. The shapes of [Rh(phi)]^(3+) complexes also govern their sequence-specific DNA recognition. The more sterically bulky complexes with methyl or phenyl groups on their ancillary ligands cleave at a subset of sequences recognized by their parent molecules. The ∆ and Λ isomers of [Rh(5,5'-dimethylbpy)2phi]^(3+) cleave specifically at sites that are defined by the consensus sequences 5'-C-T-pu/py-G-3' and 5'-A-C/G-T-C/G-3', respectively. This sequence-specificity may be understood on the basis of negative steric clashes and positive van der Waals interactions between methyl groups on the metal complex and thymine methyl groups in the DNA major groove. The complex [Rh(4,4'diphenylbpy) 2phi]^(3+) recognizes the self-complementary eight base-pair sequence 5'CTCTAGAG- 3', both due to its bulky shape and its ability to cooperatively associate through non-covalent dimerization on the DNA helix. [Rh(4,4'-diphenylbpy)2phi]^(3+) is shown to inhibit sequence-specific cleavage by the restriction enzyme Xbal. It is likely that, like [Rh(phi)]^(3+) complexes, DNA binding proteins exploit shape selection to achieve high levels of sequence-specificity.

Thesis Files