Title

Non-random double strand cleavage of DNA by a monofunctional metal complex: Binding, mechanistic, and molecular recognition studies of ((2S,8R)-5-amino-2,8-dibenzyl-5-methyl-3,7-diazanonanedioate)copper(II)

Date of Completion

January 1998

Keywords

Biology, Molecular|Biology, Genetics|Chemistry, Biochemistry

Degree

Ph.D.

Abstract

Double strand breaks in duplex DNA are thought to be significant sources of cell lethality because they appear to be less readily repaired by DNA repair mechanisms. A study of the binding, mechanistic, and molecular recognition of ((2S,8R)-5-amino-2,8-dibenzyl-5-methyl-3,7-diazanonanedioato)copper(II) (1), which effects nonrandom double strand cleavage of duplex DNA is presented. Complex 1 creates double strand breaks via hydroxy radical $\rm (OH\cdot)$ produced through Haber-Weiss chemistry, which is directed to the DNA strand by hydrophobic and electrostatic binding recognition elements. The cleavage chemistry has also been studied kinetically, giving half-lives of 34.5, 20.8 and 100 min for single-strand breaks, double strand breaks, and base propenal release, respectively. Molecular recognition by the complex has been studied with relaxation and $\sp2$H NMR methods; these studies indicate that the scD, scL-phenylalanine-derived hydrophobic side chains interact with the DNA surface in an asymmetric fashion. ^