Title

Copper complexes bearing pendant, protonatable noncoordinating groups: Synthesis, structural characterization and DNA cleavage activity

Date of Completion

January 1998

Keywords

Chemistry, Biochemistry|Chemistry, Inorganic

Degree

Ph.D.

Abstract

Copper proteins belong to a class of metalloproteins which possess unusual spectroscopic properties and a wide range of redox potential. Low molecular weight synthetic analogues have been used to help explain these unique properties. The pyridine-carboxaldehyde Schiff base derivatives of the parent complex (5-amino-5-methyl-3,7-diaza-1,9-nonanedioate) (chloro) copper(II) have been synthesized and characterized to serve as functional models for the electrostatic interactions in copper proteins. The changes in their spectroscopic properties and redox potential have been found to be largely dependent on the distance from the metal center and orientation of a proximate, noncoordinated positively-charged group.^ Previous work in our laboratory has shown that a simple monofunctional copper(II) coordination complex, ((2S,2R)-5-amino-2,8-dibenzyl-5-methyl-3,7-diaza-$1 ,9$-nonanedioate)copper(11) (1), equipped with essential recognition elements, can effect nonrandom double-strand DNA cleavage similar to those of enediynes and bleomycins. Related copper(II) complexes have been designed and synthesized to investigate the efficiency of double-strand break (dsb) formation in duplex DNA as a function of structure.^ In the course of the synthesis of the (2S,2S)- or (2R,2R)- diastereomers of 1, an intermediate has been trapped, crystallized and identified as ((2S)-5- amino-2-benzyl-6-hydroxy-5-methyl-3-azahexanoate)copper(II) or its (2R)-enantiomer. A possible reaction mechanism for the synthesis of the intermediate under the reaction condition used is proposed.^ The variation in the cleavage efficiencies of 1 versus the other four complexes appears to be due to differences in binding DNA rather than differences in reactivities. The most efficient double-strand DNA cleavage agents are the two intermediate enantiomers which contains only a single hydrophobic moiety. It seems that the presence of two hydrophobic side chains sterically hinders binding and/or intercalation between DNA bases. ^