Chemistry Reference
In-Depth Information
supercoiled form, in the presence of 25 mM complex concentration, to only 26
minutes.
In the last few years several other reports on copper complexes able to cleave
DNA have appeared in the literature.
26
In most cases, the authors suggest a hydro-
lytic mechanism, basing their proposal only on the observation of reactivity in
anaerobic conditions and on insensitivity to radical scavengers. However, although
these behaviours are compatible with a hydrolytic mechanism, they have also been
reported in the case of oxidative systems (see Section 13.2) and, therefore, they
cannot be taken as clear-cut mechanistic evidence. Particularly when a metal ion
such as Cu(II) is involved, the elucidation of the mechanism requires more stringent
evidence, such as, for example, enzymatic religation or chemical identifi cation of the
cleaved DNA fragments. In the absence of such experiments the fi nal decision on
the true nature of the DNA cleavage remains uncertain.
13.4 Bimetallic Complexes
The extraordinary catalytic effi ciency of natural metallonucleases most often relies
on the cooperative action of two or more metal ions. Available X-ray structures of
these proteins indicate that most of these metal ions are placed within a narrow
range of distances from each other.
2
Accordingly, in a synthetic catalyst a precise
spatial localization of the ions appears to be mandatory to ensure multiple interac-
tions with the substrate and, consequently, to take advantage simultaneously of all
the different activation modes that metal ions can provide for the hydrolysis of
phosphate esters (substrate, leaving group and nucleophile activation).
1b
On the
basis of these guidelines, a series of bimetallic complexes have been synthesized and
investigated as catalysts for the hydrolytic cleavage of DNA.
In 1996, Schneider and coworkers studied a 30-membered azacrown macrocy-
cle (Figure 13.9a) that can bind two Eu(III) or Pr(III) ions.
27
The Pr(III) complex
was able to promote plasmid DNA nicking with a
k
max
= 2.8
×
10
− 4
s
− 1
and
K
a
= 3.0
10
3
M
− 1
at 37 °C and pH 7.0. However, the activity of the binuclear complex
was only twofold that of the free metal ion.
More effective are the Er(III)
2
complexes of a Schiff-base-containing macro-
cycle (Figure 13.9b), proposed by Zhu and coworkers, which degrades supercoiled
DNA at 37 °C, pH 7.0 with a maximum rate constant of 1.0
×
×
10
− 3
s
− 1
.
28
Unfortunately
Figure 13.9
Macrocyclic ligands capable of binding two lanthanide ions reported by Sch-
neider (a) and Zhu (b)
