Chemistry Reference
In-Depth Information
values reported are examined, several agents appear have the potential to reach a
good reactivity provided their affi nity for DNA is increased.
As inspired by natural enzymes, the development of bimetallic systems should
be a promising strategy in order to increase the activity of the artifi cial hydrolytic
agents. In these systems, not only the intrinsic reactivity may increase as a result of
the cooperative action of the two metal centres, but also the DNA affi nity should
increase due to the larger positive charge of the complex and to the possibility of
multipoint interaction with the DNA phosphate backbone. As a matter of fact, two
of the most reactive agents so far reported, Liu's Fe(III)
2
- DTPB
33
and Que ' s Ce(IV)
2
-
HXTA,
29
are bimetallic. This strategy is particularly important, both in the case of
Zn(II)-based systems, as the intrinsic hydrolytic activity of this metal is somewhat
lower that that of the other ions, and in the case of lanthanide systems, since the
obtainment of nonlabile metal complexes with free coordination sites usually leads
to the use of polycarboxylic ligands which, as a drawback, reduce the reactivity of
these ions. Nevertheless, the binuclear agents so far reported are relatively few and,
in many cases, the reactivity gains are not so impressive when compared to the cor-
responding mononuclear complexes. Studies on model phosphate esters clearly
indicate that the design of such systems is more delicate than the simple synthesis
of ligands capable of binding two metal ions. The intermetallic distance and
the rigidity of the complex are crucial features in order to allow full cooperation
between the metal centres. Moreover, at least in the case of Cu(II)- and Zn(II)-
based agents, the formation of m-hydroxo bridges between the two ions can dramati-
cally decrease the reactivity and must, accordingly, be strictly avoided.
24a,53
Besides the realization of bimetallic systems, the main route toward the obtain-
ment of effi cient artifi cial agents requires, as mentioned before, an increase in the
affi nity of the hydrolytic complexes for DNA. The mechanism of the metal-ion-
catalysed hydrolysis of phosphate esters involves, as a crucial initial step, the coor-
dination of the substrate to the metal ion. This coordination is an essential requisite
in order to deliver the metal-ion-coordinated hydroxide nucleophile close to the
phosphate group, thus offsetting the electrostatic repulsion between the two nega-
tively charged species, and allowing the activation of the phosphate toward nucle-
ophilic attack. The metal-ion binding ability of phosphate diesters is rather poor and
it is only slightly favoured by the polyanionic nature of DNA. It is not accidental
that all the most reactive systems so far reported feature DNA affi nity elements,
such as two metal ions, intercalators, positively charged ammonium groups and ami-
nosugars. Even in the cases where DNA binding has not been investigated, such as
the Zn - (quercetin)
2
complex,
21
an effect of the poliphenolic ligand to increase the
substrate affi nity is probably present. However, the results reported indicate that the
simple conjugation of a metal complex to a DNA-binding unit is not suffi cient, par-
ticularly in the case of intercalating groups, and that a very careful design of the cata-
lyst structure is required. In fact, in order to obtain the desired activity, the binding
must lead to the correct geometry favouring a close contact between the metal
complex and the DNA phosphate backbone. In this context, it appears that the
design of the linker that connects the metal ion complex to the DNA-binding subunit
is of great importance and, in particular, its length and fl exibility. This is not an easy
task since these features may easily change depending on the DNA binding site
(major groove, minor groove, mismatches) and need to be tailored accordingly. In
