Chemistry Reference
In-Depth Information
ligands that bear structural similarity to
Dipic
have been used to create [3
1] metal bind-
ing sites with
Py
in DNA, namely pyridine-2,6-dicarboxamide (
Dipam
; Table 10.1, entry
21) [63], pyridine-2,6-(N-methyl-)dicarboxamide (
Me-Dipam
; Table 10.1, entry 22) [63],
and 2,6-bis(ethylthiomethyl)pyridine (
SPy
; Table 10.1, entry 23) [47]. In the absence of a
metal ion, incorporation in DNA duplexes of any of the four tridentate ligands opposite a
pyridine destabilized the duplexes in a manner similar to that of a mismatch or prevented
completely the formation of a duplex.
Carboxamide ions, of which
Dipam
is an example, are the conjugate bases of amides.
They form readily in aqueous solution at neutral pH and coordinate to metal ions through
the amide nitrogen. For example, in neutral solutions of picolinamide and Cu
2þ
or Ni
2þ
,
a bis chelate complex forms in which the ligand is deprotonated and coordinated to
the metal ion through the pyridine and amide nitrogens [64]. The methyl carboxamide
group in
Me-Dipam
has a higher p
K
a
than the carboxamide group in
Dipam
, and thus the
protonation equilibrium at neutral pH is shifted towards the neutral form of the ligand and
reduces the ligand's metal-binding affinity. This reduction is further accentuated by the
steric effect of the methyl group. These considerations explain the relative stability of
DNA duplexes containing one of the first three tridentate ligands across pyridine in the
presence of hard metal ions, which decreases in the order [M(
Dipam
)
Py
]
>
[M(
Dipic
)
Py
]
þ
[M(
Me-Dipam
)
Py
] (Table 10.1, entries 20-22). In the presence of Cu
2þ
, the stabil-
ity of the duplexes that contained a central
Dipic
Py
or a
Dipam
Py
pair of ligands was
similar to or higher than that of duplexes with all-natural base pairs [10,63].
Interestingly, to achieve stabilization of the Dipam.Py modified double helix duplex, a
minimum amount of 15 equivalents of Cu
2þ
per duplex was required although for the
apparently less stable
Dipic
Py
duplex, one equivalent of Cu
2þ
was sufficient. Possible
explanations for this observation could be that the binding constant of Cu
2þ
to
Dipic
Py
is higher than that to
Dipam
Py
, and that either: (a) the binding constant does not corre-
late directly with the stabilization of the duplex, or (b) small steric (or electronic) factors
related to the presence of the proton on the carboxamide of
Dipam
have a subtle influence
on the duplex stability.
EPR spectroscopy has been used to demonstrate quantitative binding of Cu
2þ
to DNA
duplexes that contained a central
Dipic
Py
pair of ligands and to obtain information on
the coordination environment of Cu
2þ
[10]. The EPR spectrum of the ligand-modified
duplex in the presence of Cu
2þ
was rhombic, which is characteristic of a complex with
square planar geometry but does not exclude. Weak coordination of ligands to the axial
position of the complex. The
g
and hyperfine
A
Cu
values for Cu
2þ
and the superhyperfine
A
N
values determined by simulation of the spectrum were close to those measured for the
synthetic [Cu(
Dipic
)(
Py
)] complex [65]. The square planar geometry of the [3
>
1] Cu
2þ
complex was further confirmed by a crystal structure of a related DNA duplex, which
contained two isolated
Dipic
-Cu
2þ
-
Py
alternative base pairs [66] (see Section 10.4).
By virtue of its coordination through sulfur, the
Spy
ligand is a soft Lewis base and has
a high affinity for soft metal ions. The addition of one equivalent of Ag
þ
to the duplex that
contained a
Spy
Py
pair led to an increase in duplex stability compared to the metal-free,
ligand-modified duplex (Table 10.1, entry 23). Although this ligand pair was designed
specifically to bind a soft metal ion, addition of other soft Lewis acids such as Pd
2þ
,Pt
2þ
,
or Au
3þ
had no effect on the duplex stability. The same selectivity for one metal ion has
been observed, for example, for DNA duplexes that contained a
Dipic
Py
pair of ligands.
þ
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