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with the natural bases. This condition was verified when polymerases were used to extend
ss DNA containing either thymine or salicylaldehyde as ligands in the presence of Hg
or ethylene diamine and Cu , respectively [15i,40]. Bipyridine may be another candidate
for genetic code expansion because metal coordination to bipyridine ligands introduced
opposite a natural nucleobase in DNA (as well as PNA) duplexes had no effect on- or
caused a decrease in- the thermal stability of the duplexes [16a,41]. This result suggests
that the metal ion does not form an alternative base pair with mixed bipyridine-nucleobase
coordination. The decrease in the melting temperature upon metal addition may have been
caused by metal coordination to bipyridine only, which in turn may cause a distortion of
the duplex and/or a loss of stacking interactions.
Incorporation of multiple metal ions in adjacent positions within duplexes is likely to
depend on the overall charge of the metal complex and of the nucleic acid. In DNA
duplexes, the phosphodiester backbone can act as intrinsic counter anion for positively
charged metal complexes incorporated in the duplex and thus can mitigate electrostatic
repulsion between adjacent metal-ligand complexes. In DNA analogues that are neutral,
the electrostatic repulsion is weak if neutral metal complexes are incorporated in the
duplex.
10.3.2 Duplexes Containing One Alternative Metal-Ligand Base Pair with
Identical Ligands
Incorporation of a pair of ligands in complementary positions in the middle of DNA
duplexes creates a metal-binding site of [ n
m ] type, where n and m are the number of
donor atoms through which the two ligands coordinate to the metal ion. Metal binding
sites of the [ n
þ
n ] type are simpler to create because the same ligand-containing phos-
phoramidite can be used to incorporate the n -dentate ligand in both complementary
strands of the duplex. In the following paragraph, we describe the nucleic acid duplexes
that contain metal-mediated alternative base pairs reported to date according to their [ n
þ
þ
m ] coordination schemes.
10.3.2.1 [1
1] Coordination
Ag þ and Hg ions can form linear, two-coordinate complexes with monodentate ligands,
such as the nitrogen-coordinating thymine ( T ), pyridine ( Py ) and imidazole ( Imidazole) .
Both Ag þ and Hg have been shown to interact with nucleic acids duplexes. For exam-
ple, Hg forms [ T
þ
Hg T ] complexes in which Hg coordinates to the N3 atom of the
thymine nucleobase. This property of Ag þ and Hg has been exploited in recent years to
create [ T
Ag þ C ] alternative base pairs within DNA duplexes. For a
review of research on metal incorporation in DNA using as ligands natural nucleobases or
purine and pyrimidine derivatives, we refer the reader to reference [42].
b-Carbon ligandosides containing imidazole, 1,2,4-triazole ( Triazole) , or tetrazole lig-
ands had been synthesized [43]. The basicity and the related, metal-binding affinity of
these ligandosides decreases from imidazole, to 1,2,4-triazole, to tetrazole. In keeping
with this relationship, the imidazole ligandoside formed 2 : 1 complexes with both Ag þ
and Hg but the tetrazole did not form complexes with these metal ions (Figure 10.6).
The Triazole [44] and Imidazole [45] ligandosides have been incorporated in DNA
duplexes. These duplexes contained three pairs of ligands in the middle of their sequence
Hg T ]and[ C
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