Artificial DNA Directed toward Synthetic Metallofoldamers - Metallofoldamers: Supramolecular Architectures from Helicates to Biomimetics - page 310

natural bases). Therefore, the HSAB principle should be considered and the inorganic
chemistry literature should be consulted for the binding constant and geometry of corre-
sponding metal complexes, if available. The redox and pH stabilities of the metal complex
in the aqueous media used in DNA chemistry should also be considered.
Figure 9.5f and g show for two ligands, which were extensively studied in DNA metal
base pairing, that the connection of the ligand moiety to the C1 0 position of the backbone
sugar may be achieved via an N -glycosidic bond (likewise to the natural nucleobases) or
via a C -glycosidic bond (which requires an sp 3 -sp 2 C - C coupling reaction as a key syn-
thetic step). Furthermore, the synthesis and use of the building blocks in automated DNA
synthesis may require the implementation of a suitable protecting group strategy. These
and other synthetic issues are discussed again in Section 9.3.3.
9.3.2 Model Studies
In case where the metal base pair design does not follow the example of a literature
known metal complex or the planned coordination chemistry is not trusted to work out in
the context of DNA chemistry, model studies and test experiments should be carried out
before the decision is made to synthesize a new ligand-functionalized nucleobase for the
incorporation into duplex DNA [33].
The required test experiments using simple model compounds based on the same lig-
and design or even the monomeric ligand-functionalized nucleoside might include:
(1) determination of the p K a value(s) of the donor site(s) of the ligand as a measure for
the prospective metal binding ability, (2) metal ion binding in aqueous buffer solution at
high ionic strength or at various pH values as monitored by NMR, UVand mass spectrom-
etry, (3) thereupon calculation of binding stoichiometry (Job's plot) and binding constant,
(4) preparation of single-crystalline samples of the coordination compound and compari-
son of the obtained X-ray structure with the structural features of (B-type) DNA and
(5) control experiments evaluating the influence of the used metal ions on unmodified
DNA (non-specific binding?) and likewise the compatibility of the prepared model com-
plexes in the presence of DNA in the solution.
Computer-aided model studies may include: (1) comparing the structures and energies
of alternative metal binding patterns by quantum mechanical modeling, (2) the generation
of a simple molecular mechanics (or even physical plastic) model in order to estimate the
impact of the metal base pair incorporation on the DNA secondary structure and (3) a
more sophisticated atomistic molecular mechanics or molecular dynamics (or even higher
theory level) model study considering the base stack integrity, helical twist, deviation
from linear duplex structure and other parameters affected by the metal base pair and the
surrounding solvent and counter ions.
9.3.3 Synthesis of Modified Nucleosides
Following the design of a new metal base pairing system, test experiments and modeling
studies, a synthetic strategy has to be developed for the successful incorporation of the
artificial nucleoside into DNA double strands. Figure 9.6 depicts the general strategy for
the synthesis of an N -or C -glycosidic nucleoside based on the standard DNA sugar 2 0 -
deoxyribose (note, however, that combinations of metal base pairing with backbone mod-
ifications such as open chain carbohydrates and peptides have also been described) [34].