Inhibition of the STAT3 Protein by a Dinuclear Macrocyclic Complex

A new
diethylenetriamine-derived macrocycle bearing 2-methylpyridyl arms
and containing m-xylyl spacers, L, was prepared,
and its dinuclear copper­(II) and zinc­(II) complexes were used as receptors
for the recognition in aqueous solution of a phosphorylated peptide
derived from a sequence of the STAT3 protein. A detailed study of
the acid–base behavior of L and of its complexation properties
as well as of the association of the phosphorylated peptide to the
receptor was carried out by potentiometry in aqueous solution at 298.2
K and I = 0.10 M in KNO3. The data revealed
that the receptor forms stable associations with several protonated
forms of the substrate, with constant values ranging from 3.32 to
4.25 log units. The affinity of the receptor for the phosphorylated
substrate studied is higher at a pH value where the receptor is mainly
in the [Cu2L]4+ form and the pY residue of the
substrate is in the dianionic form (pH 6.55). These results, also
supported by 31P NMR studies, showed that the phosphopeptide
is bound through the phosphoryl group in a bridging mode. Additionally,
the receptor inhibited binding between active (phosphorylated) STAT3
and its target DNA sequence in a dose-dependent manner (IC50 63 ± 3.4 μM) in human nuclear extracts in vitro. Treatment
of whole cells with the inhibitor revealed that it is bioactive in
living cells and has oncostatic properties that could be interesting
for the fight against cancer and other pathologies involving the STAT3
protein.