Rational Design of Copper(II)–Uracil Nanoprocessed Coordination Polymers to Improve Their Cytotoxic Activity in Biological Media

This
work is focused on the rational structural design of two isostructural
Cu­(II) nano-coordination polymers (NCPs) with uracil-1-acetic acid
(UAcOH) (CP1n) and 5-fluorouracil-1-acetic acid (CP2n). Suitable single crystals for X-ray diffraction studies
of CP1 and CP2 were prepared under hydrothermal
conditions, enabling their structural determination as 1D-CP ladder-like
polymeric structures. The control of the synthetic parameters allows
their processability into water colloids based on nanoplates (CP1n and CP2n). These NCPs are stable in water
at physiological pHs for long periods. However, interestingly, CP1n is chemically altered in culture media. These transformations
provoke the partial release of its building blocks and the formation
of new species, such as [Cu­(UAcO)2(H2O)4]·2H2O (Cu­(II)-complex), and
species corresponding to the partial reduction of the Cu­(II) centers.
The cytotoxic studies of CP1n versus human pancreatic adenocarcinoma and human uveal melanoma cells show
that CP1n produces a decrease in the cell viability,
while their UAcOH and Cu­(II)-complex are
not cytotoxic under similar conditions. The copper reduction species
detected in the hydrolysis of CP1n are closely related
to the formation of the reactive oxygen species (ROS) detected in
the cytotoxic studies. These results prompted us to prepare CP2n that was designed to improve the cytotoxicity by the
substitution of UAcO by 5-FUAcO, taking into account the anticancer
activity of the 5-fluorouracil moiety. The new CP2n has
a similar behavior to CP1n both in water and in biological
media. However, its subtle structural differences are vital in improving
its cytotoxic activity. Indeed, the release during the hydrolysis
of species containing the 5-fluorouracil moiety provokes a remarkable
increase in cellular toxicity and a significant increase in ROS species
formation.