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) () and 5-fluorouracil-1-acetic acid (). Suitable single crystals for X-ray diffraction studies of and 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 ( and ). These NCPs are stable in water at physiological pHs for long periods. However, interestingly, 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)(HO)]·2HO (), and species corresponding to the partial reduction of the Cu(II) centers. The cytotoxic studies of human pancreatic adenocarcinoma and human uveal melanoma cells show that produces a decrease in the cell viability, while their UAcOH and - are not cytotoxic under similar conditions. The copper reduction species detected in the hydrolysis of are closely related to the formation of the reactive oxygen species (ROS) detected in the cytotoxic studies. These results prompted us to prepare 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 has a similar behavior to 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.