Water‐Soluble Curcumin Derivatives Including Aza‐Crown Ether Macrocycles as Enhancers of their Cytotoxic Activity.

The synthesis of three novel curcumin derivative compounds, featuring aza‐crown ether macrocycles of various sizes (aza‐12‐crown‐4, aza‐15‐crown‐5, and aza‐18‐crown‐6), is described. The incorporation of these aza‐crown macrocycles significantly enhances their water solubility, positioning them as groundbreaking instances of curcumin derivatives that are fully soluble in aqueous environments. These curcumin ligands (L1, L2, and L3) were then reacted with zinc acetate to afford the coordination metal complexes (L1‐Zn, L2‐Zn, and L3‐Zn). Comprehensive characterization of all compounds was achieved using various analytical techniques, including 1D and 2D NMR spectroscopy, ATR‐FTIR spectroscopy, mass spectrometry (ESI+), elemental analysis and UV‐Vis spectroscopy. The in vitro cytotoxic activity of both, ligands and complexes were evaluated on three human cancer cell lines (U‐251, MCF‐7, and SK‐LU‐1). Compared to conventional curcumin, these compounds demonstrated improved antiproliferative potential. Additionally, a wound healing assay was conducted to assess their antimigration properties. The obtained results suggest that these modifications to the curcumin structure represent a promising approach for developing therapeutic agents with enhanced cytotoxic properties.