Synthesis of the First Copper Metal Complex of a C=C Extended Curcuminoid Analogue: Structure, β-Cyclodextrin Association and Biological Properties

The search for bioactive compounds against chronic diseases such as cancer and diabetes includes curcuminoids as promising scaffolds. Here, we report the synthesis of a family of curcuminoid analogue compounds with an extended unsaturated central chain: difluoroboron complex 1, the enolised curcuminoid 2, and its homoleptic copper complex 3, in moderate to good yields (68-90%). Additionally, their β-cyclodextrin (BCD) association complexes, 4 and 5, were prepared through a mechanochemical method and characterised by spectroscopic techniques. Complete ¹H and ¹³C NMR assignments and NOESY correlations revealed unique solvent effects on the conformational disposition of compound 2, while the copper complex 3 displayed the highest extinction coefficient (1.20 × 10⁵ M⁻¹cm⁻¹). Furthermore, the authentication of the polymorph of 1 and the new crystal structures of 2 and 3, determined by single-crystal X-ray analysis, are highlighted. Although the copper complex three initially exhibited the lowest a-glucosidase inhibitory activity (IC50>100 µM), it showed a significant increase (IC50= 36.27 µM) upon association with BCD, reaching values comparable to the free ligand (IC50= 45.63 µM). Compounds 1-5 were non-toxic to healthy cells (COS-7), but compound 5 stands out as a promising candidate against this metabolic condition.