BIOLOGICAL EVALUATION OF Cu(I) AND Ag(I) COMPLEXES WITH β-DIKETONE LIGANDS FEATURING MESITYL AND TRIFLUOROMETHYL SUBSTITUTENTS

Recent advances in medicinal inorganic chemistry have led to the development of innovative chelating ligands and delivery systems to enhance the potency and selectivity of metal-based anticancer drugs. In this regard, group 11 metal complexes have emerged as promising candidates due to their unique therapeutic potential.[1] Although β-diketones represent one of the oldest classes of chelating ligands, their coordination chemistry continues to attract much interest. Therefore, as part of our investigation on the chemical and biological properties of metal-based anticancer complexes supported by β-diketonate ligands,[2,3] we synthesized a series of Cu(I) and Ag(I) complexes stabilized by β-diketone ligands (Figure 1): 1,3-dimesitylpropane-1,3-dione (HLMes), 1,3-bis(3,5-bis(trifluoromethyl)phenyl)-3-hydroxyprop-2-en-1-one (HLCF3), and 1,3-diphenylpropane-1,3-dione (HLPh). As co-ligands to stabilize the metal in the +1 oxidation state and to modulate lipophilicity, we employed triphenylphosphine (PPh3) and 1,3,5-triaza-7-phosphaadamantane (PTA). X-ray crystallographic analysis revealed that [Cu(LCF3)(PPh3)2] and [Ag(LPh)(PPh3)2] adopt distorted tetrahedral geometries (Figure 2). The planar CuO2C3 metallacycle of [Cu(LCF3)(PPh3)2] and the half-boat AgO2C3 core of [Ag(LPh)(PPh3)2] point out the variability in coordination environments. While the influence of coordination geometry on biological activity remains to be fully elucidated, the observed differences may contribute to the distinct cytotoxic profiles of these complexes. Biological evaluation demonstrated that Ag(I) and Cu(I) complexes with PPh3 as the phosphane coligand possessed greater antitumor activity against human tumor cell lines derived from solid tumors, compared to cisplatin. Among them, copper complexes with HLCF3 and HLMes ligands were the most active derivatives. Particularly, [Cu(LMes)(PPh3)2] was up to 16 times more active than cisplatin in inhibiting the cell proliferation of 2D testicular carcinoma cell cultures (NTERA-2). Furthermore, cytotoxicity experiments performed on HCT-15 spheroids indicated that [Cu(LCF3)(PPh3)2] possessed remarkable antiproliferative activity, confirming its ability to penetrate the whole spheroid domain and reach the inner hypoxic core.[4] These results indicate Cu(I) complexes with fluorinated or bulky β-diketone ligands as promising candidates for anticancer applications, underscoring the importance of ligand design in improving biological activity.