Insights into the cytotoxic activity of the phosphane copper(I) complex [Cu(thp)4][PF6]

The phosphane Cu(I) complex [Cu(thp)4][PF6], 1 (thp=tris(hydroxymethyl)phosphane) shows notable in vitro antitumour activity against a wide range of solid tumours. Uptake experiments performed in 1-treated colon cancer cells by atomic absorption spectrometry, reveal that the antiproliferative activity is consistent with the intracellular copper content. The solution chemistry of this agent, investigated by means of X-ray Absorption Spectroscopy and spectrophotometric titrations in aqueous media, indicates that 1 is labile giving coordinative unsaturated [Cu(thp)n]+ species (n=3 and 2) at micromolar concentrations. [Cu(thp)n]+ are reactive species that yield the mixed-ligand complex [Cu(thp)2(BCS)]− (BCS: bathocuproinedisulphonate(2-)) upon interaction with N,N-diimine. Analogously, [Cu(thp)n]+ interact with the methionine-rich peptide sequence (Ac-MMMMPMTFK-NH2; Pep1), relevant in the recruiting of physiological copper, giving [Cu(thp)(Pep1)]+ and [Cu(Pep1)]+ species. The formation of these adducts was assessed by electrospray mass spectrometry in the positive ion mode and validated by density functional theory investigations. The possibility to trans-chelate Cu(I) from pure inorganic [Cu(thp)n]+ assemblies into more physiological adducts represents a pathway that complex 1 might follow during the internalization process into cancer cells. The phosphane copper(I) complex [Cu(thp)4][PF6], 1 (thp=tris(hydroxymethyl)phosphane) undergoes phosphane dissociation upon dilution, and interacts with methionine-rich peptide sequences comprised in the extra-cellular portion of a human copper transporter. Excess of exogenous copper is then observed in 1-treated cancer cells. [Display omitted] •A tetrahedrally arranged phosphane Cu(I) complex exhibits notable antitumour activity.•The tetrahedral Cu(I) complex is labile upon dilution at micro-molar concentration.•Cu(I) can be trans-chelated from phosphane Cu(I) species into Cu(I)-peptide adducts.•Exogenous copper arising from phosphane Cu(I) species accumulates in cancer cells.