Synthesis and structural characterization of copper(I) complexes bearing N-methyl-1,3,5-triaza-7-phosphaadamantane (mPTA): Cytotoxic activity evaluation of a series of water soluble Cu(I) derivatives containing PTA, PTAH and mPTA ligands

New copper(I) complexes containing the water soluble N-methyl-1,3,5-triaza-7-phosphaadamantane (mPTA) phosphine have been synthesized by ligand-exchange reactions starting from [Cu(CH3CN)4][BF4] or [Cu(CH3CN)4][PF6] precursors and (mPTA)X (X = CF3SO3, I). Depending on the ligand counter ion, the hydrophilic [Cu(mPTA)4][(CF3SO3)4(BF4)] 3a and [Cu(mPTA)4][(CF3SO3)4(PF6)] 3c complexes or the iodine-coordinated [Cu(mPTA)3I]I3 4 species were obtained respectively and fully characterized by spectroscopic methods. Single crystal structural characterization was undertaken for [Cu(mPTA)3I]I3·H2O, 4·H2O, and [Cu(mPTA)4][(CF3SO3)2(BF4)3] ·0.25H2O, 3b·0.25H2O, the latter obtained by crystallization of [Cu(mPTA)4][(CF3SO3)4(BF4)] 3a. The cytotoxicity of analogous tetrahedral homoleptic Cu(I) derivatives [Cu(PTA)4](BF4) 1, [Cu(PTAH)4][Cl4(BF4)] 2, [Cu(mPTA)4][(CF3SO3)4(BF4)] 3a and [Cu(mPTA)4][(CF3SO3)4(PF6)] 3c was evaluated against a panel of several human tumor cell lines. All the complexes showed in vitro antitumor activity comparable to that of the reference metallodrug cisplatin. Tests performed on cisplatin sensitive and resistant cell lines showed that against human ovarian 2008/C13* cell line pair, the resistance factor of copper derivatives was roughly 7-fold lower than that of cisplatin, whereas against human cervix cancer A431/A431-Pt cell line pair it was about 2.5-fold lower. These results, confirming the circumvention of cisplatin resistance, support the hypothesis that phosphine copper(I) complexes follow different cytotoxic mechanisms than do platinum drugs.