2D and 3D anticancer activity of diiron bis-cyclopentadienyl complexes incorporating flurbiprofen and chlorambucil.

The new diiron complex [Fe(2)Cp(2)(CO){Ph(2)P(4-C(6)H(4)CO(2)H)}(μ-CO){μ-CNMe(Cy)}]CF(3)SO(3), [2]CF(3)SO(3) (Cp = η(5)-C(5)H(5), Cy = C(6)H(11)), was synthesized with a 92% yield from a tricarbonyl precursor and 4-(diphenylphosphanyl)benzoic acid. The carboxylic acid group in [2](+) was exploited for bio-conjugation with flurbiprofen and chlorambucil through esterification procedures, affording complexes [3-4]CF(3)SO(3) (36-55% yields). Comprehensive characterization of the products was achieved using IR, multinuclear NMR spectroscopy and mass spectrometry. The log P (ow) values and the stability under physiologically relevant conditions were determined, revealing a considerable fraction of [3-4](+) still detectable in water/methanol solution after 72 hours and in DMEM culture medium/methanol solution after 24 hours. The antiproliferative activity was assessed in 2D across a panel of nine cancer cell lines, where [3,4](+) displayed IC(50) values in the low-micromolar range and revealed the ability to overcome oxaliplatin resistance mechanisms. When tested in 3D cultures of human colon cancer and melanoma cells, [3,4](+) exhibited cytotoxic activity comparable to that of cisplatin. Targeted assays revealed that both [3](+) and [4](+) substantially preserved the COX inhibitory effect of flurbiprofen and the DNA damaging efficacy of chlorambucil, respectively.