Anticancer C,N-Cycloplatinated(II) Complexes Containing Fluorinated Phosphine Ligands: Synthesis, Structural Characterization, and Biological Activity

A series
of potent C,N-cycloplatinated­(II) phosphine antitumor complexes containing
fluorous substituents in the cyclometalated or the ancillary phosphine
ligands [Pt­(C–N)­(PR3)­Cl] or both have been synthesized
and characterized. The crystal structure of [Pt­(dmba)­{P­(C6H4CF3-p)3}­Cl]·2CH2Cl2 (dmba = dimethylaminomethyl)­phenyl) has been established
by X-ray diffraction. Values of IC50 of the new platinum
complexes were calculated toward a panel of human tumor cell lines
representative of ovarian (A2780 and A2780cisR) and breast cancers
(T47D). Complexes containing P­(C6H4CF3-p)3 as ancillary ligand (with a bulky and electronegative
CF3 substituent in para position) were
the most cytotoxic compounds in all the tested cancer cell lines.
In some cases, the IC50 values were 16-fold smaller than
that of cisplatin and 11-fold smaller than the non-fluorous analogue
[Pt­(dmba)­(PPh3)­Cl]. On the other hand, very low resistance
factors (RF) in A2780cisR (cisplatin-resistant ovarian carcinoma)
at 48 h were observed (RF ≈ 1) for most of the new compounds.
Analysis of cell cycle was done for the three more active compounds
in A2780. They arrest cell growth in G0/G1 phase in contrast to cisplatin
(S phase) with a high incidence of late-stage apoptosis. They are
also good cathepsin B inhibitors (an enzyme implicated in a number
of cancer related events).