Synthesis, Characterization, and Cytotoxic Activity of Novel Potentially pH-Sensitive Nonclassical Platinum(II) Complexes Featuring 1,3-Dihydroxyacetone Oxime Ligands

The reaction of 1,3-dihydroxyacetone oxime with diam(m)minediaquaplatinum(II)
under basic conditions produced zwitterionic diam(m)mine(3-hydroxy-2-(oxidoimino)propan-1-olato-κ2N,O)platinum(II) complexes featuring the N,O-chelating ligand. Upon reaction with hydrochloric
acid, it was possible to isolate either the singly protonated species
still exhibiting the intact N,O-chelate
or the open-chain chlorido complex. All complexes were characterized
in detail with multinuclear (1H, 13C, and 195Pt) NMR spectroscopy, ESI mass spectrometry, and in one
case X-ray diffraction. Cytotoxicity was investigated in three human
cancer cell lines (CH1, SW480, and A549). The obtained IC50 values are in the medium or even low micromolar range, remarkable
for platinum complexes having N3O or N3Cl coordination
spheres. To study the solution behavior of the prepared complexes
at physiologically relevant proton concentrations, time-dependent 1H NMR measurements were performed for the ethane-1,2-diamine-containing
series at pH values of 7.4, 6.0, and exemplarily 5.0. While the zwitterionic
complex proved to be stable at both pH 7.4 and 6.0, the protonated
species were deprotonated at pH 7.4, tending toward ring opening in
slightly acidic environments, as characteristic for many solid tumors.
Finally, the open-chain form stayed intact at pH 6.0, being completely
converted into its chelated analogue at pH 7.4. A pH-dependent evaluation
of antiproliferative effects of the two latter complexes at pH 7.4
and pH 6.0 revealed an activation under slightly acidic conditions,
which might be of interest for further in vivo studies.