Given the potent anticancer properties of cisdiamminedichloroplatinum(
II) and knowing its mode of action, we
synthesized four new cis-[PtCl2(N^N)] organoplatinum complexes, two
with N-substituted pbi ligands (pbiR = 1-R-2-(2-pyridyl)benzimidazole)
(namely, 1 and 2) and two more with 4,4′-disubstituted bpy ligands (bpy =
2,2′-bipyridine) (namely, 3 and 4). We explored their cytotoxicity and
ability to bind to deoxyguanosine monophosphate (dGMP), DNA, and
albumin models. By 1H NMR and UV−vis spectroscopies, circular
dichroism, agarose gel electrophoresis, differential scanning calorimetry
measurements, and density functional theory calculations, we verified that
only 3 can form aquacomplex species after dimethyl sulfoxide solvation;
surprisingly, 1, 2, and 3 can bind covalently to DNA, whereas 4 can form a noncovalent complex. Interestingly, only complexes 1
and 4 exhibit good cytotoxicity against human ovarian carcinoma (HeLa) cell line, whereas 2 and 3 are inactive. Although lung
carcinoma (A549) cells are more resistant to the four platinum complexes than HeLa cells, when the protein concentration in the
extracellular media is lower, the cytotoxicity becomes substantially enhanced. By native electrophoresis of bovine seroalbumin
(BSA) and inductively coupled plasma mass spectrometry uptake studies we bear out, on one hand, that 2 and 3 can interact
strongly with BSA and its cellular uptake is negligible and, on the other hand, that 1 and 4 can interact with BSA only weakly, its
cellular uptake being higher by several orders. These results point up the important role of the protein binding features on their
biological activity and cellular uptake of cis-“PtCl2” derivatives. Our results are valuable in the future rational design of new
platinum complexes with improved biological properties, as they expose the importance not only of their DNA binding abilities
but also of additional factors such as protein binding.
