The synthesis, chemical characterization, and interaction with cells of new sterically hindered trans- and cis-diaminedichloroplatinum(II) complexes are described. The
amine ligands include monofunctional
piperidine (pip) and
piperazine (pz). The poor solubility of trans-diaminedichloroplatinum complexes was overcome by introducing the positively charged pz
ligand, which allows retaining of the classic
platinum coordination sphere. In vitro evaluation in OV-1063 and C-26
tumor cells revealed that replacing one NH3 of the inactive
transplatin by an aromatic planar
ligand (4-picoline, 4-pic) or by an aliphatic nonplanar heterocyclic
ligand (pip) or replacing both NH3 groups with a 4-pic
ligand and a pip or pz
ligand significantly increases the cytotoxic activity of these complexes. The unsymmetric complexes trans-[PtCl2(4-pic)(pip)] and trans-[PtCl2(4-pic)(pz)]HCl were the most cytotoxic compounds against the
cisplatin-sensitive tumor cell line C-26 (IC50 = 4.5 and 5.5 microM, respectively) and the
cisplatin-sensitive tumor cell line OV-1063 (IC50 = 6.5 and 7.4 microM, respectively). In contrast, replacing one NH3 of the cis isomer by an aromatic planar
ligand (4-pic) or by an aliphatic
amine lowered their cytotoxiciy in comparison to
cisplatin. Cell penetration and Pt-
DNA adduct formation were also evaluated, and it was clearly shown that both trans-[PtCl2(4-pic)(pip)] and trans-[PtCl2(4-pic)(pz)]HCl penetrate efficiently the cellular membrane of the
tumor cells and platinate the cellular
DNA. When comparing cellular
DNA platination, positively charged trans-[PtCl2(4-pic)(pz)]HCl was 7-fold higher than both
cisplatin and its neutral analogue trans-[PtCl2(4-pic)(pip)]. Moreover, in contrast to
cisplatin, in the cell lines used, cell death caused by both complexes appeared to be apoptotic according to several criteria including early
phosphatidylserine exposure, activation of
caspases, and characteristic morphological changes. Our results suggest that these novel mixed nonclassical trans-Pt(II) complexes are biologically and mechanistically distinct from known Pt complexes and deserve evaluation of their efficacy in
tumor-bearing animals.