Novel Apoptosis-Inducingtrans-Platinum Piperidine Derivatives:  Synthesis and Biological Characterization

Abstract

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.

Activation of Trans Geometry in Bifunctional Mononuclear Platinum Complexes by a Piperidine Ligand

“…A, the substrates were incubated with CHO AA8 CFE and subsequently treated overnight with NaCN prior to analysis in 10% PAA/8 M urea denaturing gel. Lanes 1 and 2, control, unplatinated substrate; lanes 3 and 4, the substrate containing the 1,3-GTG intrastrand CL of cisplatin; lanes 5 and 6, the substrate containing the 1,3-GTG intrastrand CL of trans-(PtCl 2 (NH 3 )(pip)); lanes 7 and 8, 1,2-GG intrastrand CL of cisplatin; lanes 9 and 10, the substrate containing the interstrand CL (ICL) of transplatin; lanes 11 and 12, the substrate containing the interstrand CL of trans-(PtCl 2 (NH 3 )(pip)); lanes 1,3,5,7,9, and 11, no extract added; lanes 2,4,6,8,10, and 12, the substrates were incubated with CHO AA8 CFE for 40 min at 30°C. Lane 13, the 20-and 30-nucleotide markers.…”

“…We have recently reported (7)(8)(9) that the replacement of one ammine ligand by the heterocyclic ligand, such as piperidine (pip) (Fig. 1A), piperazine, or 4-picoline in the molecule of transplatin results in a radical enhancement of its activity in tumor cell lines both sensitive and resistant to cisplatin.…”

Spectroscopic, structure and DFT studies of palladium(II) complexes with pyridine-type ligands

“…Palladium complexes with aromatic N-containing ligands, e.g., derivatives of pyridine, quinoline, pyrazole, and 1,10-phenanthroline, have shown very promising antitumor characteristics [1][2][3][4]. Some of these complexes, especially the trans analogs with nonplanar heterocyclic amine ligands, have been found to overcome multifactorial cisplatin resistance in human ovarian cell lines [5,6]. On the other hand, Pd(II) complexes have been widely explored due to their catalytic efficiency, e.g., for various carbon-carbon and carbon-nitrogen bond-forming reactions [7][8][9][10][11].…”

Cytotoxicity and DNA interactions of some platinum(II) complexes with substituted benzimidazole ligands

“…At this stage of the study, it is not possible to explain clearly why complex 3 was the most cytotoxic compound in the cell lines used, compared with the other benzimidazole-Pt(II) complexes tested. However, considering the literature data mentioned above and other data reporting that DNA platination is a necessary condition for the cytotoxic activity of platinum complexes but may not be the sole mechanism that determines their cytotoxicity 28 , it may be concluded with great caution that chloro substituents on the benzimidazole carrier ligands of complex 3 may play a role in its cytotoxicity. Further experiments are required to verify this conclusion.…”