José M. Pérez

Pd(II) and Pt(II) Complexes of 2‐Phenyl‐ and 2‐Benzyl‐imidazoline: Synthesis, Structural Characterization, DNA Modification and in vitro Antileukaemic Activity

In this paper we describe the synthesis and chemical characterization of three new Pd(II)-imidazoline complexes: [PdCl 2 (C 6 H 5 -CH 2 -C 3 H 5 N 2 ) 2 ] (2), [PdCl(SEt 2 ) (C 6 H 4 -C 3 H s N 2 )] (5) and [Pd(C 6 H 4 -C 3 H 5 N 2 ) (μ-Br)] 2 (6). We have also analyzed the DNA modifications and in vitro antileukaemic activity of these compounds and of their previously reported analogs [Pd Cl 2 (C 6 H 5 -C 3 H 5 N 2 ) 2 ] (1), [Pd (C 6 H 4 -C 3 H 5 N 2 ) (μ-OAC)] 2 (3), [Pd (C 6 H 4 -C 3 H 5 N 2 ) (μ-Cl)] 2 (4) and [Pt(C 6 H 4 -C 3 H 5 N 2 )(μ-Cl] (7). All these compounds modify the DNA secondary structure since they alter the melting temperature (T m ) of the DNA. Circular dichroism spectra indicated, moreover, that compounds 3, 5 and 6 induced higher modification on the double helix than compounds 1, 2 and 4. While compounds 1, 2 and 5 seem to induce slight changes in the electrophoretic mobility of the open and covalently closed circular forms of pUC8 DNA at high r i (input molar ratio of Pd or Pt to nucleotides), compounds 3, 6 and 7 do not modify at any r i the tertiary structure of the plasmid DNA. Antileukaemic tests suggest that compounds 1, 4 and 7 exhibit important cytotoxic activity since their IC 50 values against HL-60 human leukaemic cells were below 10 μg ml -1 .

Induction of apoptosis by the bis-Pt(III) complex [Pt2(2-mercaptopyrimidine)4Cl2]

We analyzed both the cytotoxicity and the type of cell death produced by the novel binuclear Pt(III) compound Pt-Spym ([Pt(2)(2-mercaptopyrimidine)(4)Cl(2)]) in kidney human fibroblasts and in human tumor cell lines (HeLa, CH1, CH1cisR and HL-60). The data showed that Pt-Spym displayed higher cytotoxicity against these tumor cells than cisplatin. In contrast, Pt-Spym had low toxicity against normal human fibroblasts. Interestingly, Pt-Spym circumvented cisplatin resistance in CH1cisR cells. We also observed that Pt-Spym induced the characteristic changes attributed to apoptosis in cells with normal levels of p53 protein (CH1 and CH1cisR) and with low levels of p53 protein (HeLa), but not in cells lacking p53 (HL-60). Interestingly, Western blot data indicated that apoptosis induction by Pt-Spym in HeLa, CH1, and CH1cisR cells was not associated with drastic changes in p53 levels. However, cis-DDP strongly decreased p53 levels in CH1 and CH1cisR cells and abolish p53 protein in HeLa cells. Altogether, these results suggest that induction of apoptosis by Pt-Spym requires the presence of p53 protein.

Palladium(II) 4,5-Diphenylimidazole Cyclometalated Complexes: DNA Interaction

In this paper, we show the synthesis of palladium(II) 4,5-phenylimidazole cyclometalated complexes. They have been characterized by IR, 1 H- and 13 C-NMR spectroscopy. The cyclometalated dimer compound 2 [Pd(C 15 H 11 N 2 1)(μ-OAc)] 2 and the cyclometalated monomer compound 5 [PdBr(SEt 2 )(C 15 H 11 N 2 )], having OAc and Br as leaving groups, interact with DNA, modifying its secondary structure (as measured by T m and CD), without modifying its tertiary structure (as determined by measurement of the electrophoretic mobility in agarose gels). The monomeric compound 5 seems to be the one that induces the highest alterations in DNA secondary structure since it strongly modifies the CD spectrum of the DNA. Melting data of drug-DNA complexes suggest that, at low drug concentration, the 4,5-Imd ligand intercalates between the base pairs in the DNA molecule, increasing the T m , while at high drug concentrations the palladium(II) centers destabilize the double helix, producing a lowering in T m values. These results indicate that complexes containing planar structures might selectively bind to DNA that is not supercoiled, and that therefore it only has a secondary structure.