Synthesis, characterization, cytotoxicity and radical scavenging activities of new palladium complexes

In recent years, there is an increasing interest in the chemistry of transition metal complexes containing novel ligands in biological field. Platinum and palladium complexes are the most studied bio-organometallics compounds and the structural features have been recently reviewed by Marques.1
Transition metal complexes derivatives are also known to exhibit a wide range of biological activities such as antiviral, antibacterial, antifungal, anticancer, antitubercular, antithyroidal, insecticidal, antimalarial, etc.2
In this contribution, we present the synthesis of new palladium complexes and evaluate their radical scavenging activities using both ABTS and DPPH tests according to literature procedure.3 The in vitro cytotoxicity of these complexes against promyelocytic leukemia cell line (HL-60) was evaluated using Trypan blue test.
The complex with iodide anion [Pd(PPh3)2(4-RC6H4I)] was obtained by oxidative addition of 4-RC6H4I on Pd(PPh3)4. Complexes 1 and 4 are isolated in good yield as yellow powder. While bromo- and chloro-containing palladium complexes ([Pd(PPh3)2(4-RC6H4Br)], [Pd(PPh3)2(4-RC6H4Cl)] were prepared by anion metathesis from the iodide complexes using saturated solution of KBr and KCl. The conversion is followed by 31P NMR. We have also developed new one-pot synthesis of bromo- and chloro- palladium complexes in the presence of water. This new method could be a solution to avoid degradation of complexes during decantation in the air. Interestingly, it appears that one-pot reaction leads to complete conversion in diluted mixture (Pd(PPh3)4:0.25mmol, Toluene: 20 ml: H2O: 40ml) and after one day. All compounds have been characterized by 1H, 13C and 31P NMR and by X-ray diffraction. Peaks during electrospray mass spectrometry shows that for every complex a loss of halogen is observed. In each case, the isotopic profile of peak at m/z [M – X]+ (X = halogen) ensures that we have the right complex.After 30 min. of incubation at room temperature, the absorbance of each sample was measured at 734 nm for ABTS and at 517 nm for DPPH.4 Antioxidant studies showed that almost all the complexeshave a strong antioxidant activity against DPPH radical, in a dose-dependent manner except for [PdI(PPh3)2(4-OAcC6H4)]. For the ABTS radical scavenging activity, [PdI(PPh3)2(4-OMeC6H4)] exhibited the highest activity than the other ones. Moreover, the activity of this last compound at the highest concentration (5.10-5 M) is almost instantaneous. In the two anti-radical assays, the effects of complexes were compared to Cis-Pt (cisplatin) taken as reference and DMSO used as vehicle.
Cells toxicity of 6 complexes was evaluated using Trypan blue test against HL-60 cells line. Cells (2. 105 cells/well) were incubated with increasing final concentrations (10-6 M, 10-5 M and 10-4 M) of complexes for 1 hour and 24 hours prior assessing dye exclusion test. After 1 hour compound 1 [PdI(PPh3)2(4-OMeC6H4)] showed the highest toxicity but overnight incubation leads to best activity of PdCl(PPh3)2(4-OMeC6H4)]. The latter one exhibited a mortality of 87% on HL-60 cells at the final concentration 10-4 M. The activities of some of our compounds were similar to that of cis-platine which was used as reference.
Overall, our results indicate that most of the tested complexes can be rapidly achieved using a one-pot method. The phosphorous NMR and Xray diffraction structure confirmed the square planar geometry of the complexes and the trans position of triphenyl phosphine group. Their antioxidant activities were found very good except those of the complexes having acetoxy (R = OAc) group. The comparison of these activities in the same group (compound 1 to 3 and 4 to 6) allowed us to discuss the effect of the halide bind palladium. For the ABTS scavenging activity test, in any group we note that the activity increase in the order Cl, Br and I. This order is maintened in des DPPH test for the first group (compound 1 to 3) but is inverted in the second one (compound 4 to 6). The in vitro cytotoxicity of these complexes against promyelocytic leukemia cell line reveals that compound where para-metoxyphenyl is linked to palladium are the most toxic and lPdCl(PPh3)2(4-OMeC6H4)] is more toxic than Cis-Pt but also with a good antioxdant activity.