Synthesis of new allyl palladium complexes bearing purine-based NHC ligands with antiproliferative and proapoptotic activities on human ovarian cancer cell lines

Abstract

A series of new palladium allyl complexes bearing purine-based carbenes derived from caffeine, theophylline and theobromine have been prepared and characterized by NMR spectroscopy, and elemental analysis and in two cases by single crystal X-ray diffraction. The cytotoxic and proapoptotic activities of compounds have been determined in vitro on human ovarian cancer A2780 and SKOV-3 cell lines. These experiments have shown that the palladium-allyl fragment induces a general cytotoxicity, but the choice of the supporting ligands is of paramount importance for achieving the best results. In particular complexes 4c, 4d and 5d exhibit a higher antiproliferative effect (IC50: 0.09, 0.81 and 0.85 μM respectively) than cisplatin (IC50: 1.5 μM) on A2780 cells, and 4d (IC50: 1.7 μM vs. 5.94 μM) on SKOV-3 cell line. Moreover in many cases it has been proved that the cytotoxicity of our complexes is associated with the induction of apoptosis.

Palladacyclopentadienyl complexes bearing purine‐based N‐heterocyclic carbenes: A new class of promising antiproliferative agents against human ovarian cancer

“…In Table , the results obtained from three independent experiments are reported. The strong antiproliferative activity of cisplatin (IC 50 = 0.6 ± 0.1 μM) on the A2780 cell line was confirmed; in addition, the obtained data confirmed the cisplatin resistance of the A2780cis cell line (IC 50 = 6 ± 1 μM). For all the complexes investigated, with the exception of 2c , the IC 50 values against the A2780 and A2780cis cell lines were similar, indicating that they were active also on the resistant cell line.…”

“…Compounds a – c were obtained pure and in quantitative yields by metathesis of tetrafluoroborate ions with tetraphenylarsonium chloride of alkylated xanthines, synthesized according to methods published elsewhere (Figure S1a, supporting information).…”

“…Complexes 1 were synthesized by reacting compounds Aga – c and the polymeric precursor [PdC 4 (COOCH 3 )] n . The synthesis was conducted according to published methods . Despite the difficulty we have hitherto faced when bulky carbenes are used for the preparation of bis‐carbene complexes,15e the synthesis of derivatives 1 proceeded without particular problems and they were obtained in reasonable yields.…”

“…On the basis of such observations, we have recently carried out a study describing the synthesis of several allyl palladium complexes stabilized by various N‐heterocyclic carbene (NHC) spectator ligands derived from three appropriately functionalized methylxanthines which show an antiproliferative activity, in many cases markedly higher than that of the reference cisplatin 11a. We have planned this sort of investigation accepting some literature suggestions.…”

“…In the work presented here and at variance with previous work focused on the palladium–allyl moiety,11a we opted for the palladacyclopentadienyl group since it was shown that palladacycles can be very effective against various cancer cell lines 9d. Moreover, the experience we developed on these substrates suggests that this organometallic fragment should remain stable in a biological environment.…”