A critical review of palladium organometallic anticancer agents

With the aim of overcoming the well-known limitations of platinum-based antineoplastic drugs, recent efforts have focused on the development of new anticancer agents containing metals other than platinum. Among these agents, organopalladium compounds have received significant recent attention due to their generally high stability under physiological conditions. A significant number of these compounds have shown promising in vitro and in vivo antiproliferative activity toward several cisplatin-sensitive and cisplatin-resistant tumors and have sometimes exhibited a different mechanism of action compared to platinum-based drugs. In this review, recent advances in the field of organopalladium compounds as potential anticancer agents are discussed

Synthesis and anticancer activity of Pt(0)-olefin complexes bearing 1,3,5-triaza-7-phosphaadamantane and N-heterocyclic carbene ligands

A series of Pt(0)-η2-olefin complexes bearing 1,3,5-triaza-7-phosphaadamantane (PTA) or N-heterocyclic carbenes are prepared following different synthetic strategies depending on the nature of coordinated alkene and spectator ligands. These new platinum(0) derivatives have been tested in vitro as anticancer agents toward three different tumor (human ovarian cancer A2780 and A2780cis and K562 myelogenous leukemia) and one non-tumor (Hacat keratinocytes) cell lines, proving to be in several cases highly and selectively cytotoxic against ovarian cancer cells. Furthermore, this antiproliferative effect is associated with the activation of an apoptosis process. In particular, complexes equipped with PTA as spectator ligand give comparable IC50 values on A2780 (cisplatin sensitive) and A2780cis (cisplatin resistant) cell lines, indirectly proving that these new Pt(0) substrates act with a mechanism of action conceivably different from cisplatin. This hypothesis is also confirmed by the fact that our compounds, in contrast to cisplatin, are not able to promote erythroid-differentiation activity on the K562 myelogenous leukemia cell line

Palladium(II)-η3-Allyl Complexes Bearing N-Trifluoromethyl N-Heterocyclic Carbenes: A New Generation of Anticancer Agents that Restrain the Growth of High-Grade Serous Ovarian Cancer Tumoroids

The first palladium organometallic compounds bearing N-trifluoromethyl N-heterocyclic carbenes have been synthesized. These η3-allyl complexes are potent antiproliferative agents against different cancer lines (for the most part, IC50 values fall in the range 0.02–0.5 μm). By choosing 1,3,5-triaza-7-phosphaadamantane (PTA) as co-ligand, we can improve the selectivity toward tumor cells, whereas the introduction of 2-methyl substituents generally reduces the antitumor activity slightly. A series of biochemical assays, aimed at defining the cellular targets of these palladium complexes, has shown that mitochondria are damaged before DNA, thus revealing a behavior substantially different from that of cisplatin and its derivatives. We assume that the specific mechanism of action of these organometallic compounds involves nucleophilic attack on the η3-allyl fragment. The effectiveness of a representative complex, 4 c, was verified on ovarian cancer tumoroids derived from patients. The results are promising: unlike carboplatin, our compound turned out to be very active and showed a low toxicity toward normal liver organoids

Synthesis and characterization of novel olefin complexes of palladium(0) with chelating bis(N-heterocyclic carbenes) as spectator ligands

We have synthesized several novel palladium(0) olefin complexes stabilized by strong σ-donating bis-chelating carbene ligands characterized by one or two CH2spacers and electron-withdrawing olefins. Although it appears obvious that the σ-donating carbenes and electron-withdrawing olefins should cooperate in the stabilization of the ensuing complexes, the limit of their coexistence was not hitherto clear. On the basis of previously measured stabilizing capability of the olefins toward Pd(0) complexes we were able to synthesize ten complexes (nine new and one synthesized by a different protocol from that of the literature). The less electron-withdrawing olefin capable of stabilizing the complex was dimethylfumarate. However, the most interesting results were obtained with the (Z)-1,2-bis(p-tolylsulfonyl)ethene (cis-sulf) which instantly isomerizes upon coordination and in the case of the derivative bearing the olefin tetramethyl ethene-1,1,2,2-tetracarboxylate (tmetc) whose decomposition in CD2Cl2yields the saturated tetramethyl ethane-1,1,2,2-tetracarboxylate (D2). The solid-state structure of the complex 4d bearing the bis-carbene 1,1′-dibenzyl-3,3′methylenediimidazol-2,2′-diylidene and the olefin (E)-1,2-bis(p-tolylsulfonyl)ethene (trans-sulf) was also determined

Synthesis of novel olefin complexes of palladium(0) bearing monodentate NHC, phosphine and isocyanide spectator ligands

We have synthesized and characterized seventeen new bis-NHC, mixed NHCâ\u80\u93phosphines or NHCâ\u80\u93isocyanides Pd(0) olefin complexes that can potentially act as catalysts. The complexes were characterized by standard spectroscopic methods and elemental analysis and in two cases by SC-XRD technique. We have analyzed with particular care the thermodynamic and kinetic conditions governing the one-pot synthesis of the mixed complexes. In this respect we tried to validate our results by a dedicated computational study on the mutual distribution of the isomers that could be potentially formed. However, the computational result is not clear-cut owing to the not significant value of the calculated Î\u94G0. Finally, in one case we have measured the rate of the exchange reaction between not particularly encumbered olefins

The anticancer activity of an air-stable Pd(i)-NHC (NHC = N-heterocyclic carbene) dimer

A new dinuclear Pd(i) complex coordinating two bis(NHC) ligands revealed an unsuspected stability despite the unsaturation of the two metal centres. Even more surprisingly, the compound showed high and selective antiproliferative activity against different cancer cell lines and ovarian cancer tumoroids, and the mechanism of action was different from that of cisplatin

The anticancer activity of an air-stable Pd(i)-NHC (NHC = N-heterocyclic carbene) dimer

A new dinuclear Pd(i) complex coordinating two bis(NHC) ligands revealed an unsuspected stability despite the unsaturation of the two metal centres. Even more surprisingly, the compound showed high and selective antiproliferative activity against different cancer cell lines and ovarian cancer tumoroids, and the mechanism of action was different from that of cisplatin

Synthesis and in-depth studies on the anticancer activity of novel palladacyclopentadienyl complexes stabilized by N-Heterocyclic carbene ligands

New palladacyclopentadienyl complexes with bis-N-heterocyclic carbenes as spectator ligands have been synthesized and exhaustively characterized. The crystal structure of complex 1a has been also determined by X-ray diffraction analysis. Their in vitro cytotoxicity and that of other palladacyclopentadienyl derivatives coordinating different ancillary ligands has been determined against different cancer cell lines. Many complexes have shown an antiproliferative activity toward tumor cells often definitely better than cisplatin, whereas they have resulted practically inactive against the non-cancer MRC-5 cell line. The mechanism of action of bis-NHC derivative 1a, particularly active against ovarian cancer cell lines was studied in depth. Through a longitudinally analysis, it is shown that compound 1a induces apoptosis via DNA damage and release of cytochrome C. We propose compound 1a as a powerful and specific drug for the therapy of a deadly disease such as high grade serous ovarian cancer

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

A complete protocol for the synthesis of new palladacyclopentadienyl complexes with purine‐ based carbenes as supporting ligands is described. The new organometallic compounds were exhaustively characterized using NMR and infrared spectroscopies and elemental analysis. The single‐ crystal X‐ ray structure of complex 2b coordinating also a triphenylphosphine was resolved. Some of these complexes showed an antiproliferative activity comparable to or better than that of cisplatin on two human ovarian cancer lines: A2780 (cisplatin‐ sensitive) and A2780cis (cisplatin‐ resistant). Moreover, for complexes 2 and 3 (coordinating one purine‐ based N‐ heterocyclic carbene ligand and one phosphine) the cytotoxicity is associated with an evident induction of apoptosis. Finally, complexes 3 , bearing one purine‐ based N‐ heterocyclic carbene ligand and one 1,3,5‐ triaza‐ 7‐ phosphaadamantane, proved practically inactive on non‐ tumour fibroblast cells (MRC‐ 5)