Lorella Marchetti

Chemistry and Biology of Two Novel Gold(I) Carbene Complexes as Prospective Anticancer Agents

Two novel gold carbene compounds, namely, chlorido (1-butyl-3-methyl-imidazole-2-ylidene) gold(I) (1) and bis(1-butyl-3-methyl-imidazole-2-ylidene) gold(I) (2), were prepared and characterized as prospective anticancer drug candidates. These compounds consist of a gold(I) center linearly coordinated either to one N-heterocyclic carbene (NHC) and one chloride ligand (1) or to two identical NHC ligands (2). Crystal structures were solved for both compounds, the resulting structural data being in good agreement with expectations. We wondered whether the presence of two tight carbene ligands in 2 might lead to biological properties distinct from those of the monocarbene complex 1. Notably, in spite of their appreciable structural differences, these two compounds manifested similarly potent cytotoxic actions in vitro when challenged against A2780 human ovarian carcinoma cells. In addition, both were able to overcome resistance to cisplatin in the A2780R line. Solution studies revealed that these gold carbene complexes are highly stable in aqueous buffers at physiological pH. Their reactivity with proteins was explored: no adduct formation was detected even upon a long incubation with the model proteins cytochrome c and lysozyme; in contrast, both compounds were able to metalate, to a large extent, the copper chaperone Atox-1, bearing a characteristic CXXC motif. The precise nature of the resulting gold-Atox-1 adducts was elucidated through ESI-MS analysis. On the basis of these findings, it is proposed that the investigated gold(I) carbene compounds are promising antiproliferative agents warranting a wider pharmacological evaluation. Most likely these gold compounds produce their potent biological effects through selective metalation and impairment of a few crucial cellular proteins.

Experimental and TDDFT Characterization of the Light-Induced Cluster-to-Iron Charge Transfer in the (Ferrocenylethynyl)-Substituted Trinuclear Platinum Derivative [Pt3(μ-PBut2)3(CO)2(C≡C−Fc)]+

The reaction between Pt(3)(mu-PBu(t)(2))(3)(CO)(2)Cl (2) and ethynylferrocene, in the presence of catalytic amounts of CuI, gives Pt(3)(mu-PBu(t)(2))(3)(CO)(2)C[triple bond]CFc (1), characterized by X-ray crystallography and representing a rare example of the sigma-coordination of an alkynyl moiety to a cluster unit. In a dichloromethane (CH(2)Cl(2)) solution, compound 1 undergoes three consecutive one-electron oxidations, the first of which is assigned to the ferrocene-centered Fe(II)/Fe(III) redox couple. Spectroelectrochemistry, carried out on a solution of 1, shows the presence of a broad band in the near-IR region, growing after the electrochemical oxidation, preliminarily associated with a metal-to-metal charge transfer toward the Fe(III) ion of the ferrocenium unit. Density functional theory (DFT) has been employed to analyze the ground- and excited-state properties of 1 and 1(+), both in the gas phase and in a CH(2)Cl(2) solution. Vertical excitation energies have been computed by the B3LYP hybrid functional in the framework of the time-dependent DFT approach, and the polarizable continuum model has been used to assess the solvent effect. Our results show that taking into account the medium effects together with the choice of an appropriate molecular model is crucial to correctly reproducing the excitation spectra of such compounds. Indeed, the nature of the substituents on P atoms has been revealed to have a key role in the quality of the calculated spectra.

A molecular wire incorporating a robust hexanuclear platinum cluster

Reaction of [Pt(6)(CO)(4)(P(t)Bu(2))(4)Cl(2)] with excess HS(CH(2))(4)SH in Et(2)NH gave highly stable [Pt(6)(CO)(4)(P(t)Bu(2))(4){S(CH(2))(4)SH}(2)], which adsorbs unchanged onto gold surfaces. This permitted the fabrication and electrical characterisation of gold|molecule|gold junctions involving a well-defined metal carbonyl cluster compound.

Anticancer Gold N-Heterocyclic Carbene Complexes: A Comparative in vitro and ex vivo Study

A series of organometallic AuI N‐heterocyclic carbene (NHC) complexes was synthesized and characterized for anticancer activity in four human cancer cell lines. The compounds’ toxicity in healthy tissue was determined using precision‐cut kidney slices (PCKS) as a tool to determine the potential selectivity of the gold complexes ex vivo. All evaluated compounds presented cytotoxic activity toward the cancer cells in the nano‐ or low micromolar range. The mixed AuI NHC complex, (tert‐butylethynyl)‐1,3‐bis‐(2,6‐diisopropylphenyl)imidazol‐2‐ylidene gold(I), bearing an alkynyl moiety as ancillary ligand, showed high cytotoxicity in cancer cells in vitro, while being barely toxic in healthy rat kidney tissues. The obtained results open new perspectives toward the design of mixed NHC–alkynyl gold complexes for cancer therapy.

Unprecedented Tris-Phosphido-Bridged Triangular Clusters with 42 Valence Electrons. Chemical, Electrochemical and Computational Studies of their Formation and Stability

This paper presents the synthesis and structural characterization of the unprecedented tris-phosphido-bridged compounds Pt3(μ-PBu(t)2)3X3 (X = Cl, Br, I), having only 42 valence electrons, while up to now analogous clusters typically have 44e(-). The new species were obtained by an apparent bielectronic oxidation of the 44e(-) monohalides Pt3(μ-PBu(t)2)3(CO)2X with the corresponding dihalogen X2. Their X-ray structures are close to the D3h symmetry, similarly to the 44e(-) analogues with three terminal carbonyl ligands. The products were also obtained by electrochemical oxidation of the same monohalides in the presence of the corresponding halide. In a detailed study on the formation of Pt3(μ-PBu(t)2)3I3, the redox potentials indicated that I2 can only perform the first monoelectronic oxidation but is unsuited for the second one. Accordingly, the 43e(-) intermediate [Pt3(μ-PBu(t)2)3(CO)2I](+) was ascertained to play a key role. Another piece of information is that, together with the fully oxidized product Pt3(μ-PBu(t)2)3I3, the transient 44e(-) species [Pt3(μ-PBu(t)2)3(CO)3](+) is formed in the early steps of the reaction. In order to extract detailed information on the formation pathway, involving both terminal ligand substitutions and electron transfer processes, a DFT investigation has been performed and all the possible intermediates have been defined together with their associated energy costs. The profile highlights many important aspects, such as the formation of an appropriate couple of 43e(-) intermediates having different sets of terminal coligands, and suitable redox potentials for the transfer of one electron. Optimizations of 45e(-) associative intermediates in the ligand substitution reactions indicate their possible involvement in the redox process with reduction of the overall energy cost. Finally, according to MO arguments, the unique stability of the 42e(-) phosphido-bridged Pt3 clusters can be attributed to the simultaneous presence of three terminal halides.

Bridging molecular clusters and fullerene

The monochloro derivative {Pt3}Cl [(1), {Pt3} = Pt3(μ-PBu(t)2)3(CO)2] was reacted with one equiv. of 4-ethynylbenzaldehyde under Sonogashira dehydrohalogenation conditions to afford {Pt3}CC-(1,4)C6H4-CHO, (3). Under analogous conditions, the condensation of the dichloride {Pt6}Cl2 [(2), {Pt6} = Pt6(μ-PBu(t)2)4(CO)4] with two equiv. of 4-ethynyl-benzaldehyde provided {Pt6}(CC-(1,4)C6H4-CHO)2, (4). The fulleropyrrolidine derivatives {Pt3}CC-(1,4)C6H4-C2H3N(C8H17)C60, (5), and {Pt6}(CC-(1,4)C6H4-C2H3N(C8H17)C60)2, (6), were obtained by reacting the formyl clusters 2 and 4 with an appropriate amount of N-octylglycine and C60. Cyclovoltammetric and IR, UV and NIR spectroelectrochemical data suggest the absence of a significant communication between the cluster and the fullerene units in covalent assemblies 5 and 6. The crystal and molecular structure of compound 3 is also reported.

Potent in vitro antiproliferative properties for a triplatinum cluster toward triple negative breast cancer cells.

The trinuclear platinum cluster [Pt3(μ-PBut2)3(CO)3]CF3SO3 (I) was designed featuring the presence of a nearly equilateral platinum triangle bridged by three di-tert-butylphosphide ligands; in addition, each platinum center bears a terminal carbonyl ligand. This triplatinum cluster was initially developed in view of applications in the field of cluster-containing innovative materials. Yet, due to the large success of platinum complexes in cancer treatment, we also decided to explore its cytotoxic and anticancer properties. Accordingly, the solubility profile of this compound in several solvents was preliminarily investigated, revealing a conspicuous solubility in DMSO and DMSO/buffer mixtures; this makes the biological testing of I amenable. UV-Vis measurements showed that the triplatinum cluster is stable for several hours under a variety of conditions, within aqueous environments. No measurable reactivity was observed for I toward two typical model proteins, i.e. lysozyme and cytochrome c. On the contrary, a significant reactivity was evidenced when reacting I with small sulfur-containing ligands. In particular, a pronounced reactivity with reduced glutathione and cysteine emerged from ESI-MS experiments, proving complete formation of I-GSH and I-Cys derivatives, with the loss of a single carbonyl ligand. Starting from these encouraging results, the cytotoxic potential of I was assayed in vitro against a panel of representative cancer cell lines, and potent cytotoxic properties were disclosed. Of particular interest is the finding that the triplatinum species manifests potent antiproliferative properties toward Triple Negative Breast Cancer Cells, often refractory to most anticancer drugs. Owing to the reported encouraging results, a more extensive biological and pharmacological evaluation of this Pt cluster is now warranted to better elucidate its mode of action.

Synthesis and Spectroscopic and Spectroelectrochemical Characterization of a New Family of 44e- Tris-Phosphido Bridged Palladium Triangles.

Triangular clusters containing a [M3(μ-PR2)3](+) core are very common in platinum chemistry but were virtually unknown for M = Pd. Herein we describe the synthesis and characterization of several palladium derivatives belonging to this class. The trinuclear monohalide clusters {Pd3}(CO)2X [{Pd3} = Pd3(μ-PBu(t)2)3; X = Br, I] were prepared by reacting [(n)Bu4N]X or KX with the dinuclear complex [Pd(PBu(t)2H)(μ-PBu(t)2)]2 and H2O under an atmosphere of CO. The reaction of {Pd3}(CO)2I with CNBu(t) leads to the substitution of all the terminal ligands to afford the symmetrical cluster [{Pd3}(CNBu(t))3]I. The latter reacts with TlPF6 (excess) or AgCF3SO3 (1:1 ratio) to give anion metathesis, whereas the addition of a second equivalent of Ag(+) causes cluster oxidation to the thermally stable paramagnetic 43e(-) dication [{Pd3}(CNBu(t))3](2+). The cationic clusters [{Pd3}(CO)2(L)]PF6 (L = NCCH3, Py or CO) were obtained by reacting {Pd3}(CO)2I with TlPF6, under nitrogen in acetonitrile or in pyridine or under 1 atm of carbon monoxide in THF. Finally, {Pd3}(CO)2Cl was achieved by the reaction of [{Pd3}(CO)3]PF6 with [(PPh3)2N]Cl. All clusters have been obtained in good yields and purity and have been characterized by microanalysis and IR and multinuclear NMR spectroscopy. Single crystal X-ray diffraction studies on {Pd3}(CO)2Br and [{Pd3}(CNBu(t))3]CF3SO3 are also reported. The cyclovoltammetric profile exhibited by the palladium clusters prepared in this work is characterized by the presence of two monoelectronic oxidation processes whose reversibility and potentials depend on the nature of the ligands. Moreover, the UV-vis and IR spectroelectrochemical analysis of {Pd3}(CO)2I, [{Pd3}(CO)3]PF6 and [{Pd3}(CNBu(t))3]PF6 allowed the spectroscopical characterization of some electrogenerated oxidized species and provided some detail for the redox-coupled reactions of metastable products.

Trinuclear and hexanuclear Platinum clusters as building blocks for organometallic one-dimensional structures

The reaction between the new hexa- and trinuclear clusters [Pt6](CC-C6H4-CCH)2, (4) [[Pt6] = Pt6(CO)4(mu-PBu(t)2)4], and [Pt3]Cl, (6) [[Pt3] = Pt3(mu-PBu(t)2)3(CO)2], in CuI/Amine gives the thermally and air stable [Pt6](CC-C6H4-CC[Pt3])2 (7), where the cluster units are separated by conjugated 1,4-diethynylphenyl groups.