Chiral cyclometalation of 6-(1-phenylbenzyl)-2,2′-bipyridine

A new bipyridine ligand, 6-(1-phenylbenzyl)-2,2′-bipyridine, has been prepared by a multistep synthesis starting from the corresponding substituted pyridine. The coordinating properties of the new ligand have been tested with two d8 metal ions, Pt(II) and Pd(II), to give the cyclometalated complexes [Pt(N,N,C)Cl] and [Pd(N,N,C)Cl], where N,N,C is a terdentate deprotonated bipyridine containing a new stereogenic carbon atom directly generated by C–H bond activation. The single-crystal of the platinum complex has been solved by X-ray diffraction. DFT calculations confirm the presence of a Pt⋯H interaction that stabilizes one of the two possible conformers by 14.7 kJ mol−1 for Pt and 12.9 kJ mol−1 for Pd. The energy barrier to pass from one conformer to the other is 25.4 and 23.8 kJ mol−1 respectively. Under different reaction conditions, regioselective activation of a pyridine C–H bond gave the less common cyclometalated rollover complex [Pt(L-H)Me(DMSO)], which was isolated and characterised

Metil derivati chirali di platino(II) con piridine 2-sostituite

Molte ricerche sui farmaci antitumorali riguardano i derivati di platino dopo la scoperta che il cisplatino, cis-diamminodicloroplatino(II) era risultato molto attivo in certi tipi di cancro. Anche complessi di Pt(II) con piridine hanno mostrato attività, in qualche caso superiore a quella del cisplatino. Noi da anni studiamo complessi di Pt(II) con leganti azotati aventi nuclei piridinici e recentemente abbiamo intrapreso un’indagine della reattività del frammento ibrido organicoinorganico ”Pt(Me)Cl” con una serie di piridine 2-R sostituite (R= alchile arile, benzile)

Exploring the potential of gold(iii) cyclometallated compounds as cytotoxic agents: variations on the C^N theme

A series of novel ((CN)-N-boolean AND) cyclometallated Au(III) complexes of general formula [Au(py(b)-H)(LL2)-L-1](n+) (py(b)-H = (CN)-N-boolean AND cyclometallated 2-benzylpyridine, L-1 and L-2 being chlorido, phosphane or glucosethiolato ligands, n = 0 or 1) have been synthesized and fully characterized using different techniques, including NMR, IR and far-IR, mass spectrometry, as well as elemental analysis. The crystal structure of one compound has been solved using X-ray diffraction methods. All compounds were tested in vitro in five human cancer cell lines including the lung, breast, colon and ovarian cancer cells. For comparison purposes, all compounds were also tested in a model of healthy human cells from the embryonic kidney. Notably, all new compounds were more toxic than their cyclometallated precursor bearing two chlorido ligands, and the derivative bearing one phosphane ligand presented the most promising toxicity profile in our in vitro screening, displaying a p53 dependent activity in colorectal cancer HCT116 cells. Finally, for the first time (CN)-N-boolean AND cyclometallated gold(III) complexes were shown to be potent inhibitors of the zinc finger protein PARP-1, involved in the mechanism of cisplatin resistance

Gold-based drug encapsulation within a ferritin nanocage: X-ray structure and biological evaluation as a potential anticancer agent of the Auoxo3-loaded protein

Auoxo3, a cytotoxic gold(iii) compound, was encapsulated within a ferritin nanocage. Inductively coupled plasma mass spectrometry, circular dichroism, UV-Vis absorption spectroscopy and X-ray crystallography confirm the potential-drug encapsulation. The structure shows that naked Au(i) ions bind to the side chains of Cys48, His49, His114, His114 and Cys126, Cys126, His132, His147. The gold-encapsulated nanocarrier has a cytotoxic effect on different aggressive human cancer cells, whereas it is significantly less cytotoxic for non-tumorigenic cells

Chemistry, antiproliferative properties, tumor selectivity, and molecular mechanisms of novel gold(III) compounds for cancer treatment: a systematic study

The antiproliferative properties of a group of 13 structurally diverse gold(III) compounds, including six mononuclear gold(III) complexes, five dinuclear oxo-bridged gold(III) complexes, and two organogold(III) compounds, toward several human tumor cell lines were evaluated in vitro using a systematic screening strategy. Initially all compounds were tested against a panel of 12 human tumor cell lines, and the best performers were tested against a larger 36-cell-line panel. Very pronounced antiproliferative properties were highlighted in most cases, with cytotoxic potencies commonly falling in the low micromolar—and even nanomolar—range. Overall, good-to-excellent tumor selectivity was established for at least seven compounds, making them particularly attractive for further pharmacological evaluation. Compare analysis suggested that the observed antiproliferative effects are caused by a variety of molecular mechanisms, in most cases "DNA-independent,” and completely different from those of platinum drugs. Remarkably, some new biomolecular systems such as histone deacetylase, protein kinase C/staurosporine, mammalian target of rapamycin/rapamycin, and cyclin-dependent kinases were proposed for the first time as likely biochemical targets for the gold(III) species investigated. The results conclusively qualify gold(III) compounds as a promising class of cytotoxic agents, of outstanding interest for cancer treatment, while providing initial insight into their modes of action. Graphical Abstract: A series of gold(III) compounds showed cytotoxic properties and tumor selectivity toward a panel of cancer cell lines. Compare analysis provided insight into their possible mechanisms of actio

Thermally stable gold(III) alkene and alkyne complexes: Synthesis, structures, and assessment of the trans‐influence on gold‐ligand bond enthalpies

The reaction of [C^C)Au(OEt2)2]+ with 1,5‐cyclooctadiene or norbornadiene affords the corresponding olefin complexes [(C^C)Au(COD)]SbF6 and [(C^C)Au(NBD)]SbF6, which are thermally stable in solution and the solid state (C^C = 4,4′‐di‐t‐butylbiphenyl‐2,2′‐diyl). The crystal structures of these complexes have been determined. By contrast, dienones such as dibenzylideneacetone are O‐ rather than C=C‐bonded. The reactions of (C^C)Au(OAcF)(L) (L = PMe3 or CNxyl) with B(C6F5)3 in the presence of bis(1‐adamantyl)acetylene give the mixed‐ligand alkyne complexes [(C^C)Au(AdC≡CAd)(L)]+, the first complexes of their type in gold chemistry. In the presence of an excess of acetylene these compounds are thermally stable in solution and as solids. The bonding of n‐ and π‐donor ligands to Au(III) fragments and the effect of the trans influence exerted by N‐ and C‐donors was explored with the aid of DFT calculations. Results show that the Au‐L bond enthalpies trans to anionic C are 35 ‐ 60% of the enthalpies trans to N, with strong π‐acceptors being particularly affected. In comparison with [Me2Au]+, the [(C^C)Au]+ fragment is more polar and in bond enthalpy terms resembles Me2Pt

Luminescent gold(III) thiolates: Supramolecular interactions trigger and control switchable photoemissions from bimolecular excited states

A new family of cyclometallated gold(III) thiolato complexes based on pyrazine-centred pincer ligands has been prepared, (C^Npz^C)AuSR, where C^Npz^C=2,6-bis(4-ButC6H4)pyrazine dianion and R=Ph (1), C6H4tBu-4 (2), 2-pyridyl (3), 1-naphthyl (1-Np, 4), 2-Np (5), quinolinyl (Quin, 6), 4-methylcoumarinyl (Coum, 7) and 1-adamantyl (8). The complexes were isolated as yellow to red solids in high yields using mild synthetic conditions. The single-crystal X-ray structures revealed that the colour of the deep-red solids is associated with the formation of a particular type of short (3.2–3.3 Å) intermolecular pyrazine⋅⋅⋅pyrazine π-interactions. In some cases, yellow and red crystal polymorphs were formed; only the latter were emissive at room temperature. Combined NMR and UV/Vis techniques showed that the supramolecular π-stacking interactions persist in solution and give rise to intense deep-red photoluminescence. Monomeric molecules show vibronically structured green emissions at low temperature, assigned to ligand-based 3IL(C^N^C) triplet emissions. By contrast, the unstructured red emissions correlate mainly with a 3LLCT(SR→{(C^Npz^C)2}) charge transfer transition from the thiolate ligand to the π⋅⋅⋅π dimerized pyrazine. Unusually, the π-interactions can be influenced by sample treatment in solution, such that the emissions can switch reversibly from red to green. To our knowledge this is the first report of aggregation-enhanced emission in gold(III) chemistry

Acridine-decorated cyclometallated gold(III) complexes: synthesis and anti-tumour investigations

(C^N) and (C^N^C) cyclometalated Au(III) represent a highly promising class of potential anticancer agents. We report here the synthesis of seven new cyclometalated Au(III) complexes with five of them bearing an acridine moiety attached via (N^O) or (N^N) chelates, acyclic amino carbenes (AAC) and N-heterocyclic carbenes (NHC). The antiproliferative properties of the different complexes were evaluated in vitro on a panel of cancer cells including leukaemia, lung and breast cancer cells. We observed a trend between the cytotoxicity and the intracellular gold uptake of some representative compounds of the series. Some of the acridine-decorated complexes were demonstrated to interact with ds-DNA using FRET-melting techniques

Heterobimetallic Catalysis: Platinum‐Gold‐Catalyzed Tandem Cyclization/C−X Coupling Reaction of (Hetero)Arylallenes with Nucleophiles

Heterobimetallic catalysis offers new opportunities for reactivity and selectivity but still presents challenges, and only a few metal combinations have been explored so far. Reported here is a Pt‐Au heterobimetallic catalyst system for the synthesis of a family of multi‐heteroaromatic structures through tandem cyclization/C−X coupling reaction. Au‐catalyzed 6‐endo‐cyclization takes place as the first fast step. Pt‐Au clusters are proposed to be responsible for the increased reactivity in the second step, that is, the intermolecular nucleophilic addition which occurs through an outer‐sphere mechanism by hybrid homogeneous‐heterogeneous catalysis

Selected cytotoxic gold compounds cause significant inhibition of 20S proteasome catalytic activities

Six structurally diverse cytotoxic gold compounds are reported to cause profound and differential inhibition of the three main catalytic activities of purified 20S proteasome whilst auranofin, an established gold(I) drug in clinical use, is nearly ineffective. In particular, the gold(I) complex [(pbiH)Au(PPh3)]PF6, turns out to be the most potent inhibitor of all three enzyme activities with sub-micromolar IC50 values. The present results further support the view that proteasome inhibition may play a major - yet not exclusive - role in the cytotoxic actions of gold based anticancer agents