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)

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

An element through the looking glass: Exploring the Au-C, Au-H and Au-O energy landscape

Gold, the archetypal “noble metal”, used to be considered of little interest in catalysis. It is now clear that this was a misconception, and a multitude of gold-catalysed transformations has been reported. However, one consequence of the long-held view of gold as inert metal is that its organometallic chemistry contains many “unknowns”, and catalytic cycles devised to explain gold's reactivity draw largely on analogies with other transition metals. How realistic are such mechanistic assumptions? In the last few years a number of key compound classes have been discovered that can provide some answers. This Perspective attempts to summarise these developments, with particular emphasis on recently discovered gold(III) complexes with bonds to hydrogen, oxygen, alkenes and CO ligands

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

Complessi di oro con leganti imidazolici di interesse farmacologico

L'imidazolo gioca un ruolo importante nella chimica biologica, difatti costituisce un componente laterale dell'istidina, amminoacido essenziale, e si trova anche in molte proteine. Nel nostro gruppo di ricerca da anni ci si occupa della sintesi di complessi con leganti eterociclici azotati, con metalli di transizione come oro, platino e palladio, sia con scopi catalitici che con scopi farmaceutici. Nello specifico il mio lavoro si e basato sulla sintesi di complessi di oro(I) e oro(III) con leganti contenenti anelli imidazolici

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

Dinuclear gold(III) complexes as potential anticancer agents: structure, reactivity and biological profile of a series of gold(III) oxo-bridged derivatives

Six homologous gold(III) dinuclear oxo-bridged complexes, of the type [(bipynR)Au(μ-O)2Au(bipynR)][PF6]2, bearing variously substituted 2,2'-bipyridine ligands (bipynR = 2,2'-bipyridine, 4,4'-di-tert-butyl-, 6-methyl-, 6-neopentyl-, 6-o-xylyl- and 6,6'-dimethyl-2,2'-bipyridine), here called Auoxos, were prepared, characterised and recently tested as potential anticancer agents. Crystal structures were obtained for five members of the series that allowed us to perform detailed comparative analyses. Interestingly, the various Auoxos showed an acceptable stability profile in buffer solution and turned out to manifest outstanding antitumor properties in vitro. In particular, one member of this family, Auoxo6 (bipynR = 6,6'-dimethyl-2,2'-bipyridine), produced more selective and far greater antiproliferative effects than all other tested Auoxos, qualifying itself as the best “drug candidate”. In turn, COMPARE analysis of the cytotoxicity profiles of five Auoxos, toward an established panel of thirty-six human tumor cell lines, revealed important mechanistic differences; a number of likely biomolecular targets could thus be proposed such as HDAC and PKC. Biophysical studies revealed markedly different modes of interaction with calf thymus DNA for two representative Auoxo compounds. In addition, a peculiar reactivity with model proteins was documented on the ground of spectrophotometric and ESI MS data, most likely as the result of redox processes. In view of the several experimental evidences gathered so far, it can be stated that Auoxos constitute a novel family of promising cytotoxic gold compounds with an innovative mechanism of action that merit a more extensive pharmacological evaluation

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

Complessi pincer NCN di Au(III) quali possibili agenti antitumorali

I composti di oro sono da molto tempo utilizzati in medicina (es. nella cura dell’artrite reumatoide). Attualmente rivestono grande importanza come possibili agenti anticancro, settore dominato dai complessi di platino(II): composti di oro(III), isoelettronici ed isostrutturali con i complessi di platino(II), dopo un esordio abbastanza deludente, hanno ridestato l’interesse come antitumorali a partire dalla metà degli anni ’90 ed ora la letteratura è ricca di lavori che ne riportano l’attività citostatica sia in vitro che in vivo. Da tempo ci occupiamo di complessi pincer tipo [M(N^C^N)Cl] M=Pd(II), Pt(II)3 e da poco abbiamo esteso questa nostra ricerca anche all’Au(III): malgrado il largo interesse per la chimica dei pincer complessi NCN i derivati di oro sono molto rari