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)

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

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

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

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 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

Complessi ciclometallati di Pt(II) e Pd(II) con la 6,6'- PH₂-2,2'-bipiridina

Proseguendo il nostro interesse sulla reattività di 2,2’-bipiridine con ioni di metalli nobili abbiamo sintetizzato e studiato la reattività di nuovi derivati di platino e palladio con la 6,6’-difenil-2,2’- bipiridina, anche per confrontarne le proprietà con quelle degli analoghi derivati della 6- fenil-2,2’-bipiridina, oggetto di notevole interesse per le proprietà in campo biomedico, fotochimico e fotofisico

Ferritin nanocages loaded with gold ions induce oxidative stress and apoptosis in MCF-7 human breast cancer cells

Two anticancer gold(III) compounds, Au2phen and Auoxo4, were encapsulated within a ferritin nanocage. The gold-compound loaded proteins were characterized by UV-Vis spectroscopy, inductively coupled plasma mass spectrometry and circular dichroism. X-ray crystallography shows that the compounds degrade upon encapsulation and gold(I) ions bind Ft within the cage, close to the side chains of Cys126. The gold-encapsulated nanocarriers are cytotoxic to human cancer cells. Au(I)-loaded Ft, obtained upon the encapsulation of Au2phen within the cage, induces oxidative stress activation, which finally leads to apoptosis in MCF-7 cell

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

New variations on the theme of gold(III) C^N^N cyclometalated complexes as anticancer agents: Synthesis and biological characterization

A new series of novel (C∧N∧N) cyclometalated gold(III) complexes have been characterized for their structural and spectroscopic properties. The anticancer activities of the compounds have been studied in vitro, and their reactivity with model biomolecules has been elucidated by mass spectrometry techniques, evidencing an unexpected preference for binding to nucleic acids with respect to proteins and amino acids