Maria Agostina Cinellu

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

AbstractThe 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 AbstractA 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 action.

Preparation and characterization of palladium(II) and platinum(II) complexes with bis(pyrazolyl)alkanes. crystal and molecular structures of [Pd2(pz)22][BF4]2 and of [PdCl2{(CH3)2C(pz)2}] (pzH = pyrazole), a new example of a Pd⋯HC agostic interaction

Abstract Neutral and cationic complexes of general formulae (LL)MCl 2 (M = Pd, (LL) = CH 2 (pz) 2 ( 1 ); CH 2 (3,5-Me 2 pz) 2 ( 2 ); (CH 3 ) 2 C(pz) 2 ( 3 ); M = Pt, (LL) = CH 2 (pz) 2 ( 4 ); CH 2 (3,5-Me 2 pz) 2 ( 5 ) and (LL) 2 M] 2+ (M = Pd, (LL) = CH 2 (pz) 2 ( 6 ); CH 2 (3,5-Me 2 pz) 2 ( 7 ); (CH 3 ) 2 C(pz) 2 ( 8 ); M = Pt, (LL) = CH 2 (pz) 2 ( 9 ); CH 2 (3,5-Me 2 pz) 2 ( 10 ) have been prepared and characterized by IR and 1 H NMR spectroscopy. The structures of 3 and 6 have been determined by X-ray diffraction; in both complexes the bis-(pyrazolyl)alkanes act as chelating ligands but the coordination around the palladium atom in the complex 6 is strictly square-planar whereas in 3 it is a slightly distorted towards pyramidal, with a significant Pd⋯HC agostic interaction. The six-membered rings in both the complexes adopt a boat-type conformations.

[Au2(phen2Me)2(μ-O)2](PF6)2, a Novel Dinuclear Gold(III) Complex Showing Excellent Antiproliferative Properties

A novel dioxo-bridged dinuclear gold(III) complex with two 2,9-dimethylphenanthroline ligands was synthesized and thoroughly characterized. Its crystal structure was solved, and its solution behavior assessed. Remarkably, this compound revealed excellent antiproliferative properties in vitro against a wide panel of 36 cancer cell lines, combining a high cytotoxic potency to pronounced tumor selectivity. Very likely, these properties arise from an innovative mode of action (possibly involving histone deacetylase inhibition), as suggested by COMPARE analysis. In turn, electrospray ionization-mass spectrometry studies provided valuable insight into its molecular mechanisms of activation and of interaction with protein targets. Gold(III) reduction, dioxo bridge disruption, coordinative gold(I) binding to the protein, and concomitant release of the phenanthroline ligand were proposed to occur upon interaction with superoxide dismutase, used here as a model protein. Because of the reported results, this new gold(III) compound qualifies itself as an optimal candidate for further pharmacological testing.

Palladium(II) and platinum(II) derivatives with chiral 2,2′-bipyridines. X-ray structure of C18H15ClN2Pd; C- and N-intramolecular coordination in a six-membered metallacycle

Abstract The reactions of (+)-( S )-5-s,butyl-2,2′-bipyridine (LH) and 6-(1-methylbenzyl)-2,2′-bipyridine (L′H) with Na 2 [PdCl 4 ] and K 2 [PtCl 4 ] give the 1 : 1 adducts (LH)MCl 2 (M = Pd, 1 ; M = Pt, 2 ) and the metallated species (L′)MCl (M = Pd, 3 ; M = Pt, 4 ), respectively. In complexes 3 and 4 , the deprotonated bipyridine behaves as a tridentate ligand; there is coordination to the metal through the two nitrogen atoms and the ortho -carbon atom of the phenyl ring to give a six-membered metallacycle. The X-ray structure of complex 3 shows that the coordination around the palladium atom is distorted towards tetrahedral from the usual square-planar geometry.

Reaction of platinum(II) derivatives with bis(pyrazolyl)propane. Cleavage of a C(sp3)-N bond in a bis(pyrazolyl)alkane promoted by platinum(II) derivatives. Crystal structure of cis-Pt(pzH)2CL2 (pzH = pyrazole)

The reactions of bis(pyrazolyl)propane (CH3)2C(pz)2, (pzH = pyrazole), with PtCl2, (RCN)2PtCl2 and K2[PtCl4 have been investigated, and the results compared with those described previously for the corresponding palladium(II) derivatives. In contrast with the behaviour of the palladium analogues, the platinum derivatives promote the rupture of the ligand: simple adducts of pyrazole, cis- or trans-Pt(pzH)2Cl2, or species containing the ligand [HNC(R)pz], formally arising from the insertion of a nitrile into the NH bond of pyrazole, are obtained. For comparison, the reaction of the platinum derivatives with pyrazole itself has been investigated under various conditions. The crystal structure of cis-Pt(pzH)2Cl2 has been determined by X-ray diffraction: monoclinic, space group C2/c, a 9.180(1), b 15.084(1), c 15.1445(9) A, β 101.536(7)°, Z - 8, R = 0.039, Rw = 0.040 for 2125 observed reflections.

Synthesis and characterization of gold(III) adducts and cyclometallated derivatives with 6-benzyl- and 6-alkyl-2,2′-bipyridines

The reaction of a series of 6-substituted-2,2′-bipyridines HL (N2C10H7R, R = CH2Ph, CHMePh, CMe2Ph, CH2Me, CMe3 or CH2CMe3) with HAuCl4 or Na[AuCl4] has been investigated. Under different experimental conditions, salts [H2L][AuCl4], adducts [Au(HL)Cl3] or cyclometallated derivatives [Au(L)Cl][X](X = AuCl4, BF4 or PF6) have been isolated. The cyclometallated species arise from direct activation of a C–H bond either of a phenyl or a methyl substituent. The structures of an adduct [Au{N2C10H7(CHMePh)-6}Cl3] and two metallated species [Au{N2C10H7(CMe2C6H4)-6}Cl][AuCl4] and [Au{N2C10H7(CMe2CH2)-6}Cl][BF4]·0.5H2O have been determined by X-ray diffraction. In the adduct the gold atom is bonded to the nitrogen atom of the unsubstituted pyridine ring: a long-range interaction with the other nitrogen atom is observed, Au ⋯ N 2.758(4)A. In the two cyclometallated species the bipyridines act as tridentate N,N,C anions, giving a [5,6] and a [5,5]-fused ring system, respectively. In [Au{N2C10H7(CMe2C6H4)-6}Cl]+ the hexaatomic N,C ring adopts a boat-like conformation: the structure reveals a rather short interaction between one hydrogen of the Me group in axial position and the gold atom, Au ⋯ H 2.62 A. The pentaatomic N,C ring in [Au{N2C10H7(CMe2CH2)-6}Cl]+ is not planar: the co-ordination around the gold atom is essentially square planar. The new cyclometallated complexes [Au(N,N,C)Cl]+ are compared with those derived from similarly substituted pyridines described previously.

The mode of action of anticancer gold-based drugs: a structural perspective

The interactions between a few representative gold-based drugs and hen egg white lysozyme were studied by X-ray crystallography. High resolution crystal structures solved for three metallodrug-protein adducts provide valuable insight into the molecular mechanism of these promising metal compounds and the inherent protein metalation processes.

Exploring the biochemical mechanisms of cytotoxic gold compounds: a proteomic study

We have recently shown that a group of structurally diverse gold compounds are highly cytotoxic toward a panel of 36 human tumor cell lines through a variety of biochemical mechanisms. A classic proteomic approach is exploited here to gain deeper insight into those mechanisms. This investigation is focused on Auoxo6, a novel binuclear gold(III) complex, and auranofin, a clinically established gold(I) antiarthritic drug. First, the 72-h cytotoxicity profiles of Auoxo6 and auranofin were determined against A2780 human ovarian carcinoma cells. Subsequently, protein extraction from gold-treated A2780 cells sensitive to cisplatin and 2D gel electrophoresis separation were carried out according to established procedures. Notably, both metallodrugs caused relatively modest changes in protein expression in comparison with controls as only 11 out of approximately 1,300 monitored spots showed appreciable quantitative changes. Very remarkably, six altered proteins were in common between the two treatments. Eight altered proteins were identified by mass spectrometry; among them was ezrin, a protein associated with the cytoskeleton and involved in apoptosis. Interestingly, two altered proteins, i.e., peroxiredoxins 1 and 6, are known to play crucial roles in the cell redox metabolism. Increased cleavage of heterogeneous ribonucleoprotein H was also evidenced, consistent with caspase 3 activation. Overall, the results of the present proteomic study point out that the mode of action of Auoxo6 is strictly related to that of auranofin, that the induced changes in protein expression are limited and selective, that both gold compounds trigger caspase 3 activation and apoptosis, and that a few affected proteins are primarily involved in cell redox homeostasis.

Structural and solution chemistry, protein binding and antiproliferative profiles of gold(I)/(III) complexes bearing the saccharinato ligand

A series of new gold(I) and gold(III) complexes based on the saccharinate (sac) ligand, namely M[Au(sac)(2)] (with M being Na(+), K(+) or NH(4)(+)), [(PTA)Au(sac)], K[Au(sac)(3)Cl] and Na[Au(sac)(4)], were synthesized and characterized, and some aspects of their biological profile investigated. Spectrophotometric analysis revealed that these gold compounds, upon dissolution in aqueous media, at physiological pH, manifest a rather favourable balance between stability and reactivity. Their reactions with the model proteins cytochrome c and lysozyme were monitored by mass spectrometry to predict their likely interactions with protein targets. In the case of disaccharinato gold(I) complexes, cytochrome c adducts bearing four coordinated gold(I) ions were preferentially formed in high yield. In contrast, [(PTA)Au(sac)] (PTA=1,3,5-triaza-7-phosphaadamantane) turned out to be poorly effective, only producing a mono-metalated adduct in very low amount. In turn, the gold(III) saccharinate derivatives were less reactive than their gold(I) analogues: K[Au(sac)(3)Cl] and Na[Au(sac)(4)] caused moderate protein metalation, again with evidence of formation of tetragold adducts. Finally, the above mentioned gold compounds were challenged against the reference human tumor cell line A2780S and its cisplatin resistant subline A2780R and their respective cytotoxic profiles determined. [(PTA)Au(sac)] turned out to be highly cytotoxic whereas moderate cytotoxicities were observed for the gold(III) complexes and only modest activities for disaccharinato gold(I) complexes. The implications of these results are thoroughly discussed in the light of current knowledge on gold based drugs.

Synthesis and characterization of gold(III) complexes of 1,4-benzodiazepin-2-ones. Crystal structure of trichloro-[7-chloro-1-(cyclopropylmethyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one]gold(III)

Abstract The reaction of gold(III) chloride with several 1,4-benzodiazepin-2-ones, L, gives 1:1 adducts, (L)AuCl3*, which were characterized by IR, Raman and 1H NMR spectroscopy. In the title compound the coordination of the ligand, ascertained through a X-ray structure determination, was shown to occur through the 4-nitrogen atom.