Annalisa Guerri

Gold(III) compounds as potential antitumor agents: Cytotoxicity and DNA binding properties of some selected polyamine-gold(III) complexes

Abstract Three gold(III)-polyamine complexes of different structure — ([Au(en) 2 Cl 3 , [AuCl(dien)]Cl 2 and [Au(cyclam)](ClO 4 ) 2 Cl) — were synthesized and tested for cytotoxic properties against a human tumor cell line (A2780) either sensitive (A2780/S) or resistant (A2780/R) to cisplatin. Significant cytotoxic activities were found for both [AuCl(dien)]Cl 2 and [Au(en) 2 ]Cl 3 , whereas [Au(cyclam)](ClO 4 ) 2 Cl was poorly cytotoxic. The stability of these gold(III) complexes under physiological conditions was investigated through absorption spectroscopy; their ability to bind DNA, the presumed final target for the cytotoxic action, and modify its conformation was studied through atomic absorption and circular dichroism spectroscopies. Attempts are made to define preliminary structure-function relationships for cytotoxic gold(III) complexes.

Biological properties of two gold(III) complexes: AuCl3(Hpm) and AuCl2(pm).

The reactivity in solution of two recently characterized gold(III) complexes, AuCl3(Hpm) and AuCl2(pm), has been investigated in view of their potential use as anti-cancer agents. In water, both compounds undergo relatively fast hydrolysis of the bound chlorides without loss of the heterocycle ligand; the process is much faster within a physiological buffer. When the two gold(III) complexes react with proteins like albumin or transferrin, reduction of gold(III) to gold(I) and/or hydrolysis is observed. On the other hand, both complexes bind rapidly and tightly to either polynucleotides or calf thymus DNA, with gold remaining in the +3 oxidation state. Circular dichroism investigations reveal a large perturbation of DNA conformation upon gold(III) binding; preferential binding to GC sequences is shown. Cytotoxicity studies on a number of tumor cell lines demonstrate a good activity of these gold(III) complexes compared to cisplatin. However, quick hydrolysis and/or reduction of these compounds under physiological conditions may represent a severe limitation to their use.

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.

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.

Structure and DNA binding properties of the gold(III) complex (AuCl2(esal))

The complex dichloro(N-ethylsalicylaldiminate) gold(III) [AuCl2(esal)] exhibits favorable cytotoxic properties toward a number of human tumor cell lines either sensitive or resistant to cisplatin. Crystallographic data show that the complex is a classical, slightly distorted square planar gold(III) complex with two chlorides and the bidentate salycilaldiminate moiety as ligands. The complex is sufficiently stable in DMSO or methanol but undergoes rapid hydrolysis in water or within a physiological buffer. The interaction of [AuCl2(esal)] with calf thymus DNA has been investigated through circular dichroism and analysis of the melting curves. Small but significant alterations of the CD spectra that are diagnostic of DNA binding are observed for r values greater than 0.02; in addition it is shown that [AuCl2(esal)] binding to DNA induces a slight increase of the melting temperature. On the ground of these results we conclude that DNA may represent a reasonable target for the cytotoxic action of this gold(III) complex, even if other mechanisms cannot be ruled out. # 1999 Elsevier Science S.A. All rights reserved.

Solvent dependent synthesis of micro- and nano- crystalline phosphinate based 1D tubular MOF: structure and CO2 adsorption selectivity

A novel porous tubular 1D-MOF, built from Cu(II), 1,2-bis(4-pyridyl)ethane and P,P′-diphenyl-diphosphinate, has been prepared by an easy and direct self-assembly process in either needle microcrystal or nanorod form depending on the synthesis conditions. The CO2 absorption kinetics drastically increased from the micrometric crystals to the nanorods. The selectivity towards other gases and polar solvents was also investigated.

New ligand bearing preorganized binding side-arms interacting with ammonium cations: Synthesis, conformational studies and crystal structureElectronic supplementary information (ESI) available: molecular modeling studies. See http://www.rsc.org/suppdata/nj/b3/b306778e/

The synthesis and characterization of the new tetraazamacrocycle 4-(N),10-(N)-bis[2-(3-hydroxy-2-oxo-2H-pyridin-1-yl)acetamido]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane (L) is reported. L shows two 3-(hydroxy)-1-(carbonylmethylen)-2(1H)-pyridinone moieties as side-arms of a tetra-aza-macrocyclic base. The key coupling of side-arms was studied and the most significant results were obtained by activating the 3-(benzyloxy)-1-(carboxymethyl)-2(1H)-pyridinone as pentafluorophenol ester. The acid–base properties of L and its capability to interact with simple ammonium cations were investigated by potentiometric measurements in aqueous solution (298.1 ± 0.1 K, I = 0.15 mol dm−3). Protonated species of L can bind NH4+ or primary ammonium cations such as MeNH3+ discriminating them from secondary or tertiary ammonium cations such as Me2NH2+ or Me3NH+ which are not bound in aqueous solution. 1 H and 13C NMR spectra showed the existence in solution of two conformers on the NMR time scale due to the rotational restriction of the two N–CO groups. The activation parameters were determined by dynamic variable-temperature NMR analysis.Molecular dynamics calculations gave results in agreement with the experimental data for both conformation and ammonium-binding studies, underlining that the transformation of the two secondary amines of the macrocyclic base to amide functions, forces the side-arms to remain fixed in position, almost face to face and thus to be preorganized to interact with other species. The crystal structure of the [HL]Cl·8H2O species shows the high number of preorganized hydrogen bond sites capable, in this case, of interacting directly with five H2O molecules.

Macrocyclic ligands bearing two 3-(Hydroxy)-2-pyridinone moieties as side-arms. Conformational studies, synthesis, crystal structure, and alkali and alkaline earth complex formation

The synthesis and characterization of the new tetraazamacrocycle 4(N),10(N)-bis[2-(3-hydroxy-2-oxo-2H-pyridin-1-yl)ethyl]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane (L1) is reported. L1 shows two 3-(hydroxy)-1-(carbonylmethylen)-2(1H)-pyridinone (HPO) moieties linked to the macrocyclic base 4,7-dimethyl-1,4,7,10-tetrazacyclododecane, as side-arms. The acid–base and coordination properties towards alkali, alkaline earth ions of L1 together with those of the structurally similar ligand 4-(N),10-(N)-bis[2-(3-hydroxy-2-oxo-2H-pyridin-1-yl)acetamido]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane (L2) are reported. L2 binds all the metal ions investigated forming stable mono-nuclear complexes, while L1 binds only some alkaline earth ions with stability constants lower than those of L2. Both compounds show selectivity towards the Mg(II) ion with respect to the alkaline earth series. The binding area is formed by the four converging oxygen atoms of the two HPO groups. L2 appears to be a more efficient ligand in the coordination of hard metal ions because the two HPO binding groups are forced by the macrocyclic skeleton to stay on the same part of the macrocyclic ring, while this conformation is unfavourable for L1. These data are supported by molecular dynamics (MD) simulations performed on both ligands and by the crystal structure of the [H2L1](ClO4)2 species which shows the two side-arms displaced opposite to the macrocyclic ring. The effects of pH and metal ion coordination on the UV-Vis absorption and fluorescence emission properties of both ligands were investigated, highlighting that the optical properties changes in acid–base reactions as well as in the coordination of metal ions.

Heavy metal ion complexes with a simple phenolic ligand. Solid state and solution studies

Abstract The coordination properties of the ligand 2-[bis-(aminoethyl)-aminomethyl]-phenol (L) toward Cd(II) and Pb(II) are reported. The studies were carried out using potentiometric measurements (298.1 K, I=0.15 mol dm−3), UV–Vis absorption and 1H, 13C, 113Cd NMR spectra both in aqueous and non-aqueous solution. By potentiometric measurements performed in aqueous solution, L was found to form only mononuclear species with both the ions investigated; [MH−1L]+ is the main species formed. A dinuclear species with stoichiometry [M2(H−1L)2](ClO4)2 was almost quantitatively isolated in solid state from an aqueous solution in the pH range in which the [MH−1L]+ mononuclear species are present. This behavior is ascribed mainly to the low solubility of the dinuclear complex formed. L does not fulfill the coordination requirement of the ion in the mononuclear species and to saturate it, each metal ion binds the phenolate oxygen of another mononuclear species. The dinuclear species were characterized in organic solution by NMR and ESI mass spectroscopy. The results are confirmed by the crystal structure of [Cd2(H−1L)2](ClO4)2, which displays the two Cd(II) ions close to each other and bridged by two phenolic oxygens each belonging to a H−1L− species.

Dinuclear Gold(III) Complexes as Potential Anticancer Agents: Structure, Reactivity and Biological Profile of a Series of Gold(III) Oxo-Bridged Derivatives~!2009-12-08~!2010-01-15~!2010-03-25~!

Six homologous gold(III) dinuclear oxo-bridged complexes, of the type [(bipy)Au(μ-O)2Au(bipy)][PF6]2, bearing variously substituted 2,2’-bipyridine ligands (bipy = 2,2’-bipyridine, 4,4’-di-tert-butyl-, 6-methyl-, 6-neopentyl-, 6-o-xylyland 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 (bipy = 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.