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Biomedical subjects

Luigi Messori

Publications and source records attributed to Luigi Messori.

At least 19 recordsLinked to original sources
PubMed2007

fac-{Ru(CO)3}2+-core complexes and design of metal-based drugs. synthesis, structure, and reactivity of Ru-thiazole derivative with serum proteins and absorption-release studies with acryloyl and silica hydrogels as carriers in physiological media.

The reaction of [Ru2(CO)6Cl4], 1, with excess THZ (1,3-thiazole) in absolute ethanol at 55 degrees C produces fac-[Ru(CO)3Cl2(THZ)], 2, in high yield. [Ru(CO)2Cl2(THZ)2], 3, is formed at higher temperature (ca 70 degrees C) and higher concentration of THZ. The X-ray structures of the new compounds have been determined, and density functional studies performed at the hybrid B3LYP/(Lanl2DZ, Ru; 6-311+G**, CHClNOS) level allowed the estimation of the structures of several conformers as well as that of their relative total electronic energies. Compound 2 is soluble (slowly) in aqueous media, where it reacts with the transport proteins bovine serum albumin (BSA) and human apotransferrin (HTF), and at a lower extent with calf thymus DNA (CT-DNA) and with guanosine-5'-monophosphate (GMP). The complex molecule is adsorbed by certain synthetic acryloyl polymers that have terminal carboxylate functions and is embedded in silica gels when these latter are prepared in the presence of a solution of 2. Ruthenium species are slowly released from the loaded gels into physiological solutions at pH 7.4. The reactivity of 2 with biomolecules and synthetic hydrogels makes it a compound of interest for anticancer and antimetastases tests.

Algorithms↗
PubMed2006

Antimalarial properties of green tea.

We show here that a crude extract of green tea as well as two of its main constituents, epigallocatechin-3-gallate (EGCG) and epicatechin gallate (ECG), strongly inhibit Plasmodium falciparum growth in vitro. Both these catechins are found to potentiate the antimalarial effects of artemisinin without interfering with the folate pathway. The importance of these findings and their mechanistic implications are discussed in view of future therapeutic strategies.

Animals↗
PubMed2006

The copper(II) coordination abilities of three novel cyclic tetrapeptides with -His-Xaa-His- motif.

Three novel cyclic tetrapeptides, containing either l- or d-histidine residues and either Lys or Asp side chains, namely c(HGd-HK) (1), cHGHD (2) and c(HGd-HD) (3), were designed, synthesized, characterized and tested as potential copper(II) ligands. Their pH dependent copper(II) binding properties were analysed in depth by a number of potentiometric and spectroscopic determinations. A rather exhaustive description of the species existing in solution has emerged for each copper(II)/oligopeptide system; solution structures for the individual species are proposed. The specific role of the various side chains in the overall metal coordination process is discussed in comparison with the case of Cu(II)-c(HGHK), previously reported. Data obtained in this study highlight the strong impact of the d-His residue on the metal binding abilities of these cyclic peptides. Remarkably, the cyclic tetrapeptides containing two l-His residues are able to form, at physiologically relevant pH values, a characteristic chromophore where the mononuclear copper(II) centre is simultaneously coordinated by two imidazole nitrogens and two amidic nitrogens of the tetrazadodecane ring. This latter type of copper(II) chromophore has been carefully modelled by computational methods. The potentialities of the applied experimental strategy are stressed.

Binding Sites↗
PubMed2006

ESI mass spectrometry and X-ray diffraction studies of adducts between anticancer platinum drugs and hen egg white lysozyme.

The interactions of cisplatin and its analogues, transplatin, carboplatin and oxaliplatin, with hen egg white lysozyme were analysed through ESI mass spectrometry, and the resulting metallodrug-protein adducts identified; the X-ray crystal structure of the cisplatin lysozyme derivative, solved at 1.9 A resolution, reveals selective platination of imidazole Nepsilon of His15.

Animals↗
PubMed2006

Structural and solution chemistry, antiproliferative effects, and DNA and protein binding properties of a series of dinuclear gold(III) compounds with bipyridyl ligands.

A series of six dinuclear gold(III) oxo complexes with bipyridyl ligands, of general formula [Au2(N,N)2(mu-O)2][PF6]2 (Auoxo1-Auoxo6) [where N,N = 2,2'-bipyridine (1), 4,4'-di-tert-butyl- (2), 6-methyl- (3), 6-neopentyl- (4), 6-(2,6-dimethylphenyl)- (5), 6,6'-dimethyl-2,2'-bipyridine (6)], were investigated as potential cytotoxic and anticancer agents, and their antiproliferative properties were evaluated in vitro toward the reference A2780 human ovarian carcinoma cell line. While five compounds manifested moderate cytotoxic properties (with IC50 approximately 10-30 microM), the sixth one (Auoxo6), turned out to be approximately 5-15 times more active against both cell lines and will merit further pharmacological studies. The interactions of Auoxo1 and Auoxo6 with a few model proteins (serum albumin, cytochrome c, ubiquitin) and with calf thymus DNA were analyzed in detail by various spectroscopic methods. Both tested compounds manifested a high and peculiar reactivity toward the mentioned model proteins; specific differences were detected in their reactivity with DNA. The mechanistic implications of these results are discussed.

2,2'-Dipyridyl↗
PubMed2006

The reaction of artemisinins with hemoglobin: a unified picture.

The reactions with hemoglobin of artemisinin and of its parent compounds, sodium artesunate and dihydroartemisinin, were investigated by visible absorption spectroscopy under standard solution conditions (50 mM phosphate buffer, pH 7, 37 degrees C). Notably, these antimalarial drugs were found to react with hemoglobin (i.e., ferrous heme), but not with methemoglobin (i.e., ferric heme). The reaction selectively occurs at the heme sites and consists of the progressive, slow decay of the Soret band, as a consequence of heme alkylation and subsequent loss of pi electron delocalization. For the various tested compounds the process reaches completion within approximately 30-70 h. Additional experiments were carried out upon adopting the solution conditions described by Meunier et al. and by Kannan et al. in their recent studies. Some reactivity of artemisinin with methemoglobin was indeed detected after addition of 50% v/v acetonitrile, most likely as a consequence of extensive protein unfolding. A unified description for the reactions of artemisinins with hemoglobin is given.

Acetates↗
PubMed2005

Mechanisms of cytotoxicity of selected organogold(III) compounds.

The effects of a few cytotoxic organogold(III) compounds on ovarian A2780 human cancer cells were investigated in comparison to cisplatin and oxaliplatin. The tested compounds produced significant antiproliferative effects and promoted apoptosis to a greater extent than platinum drugs while causing only modest cell cycle modifications. The mechanistic implications of these findings are discussed: mitochondrial pathways are proposed to be directly involved in the apoptotic process in relation to selective inhibition of thioredoxin reductase.

Antineoplastic Agents↗
PubMed2005

The C2 variant of human serum transferrin retains the iron binding properties of the native protein.

The tryptic digests of blood samples obtained from transferrin C1 and C2 (TfC 1 and TfC2 hereafter) genotypes were analysed by Liquid Chromatography coupled to Electrospray Mass Spectrometry (LC/ESI--MS/MS). The analytical results confirmed the single base change in exon 15 of the Tf gene. The solution behaviour and the iron binding properties of the two Tf variants were studied by UV-visible spectrophotometry and by circular dichroism. It appears that TfC2 globally manifests the same spectral features as the native protein. The local conformation of the two iron binding sites is conserved in the two Tf variants as evidenced by the visible absorption and CD spectra. Also, the iron binding capacities and their pH-dependent profiles are essentially the same. Overall, our investigation points out that the single amino acid substitution in TfC2 (Pro 570 Ser) does not affect the general conformation of the protein nor the local structure of the iron binding sites. The implications of these results for the etiopathogenesis of Alzheimer's disease are discussed.

Alzheimer Disease↗
PubMed2005

Structure-function relationships within Keppler-type antitumor ruthenium(III) complexes: the case of 2-aminothiazolium[trans-tetrachlorobis(2-aminothiazole)ruthenate(III)].

Keppler-type ruthenium(III) complexes exhibit promising antitumor properties. We report here a study of 2-aminothiazolium[trans-tetrachlorobis(2-aminothiazole)ruthenate(III)], both in the solid state and in solution. The crystal structure has been solved and found to exhibit classical features. Important solvatochromic effects were revealed. Notably, we observed that introduction of an amino group in position 2 greatly accelerates chloride hydrolysis compared to the thiazole analogue; this latter finding may be of interest for a fine-tuning of the reactivity of these novel metallodrugs.

Animals↗
PubMed2004

Solution chemistry and cytotoxic properties of novel organogold(III) compounds.

The solution behaviour of some novel organogold(III) compounds was investigated, and their cytotoxic properties evaluated against a few human tumour cell lines (A2780/S, A2780/R, MCF7, HT29 and A549). Specifically, the following compounds were considered: [Au(bipy(dmb)-H)(2,6-xylidine-H)][PF(6)] (AuXyl) and [Au(bipy(dmb)-H)(p-toluidine-H)][PF(6)] (AuTol) (in which bipy(dmb)=6-(1,1-dimethylbenzyl)-2,2'-bipyridine), [Au(py(dmb)-H)(AcO)(2)] (AuPyAcO) (in which py(dmb)=2-(1,1-dimethylbenzyl)-pyridine) and [Au(pz(Ph)-H)Cl(3)]K (AuPzCl) (in which pz(Ph)=1-phenylpyrazole). The solution chemistry of these compounds, under physiological-like conditions, was investigated through UV-vis absorption and (1)H NMR spectroscopies. Significant cytotoxic effects in vitro were observed in selected cases.

Antineoplastic Agents↗
PubMed2004

Synthesis, structural characterization, solution chemistry, and preliminary biological studies of the ruthenium(III) complexes [TzH][trans-RuCl4(Tz)2] and [TzH][trans-RuCl4(DMSO)(Tz)].(DMSO), the thiazole analogues of antitumor ICR and NAMI-A.

Two ruthenium(III) complexes bearing the thiazole ligand, namely, thiazolium (bisthiazole) tetrachlororuthenate (I, TzICR) and thiazolium (thiazole, DMSO) tetrachlororuthenate (II, TzNAMI) were prepared and characterized. The crystal structures of both complexes were solved by X-ray diffraction methods and found to match closely those of the corresponding imidazole complexes. The behavior in aqueous solution of bothTzICR and TzNAMI was analyzed spectroscopically. The time-dependent spectrophotometric profiles resemble closely those of the related ICR and NAMI-A anticancer compounds, respectively. It is observed that replacement of imidazole with thiazole, a less basic ligand, produces a significant decrease of the ligand exchange rates in the case of the NAMI-like compound. The main electrochemical features of these ruthenium(III) thiazole complexes were determined and compared to those of ICR and NAMI-A. Moreover, some preliminary data were obtained on their biological properties. Notably, both complexes exhibit higher reactivity toward serum albumin than toward calf thymus DNA; cytotoxicity is negligible in line with expectations. A more extensive characterization of the pharmacological properties in vivo is presently in progress.

Algorithms↗
PubMed2004

Clioquinol, a drug for Alzheimer's disease specifically interfering with brain metal metabolism: structural characterization of its zinc(II) and copper(II) complexes.

Clioquinol, a 8-hydroxyquinoline derivative, is producing very encouraging results in the treatment of Alzheimer's disease (AD). Its biological effects are most likely ascribed to complexation of specific metal ions, such as copper(II) and zinc(II), critically associated with protein aggregation and degeneration processes in the brain. We report here, for the first time, a structural characterization of the zinc(II) and copper(II) complexes of clioquinol. A ligand to metal stoichiometry of 2:1 is found in both cases, though in the presence of quite different coordination polyhedra. The present findings are discussed in the frame of modern approaches to AD treatment.

Alzheimer Disease↗
PubMed2004

Gold complexes inhibit mitochondrial thioredoxin reductase: consequences on mitochondrial functions.

The effects of gold(I) complexes (auranofin, triethylphosphine gold and aurothiomalate), gold(III) complexes ([Au(2,2'-diethylendiamine)Cl]Cl(2), [(Au(2-(1,1-dimethylbenzyl)-pyridine) (CH(3)COO)(2)], [Au(6-(1,1-dimethylbenzyl)-2,2'-bipyridine)(OH)](PF(6)), [Au(bipy(dmb)-H)(2,6-xylidine)](PF(6))), metal ions (zinc and cadmium acetate) and metal complexes (cisplatin, zinc pyrithione and tributyltin) on mitochondrial thioredoxin reductase and mitochondrial functions have been examined. Both gold(I) and gold(III) complexes are extremely efficient inhibitors of thioredoxin reductase showing IC(50) ranging from 0.020 to 1.42 microM while metal ions and complexes not containing gold are less effective, exhibiting IC(50) going from 11.8 to 76.0 microM. At variance with thioredoxin reductase, auranofin is completely ineffective in inhibiting glutathione peroxidase and glutathione reductase, while gold(III) compounds show some effect on glutathione peroxidase. The mitochondrial respiratory chain is scarcely affected by gold compounds while the other metal complexes and metal ions, in particular zinc ion and zinc pyrithione, show a more marked inhibitory effect that is reflected on a rapid induction of membrane potential decrease that precedes swelling. Therefore, differently from gold compounds, the various metal ions and metal complexes exert their effect on different targets indicating a lower specificity. It is concluded that gold compounds are highly specific inhibitors of mitochondrial thioredoxin reductase and this action influences other functions such as membrane permeability properties. Metal ions and metal complexes markedly inhibit the activity of thioredoxin reductase although to an extent lower than that of gold compounds. They also inhibit mitochondrial respiration, decrease membrane potential and, finally, induce swelling.

Animals↗
PubMed2004

The copper(II) binding properties of the cyclic peptide c(HGHK).

The new cyclic tetrapeptide c(HGHK) was synthesised in the solid phase and its complexes with copper(II) were studied in aqueous solution at various pH values by means of potentiometric and spectroscopic methods (UV, EPR, CD). Six mononuclear coordination species were clearly identified within the pH range 3-11. Spectroscopic data strongly suggest sequential formation of N, 2N, 3N and 4N equatorial donor sets around the copper(II) centre from the lowest to the highest pH, involving both imidazole nitrogens and amide nitrogens. A detailed comparison with the copper(II) binding properties of HGHG and Ac-HGHG ligands is also reported.

Amides↗
PubMed2004

Effects of chronic treatment with sodium tetrachloroaurate(III) in mice and membrane models.

Gold is a nonessential element with a variety of applications in medicine. A few gold(I) compounds are used in the clinics for treatment of rheumatoid arthritis and of discoid lupus. Some novel gold(III) compounds are under evaluation as anticancer agents. It is known that gold compounds generally produce toxic effects on the kidneys and characteristic lesions in the brain. However, information concerning the neurotoxicity of gold derivatives in humans as well as in experimental toxicology is rather scarce. For this reason we tried to shed some further light on this aspect of gold neurotoxicity by chronic treatment of mice with sodium tetrachloroaurate(III) in order to observe possible biophysical and morphological alterations that may occur in the brain. Chronic gold treatment resulted in a markedly decreased expression of metallothioneins and of glial fibrillary acidic protein in astrocytes of different brain areas. To examine its effects on cell membranes, interactions of sodium tetrachloroaurate(III) with molecular models were also evaluated. The models consisted in bilayers built-up of classes of phospholipids located in the outer and inner monolayers of biological membranes. Structural perturbation of cell membrane models was observed only at concentrations 10(5) times higher than those detected in the brains of animals after three months' treatment. These results show that toxic effects on animal brain upon treatment with sodium tetrachloroaurate develop with difficulty and may be observed only at high doses.

Animals↗