Transferrin: From Inorganic Biochemistry to Medicine

Transferrin is one of the key proteins of iron metabolism in mammalians. It is responsible for the transfer of the essential iron(III) ions through the biological fluids from absorption to storage and utilization sites. Moreover, transferrin is involved in the metabolism of other metal ions that are either trace or toxic elements. In recent years the crystal structure of transferrin has been solved at high resolution. This has allowed an extensive reinterpretation of the many spectroscopic studies carried out on this protein in the last decade as well as the elucidation of some interesting structure-function relationships. We review here recent progresses in transferrin biochemistry, particular focus being given to those aspects that are relevant from a medical point of view

The Interaction of the Antitumor Complexes Na[trans-RuCl4 (DMSO)(Im)] and Na[trans-RuCl4(DMSO)(Ind)] With Apotransferrin: a Spectroscopic Study

The interaction of two antitumor ruthenium(III) complexes,-Na[trans-RuCl4(DMSO)(Im)] and Na[trans-RuCl4(DMSO)(Ind)]- with human serum apotransferrin (apoTf) was investigated through a number of spectroscopic techniques such as UV-Vis absorption, CD and 1H NMR spectroscopy. Interestingly, the hydrolysis profiles of these complexes in a physiological buffer are markedly affected by the presence, in solution, of apoTf suggesting the occurrence of a specific interaction of their respective hydrolysis products with the protein. The formation of stable adducts with apotransferrin has been demonstrated by CD spectroscopy, and additional information obtained through 1H NMR of the hyperfine shifted signals. The bound ruthenium(III) species may be detached from these adducts by addition of excess citrate at low pH. The behavior of the investigated ruthenium(III) complexes with apoTf is compared with that of the recently described and strictly related ru-im and ru-ind antitumour complexes, and discussed in the frame of general strategies of drug targeting

Molecular Recognition of Metal Complexes by DNA: A Comparative Study of the Interactions of the Parent Complexes [PtCl(TERPY)]Cl and [AuCl(TERPY)]Cl (2) with Double Stranded DNA

The interactions of the parent complexes [AuCl(Terpy)]Cl2 and [PtCl(Terpy)]Cl with DNA were analysed by various physicochemical methods. Surprisingly, these metal complexes produce different interaction patterns with DNA in spite of their profound structural similarity. Indeed, important modifications are detected in the characteristic UV-Vis bands of [PtCl(Terpy)]Cl upon addition of ct-DNA, while the spectrum of [AuCl(Terpy)]Cl2 is almost unaffected. Gel electrophoresis studies confirm these findings: [PtCl(Terpy)]Cl — but not [AuCl(Terpy)]Cl2 — retards significantly the mobility of the supercoiled form of the pHV14 plasmid after a short incubation time. Ultrafiltration studies indicate that the affinity of [PtCl(Terpy)]Cl for ct-DNA is significantly greater than that of [AuCl(Terpy)]Cl2. On the other hand, both [AuCl(Terpy)]Cl2 and [PtCl(Terpy)]Cl induce important changes in the CD spectrum of ct-DNA, at high concentration, and increase its Tm value. Remarkably, the analysed metal-complex/DNA interaction patterns depend critically on the incubation times. We propose that [PtCl(Terpy)]Cl quickly intercalates DNA; then, formation of coordinative bonds progressively takes place with time. At variance, [AuCl(Terpy)]Cl2 first interacts electrostatically with the DNA surface, with subsequent slow formation of some coordinative bonds

Iridium(I) Compounds as Prospective Anticancer Agents: Solution Chemistry, Antiproliferative Profiles and Protein Interactions for a Series of Iridium(I) N-Heterocyclic Carbene Complexes

Aseries of structurally related mono-and bis-NHC–iridium(I) (NHC:N-heterocyclic carbene) complexeshave been investigatedfor their suitability as potential anti-cancer drugs.Their spectral behaviour in aqueous buffersunder physiologic al-like conditions and their cytotoxicityagainstthe cancercell lines MCF-7 and HT-29are reported.Notably,almostall complexes exhibit significant cytotoxic ef-fects towards both cancer cell lines. In general,the cationicbis-carbene complex es show higherstabilityand greater an-ticanceractivity than their neutral mono-carbene analogueswith IC50valuesinthe high nanomolar range.Furthermore,to gain initialmechanistic insight, the interactions of theseiridium(I)–NHC complexes with two model proteins,namelylysozyme and cytochrome c, were exploredbyHR-ESI-MSanalyses. The different protein metalation patternsofthecomplexes can be roughlyclassified into two distinctgroups. Those interactions give us afirst idea about the pos-sible mechanism of action of this class of compounds. Over-all, our findings show that iridium(I)–NHC complexesrepre-sent very interesting candidates forfurther development asnew metal-based anticancer drugs

The binding properties of two antitumor ruthenium(III) complexes to apotransferrin.

The interaction of two ruthenium(III) complexes exhibiting high anticancer activity, namely trans-indazolium(bisindazole)tetrachlororuthenate(III) (ru-ind) and trans-imidazolium(bisimidazole)tetrachlororuthenate(III) (ru-im), with human serum apotransferrin has been investigated through spectroscopic and chromatographic techniques with the ultimate goal of preparing adducts with good selectivity for cancer cells. Whereas the binding of ru-im to human serum apotransferrin takes several hours, ru-ind, the less toxic complex, gives rise to a well defined 2:1 complex within a few minutes. We have ascertained that ru-ind binding occurs around the iron binding sites; binding does not occur in the absence of bicarbonate, and this anion dictates the kinetic and mechanistic characteristics of protein binding of ru-ind. The two ruthenium(III) complexes do not behave as iron(III) complexes, e.g. Fe(EDTA) or Fe(nitrilotriacetate), which lose their respective ligands when binding apotransferrin, but the N-heterocycles remain attached to the metal in the protein-bound species. Reversion of binding is obtained by acidification in the presence of chelators such as citrate or ATP. In comparison with cisplatin and its deactivation by serum proteins, our results indicate that other metal complexes such as ru-ind could use transferrin as a drug delivery system. Furthermore, the rapid protein binding of ru-ind seems to be related to a lower toxicity while still exhibiting high antitumor activity

Comparative Analysis of [Au(en)2]3+ and [Pt(en)2]2+ non Covalent Binding to Calf Thymus DNA

Reactions of the complexes bisethylendiammine gold(III) and bisethylendiammine platinum(II) with calfthymus DNA were comparatively analysed. Both complexes bind DNA non-covalently most probably on the basis of electrostatic interactions. Binding of either complex at low ratios results into modest modifications of B-type DNA conformations, as detected by CD. Far larger CD alterations are observed at high ratios. The gold(III) chromophore is scarcely perturbed by DNA addition Binding of [Au(en)2]Cl3 to calf thymus DNA is reversed by sodium cyanide. By analogy with the case of [Pt(en)2]Cl2 it is suggested that Auen acts as a minor groove binder

Structure and Cytotoxic Properties of Some Selected Gold(III) Complexes

We prepared four representative square planar gold(III) complexes - [AuCl3(Hpm)], [AuCl2(esal)], [AuCl(dien)]Cl2 and [Au(en)2]Cl3 -and characterized them both in the solid state and in solution. Thereafter, the cytotoxicity of these compounds was evaluated in vitro against the A2780 human ovarian tumor cell line that was used as the reference cell line. Remarkably, ali these gold(III) complexes showed significant cytotoxic effects, [AuCl2(esal)] showing a potency comparable to cisplatin. The present gold(III) complexes were also tested on the corresponding cisplatin-resistant line and revealed they were able to overcome resistance to cisplatin to a large extent. The implications of these findings for the development of new gold(III) complexes to be tested as antitumor agents are discussed

Drug repositioning: auranofin as a prospective antimicrobial agent for the treatment of severe staphylococcal infections

Auranofin, (AF), a gold(I) complex in clinical use for the therapy of rheumatoid arthritis, is reported here to produce remarkable bactericidal effects in vitro against Staphylococcus sp. Noticeably, a similar antimicrobial action and potency are also noticed toward a few methicillin-resistant Staphylococcus aureus strains but not toward Escherichia coli. The time and concentration dependencies of the antimicrobial actions of AF have been characterized through recording time kill curves, and a concentration dependent profile highlighted. Overall, the present results point out that auranofin might be quickly and successfully repurposed for the treatment of severe bacterial infections due to resistant Staphylococci