Trends and Exceptions in the Interaction of Hydroxamic Acid Derivatives of Common Di- and Tripeptides with Some 3d and 4d Metal Ions in Aqueous Solution.

By using various techniques (pH-potentiometry, UV-Visible spectrophotometry, 1H and 17O-NMR, EPR, ESI-MS), first time in the literature, solution equilibrium study has been performed on complexes of dipeptide and tripeptide hydroxamic acids-AlaAlaNHOH, AlaAlaN(Me)OH, AlaGlyGlyNHOH, and AlaGlyGlyN(Me)OH-with 4d metals: the essential Mo(VI) and two half-sandwich type cations, [(η6-p-cym)Ru(H2O)3]2+ as well as [(η5-Cp*)Rh(H2O)3]2+, the latter two having potential importance in cancer therapy. The tripeptide derivatives have also been studied with some biologically important 3d metals, such as Fe(III), Ni(II), Cu(II), and Zn(II), in order to compare these new results with the corresponding previously obtained ones on dipeptide hydroxamic acids. Based on the outcomes, the effects of the type of metal ions, the coordination number, the number and types of donor atoms, and their relative positions to each other on the complexation have been evaluated in the present work. We hope that these collected results might be used when a new peptide-based hydroxamic acid molecule is planned with some purpose, e.g. to develop a potential metalloenzyme inhibitor.

Zinc(II) complexes with dithiocarbamato derivatives: structural characterisation and biological assays on cancerous cell lines.

Zinc is one of the most important trace elements in the body and it is essential as a cofactor for the structure and function of a number of cellular molecules including enzymes, transcription factors, cellular signalling proteins and DNA repair enzymes. On the other hand, recent studies have shown that zinc could play a role both in the development of various cancers and in the induction of apoptosis in some cell types, however, no established common relationships of zinc with cancer development and progression have been identified. To date, in our research group different metal-dithiocarbamato complexes have been designed that were expected to resemble the main features of cisplatin together with higher activity, improved selectivity and bioavailability, and lower side-effects. On the basis of the obtained encouraging achievements with other metals (such as gold and copper) we have decided to enlarge the studies to the complexes of zinc(II) using the same ligands. Hereby, we report the results on the synthesis and characterisation of ZnL(2) complexes with five different dithiocarbamato derivatives, such as dimethyl-(DMDT), pyrrolidine-(PyDT), methyl-(MSDT), ethyl-(ESDT) and tert-butyl-(TSDT) sarcosinedithiocarbamate. All the obtained compounds have fully been characterised by means of several spectroscopic techniques. In addition, the crystal structure of [Zn(MSDT)(2)](2) dinuclear complex is also reported. In order to evaluate the in vitro cytotoxic properties, some biological assays have been carried out on a panel of human tumour cell lines sensible and resistant to cisplatin. Some of the tested compounds show cytotoxicity levels comparable or even greater than the reference drug (cisplatin).

Noble metal-dithiocarbamates precious allies in the fight against cancer.

To date, cisplatin and its analogs are among the most effective chemotherapeutic agents for cancer treatment. However, high systemic toxicity and the propensity for patients to develop tumor resistance remain the main challenges in the clinical application. Therefore, the discovery and development of novel active chemotherapeutic agents are largely needed and the research of new metal-based anticancer drugs continues to be a very active international field. In this review paper we aim to give a detailed overview on our research work devoted to the design of novel dithiocarbamato complexes with different noble metals (such as palladium, platinum, copper, ruthenium and gold), which have gained considerable interest in both the development and the treatment of cancer. In particular, we summarize the results of the metal complexes achieved so far, focusing on the gold(III) compounds, that show outstanding in vitro and in vivo antitumor properties and reduced, or even no, systemic and renal toxicity, compared to the reference drug cisplatin.

Promising anticancer mono- and dinuclear ruthenium(III) dithiocarbamato complexes: systematic solution studies.

During the last decade, our research group has prepared a number of metal dithiocarbamato derivatives of Pt, Pd and Au that were expected to resemble the main features of cisplatin together with higher activity, improved selectivity and bioavailability, and lower side-effects. Furthermore, we have already published the synthesis, characterization and in vitro cytotoxicity studies of novel ruthenium(III) dithiocarbamato complexes such as [RuL(3)] monomers (11) and α-[Ru(2)L(5)]Cl dimers (12) with five different dithiocarbamate ligands. As both the monomer and the dinuclear complexes have shown significant antitumor activity in different human tumor cell lines, we decided to widen the characterization studies and to analyse thoroughly their behavior in physiological-like medium by UV-visible and CD spectroscopy. In the present paper we report on the crystal structure of [Ru(DMDT)(3)], [Ru(PDT)(3)] and [Ru(ESDT)(3)] complexes and we determine the spin state of the paramagnetic Ru(III) by means of Evans' method. Then, we discuss in detail the UV-visible spectral data of the complexes in different medium. All the studied complexes are stable in dimethyl sulfoxide, and show low solubility in phosphate buffered saline solution, particularly the monomer species, even at low concentration, while increased solubility for both types of complexes have been found in the presence of bovine serum albumin (BSA). Moreover, no changes on the coordination sphere of the metal, as well as no direct interaction between the BSA protein and the complex have been identified by UV-visible spectroscopy. However, some conformational changes on the BSA structure, induced by the ruthenium(III) complexes have been confirmed by CD spectroscopy, indicating a probable secondary electrostatic interaction between the metal complex and the peptide. In addition, no significant interaction has been demonstrated with the components of Dulbecco's Modified Eagle's Medium, used for the in vitro assays.

Copper(II) complexes of rat amylin fragments.

The fragments of rat amylin rIAPP(17-29) (Ac-VRSSNNLGPVLPP-NH(2)), rIAPP(17-22) (Ac-VRSSNN-NH(2)), rIAPP(19-22) (Ac-SSNN-NH(2)) and rIAPP(17-20) (Ac-VRSS-NH(2)) together with the related mutant peptides (Ac-VASS-NH(2) and Ac-VRAA-NH(2)) have been synthesized and their copper(II) complexes studied by potentiometric, UV-Vis, CD and EPR spectroscopic methods. Despite the lack of any common strongly coordinating donor functions some of these fragments are able to bind copper(II) ions in the physiological pH range. The longest fragment rat amylin(17-29) keeps one equivalent copper(II) ion in solution in the whole pH range, while two other peptides Ac-VRSSNN-NH(2) and Ac-SSNN-NH(2) are also able to interact with copper(II) ions in the slightly alkaline pH range. According to the spectral parameters of the complexes, the peptides can be classified into two different categories: (i) the tetrapeptides Ac-VRSS-NH(2), Ac-VASS-NH(2) and Ac-VRAA-NH(2) can interact with copper(II) only under strongly alkaline conditions (pH > 10.0) and the formation of only one species with four amide nitrogen coordination can be detected; (ii) the peptides Ac-VRSSNNLGPVLPP-NH(2), Ac-VRSSNN-NH(2) and Ac-SSNN-NH(2) can form complexes above pH 6.0 with the major stoichiometries [CuH(-2)L], [CuH(-3)L](-) and [CuH(-4)L](2-). These data support that rIAPP(17-29) can interact with copper(II) ions under physiological conditions and the SSNN tetrapeptide fragment can be considered as the shortest sequence responsible for metal binding. Density functional theory (DFT) calculations provide some information on the possible coordination modes of Ac-SSNN-NH(2) towards the copper(II) ion and suggest that for [CuH(-2)L], [CuH(-3)L](-) and [CuH(-4)L](2-), the binding of two, three and four deprotonated amide nitrogens, with NH(-) of the side chain of asparagine as anchoring group, is probable. Moreover, these data reveal that peptides can be effective metal binding ligands even in the absence of anchoring groups, if more polar side chains are present in a specific sequence.

Recent advances in PUVA photochemotherapy and PDT for the treatment of cancer.

Since ancient times, many cultures worldwide found out independently that the topical administration of some photoactive natural products (mainly extracted from plants) followed by exposure to sunlight, might be an effective treatment of some skin diseases, thus accidently giving birth to the so-called photochemotherapy. In the attempt to resemble nature by exploiting its teaching, during the last two centuries, scientists tried to rationalize this knowledge in order to develop more effective therapeutic strategies and to understand in depth the mechanisms of action involved, expanding the potential application of this therapy to pathologies other than skin diseases, such as some types of tumors. In this paper we aim at giving an overview on results achieved to date on state-of-the-art photochemotherapy related to the treatment of cancer. The script is organized in three sections. Subsequent to a general introduction describing the origin and basic principles of photochemotherapy, the first section deals with the issue concerning the choice of the proper light sources for each type of therapeutic application, stressing the technological advances in the field (e.g. fiber optics). The second and the third sections provide an overview of the two clinically-established phototherapies to date, that is, PUVA photochemotherapy and PDT, respectively. Both sections are further subdivided into sub-paragraphs emphasizing specific relate topics such as principles and applications, employed light sources, and available data concerning anticancer activity. The third section also provides examples of non-conventional metal-based photosensitizers for PDT.