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Bergamo A.,Callerio Foundation Onlus
Dalton Transactions | Year: 2012

With the aim of expanding the structure-activity relationship investigation, the series of Ru(ii) half sandwich coordination compounds of the type [Ru([9]aneS3)(chel)(L)] n+ previously described by us (where [9]aneS3 is the neutral face-capping ligand 1,4,7-trithiacyclononane, chel is a neutral or anonic chelating ligand, L = Cl - or dmso-S, n = 0-2) was extended to 1,4,7-triazacyclononane ([9]aneN3). In addition, new neutral N-N, and anionic N-O and O-O chelating ligands, i.e. dach (trans-1,2- diaminocyclohexane), pic - (picolinate), and acac - (acetylacetonate), were investigated in combination with both [9]aneS3 and [9]aneN3. Overall, ten new half-sandwich complexes were prepared and fully characterized and their chemical behaviour in aqueous solution was established. The single-crystal X-ray structures of eight of them, including the versatile precursor [Ru([9]aneN3)(dmso-S) 2Cl]Cl (9), were also determined. The results of in vitro antiproliferative tests performed on selected compounds against MDA-MB-231 human mammary carcinoma cells confirmed that, in this series, only compounds that hydrolyse the monodentate ligand at a reasonable rate show moderate activity, provided that the chelate ligand is a hydrogen bond donor. © 2012 The Royal Society of Chemistry.


Ang W.H.,National University of Singapore | Casini A.,Ecole Polytechnique Federale de Lausanne | Sava G.,Callerio Foundation Onlus | Sava G.,University of Trieste | Dyson P.J.,Ecole Polytechnique Federale de Lausanne
Journal of Organometallic Chemistry | Year: 2011

Both metal complexes and organic molecules are widely used for the treatment of various diseases including cancer - in addition to surgery and radiotherapy. Recent years have witnessed a surge of interest in the application of organometallic compounds to treat cancer and other diseases. Indeed, the unique properties of organometallic compounds, intermediate between those of classical inorganic and organic materials provide new opportunities in medicinal chemistry. In this review, based on the award lecture at ICBOMC'10, we describe a class of ruthenium(II)-arene complexes that are weakly cytotoxic in vitro, but show selective antimetastatic activity in vivo. These compounds, [Ru(η6-p-arene)Cl2(pta)] termed RAPTA, interact strongly with proteins, with the ability to discriminate binding to different proteins, but show a relatively low propensity to bind DNA, which is considered to be the main target of many metal-based drugs. The basic RAPTA structure is quite stable in physiological environments, and studies have shown that aquation of the chloride bonds occurs, it may not be an essential step for anticancer drug activity - direct substitution with biomolecular targets is also possible. Based on the favorable physicochemical properties of RAPTA compounds, combined with their highly promising pharmacological properties, the structure represents an ideal scaffold for rational drug design. Thus far, strategies to overcome drug resistance, by interference with critical enzymes responsible for drug deactivation, and tumor targeting, by tethering to human serum albumin via hydrolyzable linkers, have been demonstrated. However, many more approaches can be envisaged. In any case, the net result are a type of hybrid compounds, that occupy a niche somewhere between classical cisplatin-type anticancer agents that are widely applied to many tumor types and targeted therapies based on organic structures used to inhibit specific enzymes. As such, should these compounds prove themselves in the clinic it is not inconceivable that they could be rapidly refined to form personalized chemotherapies. © 2011 Elsevier B.V. All rights reserved.


Bergamo A.,Callerio Foundation Onlus | Gaiddon C.,University of Strasbourg | Schellens J.H.M.,Netherlands Cancer Institute | Schellens J.H.M.,University Utrecht | And 4 more authors.
Journal of Inorganic Biochemistry | Year: 2012

The study of metal complexes for the treatment of cancer diseases has resulted in the identification of some unique properties of ruthenium-based compounds. Among these inorganic-based agents, two of them, namely the ruthenium(III) drugs NAMI-A and KP1019 have undertaken with some success the clinical evaluations of phase I and preliminary phase II trials in patients. Here we highlight the strategies that have led to the discovery of metal-based (NAMI-A and KP1019) and of organometallic (RM175, RAPTA-T, RDC11 and DW1/2) ruthenium-based complexes, and we report their main biological/pharmacological characteristics and expectations for further development. © 2011 Elsevier Inc. All rights reserved.


Sava G.,University of Trieste | Sava G.,Callerio Foundation Onlus | Jaouen G.,Chimie Paristech | Jaouen G.,French National Center for Scientific Research | And 3 more authors.
Dalton Transactions | Year: 2012

The development of metal-based anticancer drugs is mainly governed by the experience accumulated with cisplatin and its analogues. The synthesis is focused on adding appropriate leaving and non-leaving groups to a transition metal in order to get more favorable DNA binding properties, and the biological activity is tested in vitro, always in a second step, looking for the cell line that is killed at the lowest drug concentration. This strategy seems unproductive today for the area of new drug development where the knowledge on cancer genomics is suggesting the use of targets selectively expressed, or overexpressed by cancer cells. These targets almost always are proteins, constituting membrane receptors or components of crucial biochemical pathways. Some data indicate that the antitumor activity of cisplatin might also be due to the interaction with protein targets. This critical review examines the possibilities for metal-based drugs to challenge tumors with innovative strategies, based on genomic approaches, capitalizing on the chemical experiences with metals in medicine and focusing on the nature of the ligands which are added to a metal depending on the selected tumor cells and on their molecular targets. © The Royal Society of Chemistry 2012.


Bergamo A.,Callerio Foundation Onlus | Sava G.,Callerio Foundation Onlus | Sava G.,University of Trieste
Chemical Society Reviews | Year: 2015

Cancer chemotherapy is almost always applied to patients with one or more diagnosed metastases and is expected to impact these lesions, thus providing significant benefits to the patient. The outcome of metastasis is determined by the interplay between the specific subpopulation of metastatic cells and host homeostatic factors in specific microenvironments. In clinical practice, metal-based drugs are represented by platinum compounds, which are constituents of a wide variety of chemotherapeutic regimens, and are only rarely active against tumour metastases unless they are combined with drugs that target specific pathways characterizing the malignancy of the tested tumour. On experimental grounds, a number of complexes based on ruthenium and other metals have been frequently studied in vitro using models and experimental conditions mimicking one or more steps of the metastatic process, such as invasion and migration. The ruthenium-based drug, NAMI-A, is the only one to have been subject to clinical testing for the treatment of metastatic tumours. The capacity of NAMI-A to modulate the relationship established between metastatic cells and their microenvironment suggests that metal-based drugs shall be viewed as an opportunity for the treatment of tumour metastases. © The Royal Society of Chemistry 2015.


Sava G.,Callerio Foundation Onlus | Sava G.,University of Trieste | Bergamo A.,Callerio Foundation Onlus | Dyson P.J.,Ecole Polytechnique Federale de Lausanne
Dalton Transactions | Year: 2011

In our Dalton Transactions Perspective article entitled, 'Metal-based antitumour drugs in the post genomic era', (Dalton Trans., 2006, 1929-1933) we discussed metal-based drugs in light of past decades of research. We concluded that the post-genomic era would dictate a change in the direction of the field with knowledge of the genome increasingly allowing protein targets to be identified and not simply assuming that DNA is the only relevant target of metal-based drugs. Since our article was published new insights into the mode of action of metal-based drugs have emerged making some older findings increasingly relevant to current drug design. In this article we discuss these developments in terms of what we believe should be the future direction for the field. © 2011 The Royal Society of Chemistry.


Bergamo A.,Callerio Foundation Onlus | Sava G.,Callerio Foundation Onlus | Sava G.,University of Trieste
Dalton Transactions | Year: 2011

Ruthenium anticancer drugs have attracted an increasing interest in the last 20 years and two of them have entered clinical trials. Compared to platinum drugs, the complexes based on ruthenium are often identified as less toxic and capable of overcoming the resistance induced by platinum drugs in cancer cells. These activities were attributed to the transportation to tumour cells by transferrin and to the selective activation to more reactive species by the reducing environment of solid tumours as compared to healthy tissues. Ruthenium anticancer drugs have been almost always designed to mimic platinum drugs, particularly for targeting DNA. Indeed, none of the above properties has never been clearly demonstrated even for the ruthenium drugs that entered clinical trials. The suggestion for the future is to change the perspective when designing new chemical entities, abandoning the philosophy that guided the actual panel of ruthenium drugs and to look further into the fine mechanism by which the most relevant ruthenium complexes available kill the target tumour cells, then focusing on targets selective of tumour cells and responsible for cell growth and malignancy. © 2011 The Royal Society of Chemistry.


Borgogna M.,University of Trieste | Bellich B.,University of Trieste | Zorzin L.,Callerio Foundation Onlus | Lapasin R.,University of Trieste | Cesaro A.,University of Trieste
Food Chemistry | Year: 2010

Microencapsulation is a powerful technique commonly used for the protection of a wide range of biomolecules (small molecules and protein) and cells of bacterial, yeast and animal origin. In this work, solutions of mixed biopolymers are investigated as excipients for the formulation of a model system. The influence of the different components is studied from the viscoelastic behaviour of the starting solutions to the thermal characterisation of the gel beads therefrom produced. Rheological characterisation displays an almost regular trend for the several combination of solutes and for the frequency dependence, but some peculiarities emerge when both the model protein lysozyme and the cosolvent ethanol are present in the mixture; for the latter system a delayed melting behaviour of water appears in the gel beads. Changes in the temperature dependence of water evaporation from the beads are taken as an evidence of the rate of release from the beads. © 2009 Elsevier Ltd. All rights reserved.


Bergamo A.,Callerio Foundation Onlus | Riedel T.,Ecole Polytechnique Federale de Lausanne | Dyson P.J.,Ecole Polytechnique Federale de Lausanne | Sava G.,Callerio Foundation Onlus | Sava G.,University of Trieste
Investigational New Drugs | Year: 2015

Aim of the study The tumor metastases targeting ruthenium complex NAMI-A synergistically improves the activity of gemcitabine in combination therapies. High-throughput screening was used to identify other potential drug combinations from a library of FDA approved drugs. Doxorubicin was identified as a hit compound and was therefore evaluated in combination with NAMI-A in vitro and in a preclinical in vivo model. Results High-throughput screening identified eight structurally diverse compounds that synergize with NAMI-A including doxorubicin. The combination index on MCF-7 cells showed synergism as the concentration of NAMI-A increases independent of the doxorubicin concentration. In MCa mammary carcinoma of CBA mice, NAMI-A (35 mg/kg/day i.p. on days 7-12) followed by doxorubicin (10 mg/kg i.p. on day 16), significantly increased the effects of the individual drugs on metastases with 70 % animals resulting free of macroscopically detectable tumor nodules in the lungs at sacrifice. NAMI-A, unlike doxorubicin, cured 60 % of the treated mice but the combination therapy was toxic to the animals. Conclusions The combined therapy of NAMI-A with doxorubicin synergizes on lung metastasis in a preclinical mouse model. The combination therapy at the maximum tolerated doses of the two drugs is toxic. Hence, this combination is not suitable for clinical studies using maximum tolerated doses. © 2014 Springer Science+Business Media New York.


Mendes F.,Technological and Nuclear Institute of Portugal | Groessl M.,Ecole Polytechnique Federale de Lausanne | Nazarov A.A.,Ecole Polytechnique Federale de Lausanne | Tsybin Y.O.,Ecole Polytechnique Federale de Lausanne | And 4 more authors.
Journal of Medicinal Chemistry | Year: 2011

The inhibition activity of a series of anticancer metal complexes based on platinum, ruthenium, and gold metal ions was evaluated on the zinc-finger protein PARP-1, either purified or directly on protein extracts from human breast cancer MCF7 cells. Information on the reactivity of the metal complexes with the PARP-1 zinc-finger domain was obtained by high-resolution ESI FT-ICR mass spectrometry. An excellent correlation between PARP-1 inhibition in protein extracts and the ability of the complexes to bind to the zinc-finger motif (in competition with zinc) was established. The results support a model whereby displacement of zinc from the PARP-1 zinc finger by other metal ions leads to decreased PARP-1 activity. In vitro combination studies of cisplatin with NAMI-A and RAPTA-T on different cancer cell lines (MCF7, A2780, and A2780cisR) showed that, in some cases, a synergistic effect is in operation. © 2011 American Chemical Society.

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