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Digital archive of theses discussed at the University of Pisa


Thesis etd-02262019-114946

Thesis type
Tesi di dottorato di ricerca
Thesis title
Diiron complexes with derivatizable bridging hydrocarbyl ligands as potential bioactive agents
Academic discipline
Course of study
tutor Prof. Marchetti, Fabio
  • alkylidene
  • anticancer
  • CO releasing
  • diiron complexes
  • vinyliminium
Graduation session start date
Release date
This work of thesis is focused on the study of the chemistry of iron dinuclear carbonyl systems and a preliminary evaluation of their perspective in bioorganometallic chemistry.
The synthetic procedure leading to dinuclear bridging aminocarbyne complexes was improved and extended through the incorporation of unprecedented isocyanides. The reactivity of these aminoalkylidyne compounds with a selection of nucleophiles was studied. The aminoalkylidyne compounds were employed as starting material for the synthesis of more sophisticated structures.
Substitution of CO with alkynes lead to the synthesis of a series of vinyliminium compounds, that were investigated as well. The reactivity of vinyliminium compounds was extended, starting from functionalization strategies reported in literature. Unprecedented compounds are herein presented, including mononuclear and tetranuclear products.
The new complexes were fully characterized by analytical and spectroscopic methods and in some cases with single crystal X-ray diffraction.
A particular attention was given to the physico-chemical properties of the products (in particular air stability, water stability and water solubility) to select the compounds suitable for biological tests.
Indeed, aminoalkylidyne compounds, as well as several other derivatives treated in this work, intrinsically present an interesting degree of solubility in water, thanks to their cationic nature. This particular feature, together with the high biotolerance of iron, suggests that a deeper investigation of the possible biological activity of these structures would be attractive.
A preliminary evaluation of the biological activity was carried on evaluating the antiproliferative activity and measuring the CO release upon irradiation of a selection of compounds.
The antiproliferative activity was evaluated as IC50 values on both cancerous and non-cancerous cell lines. A comparison between the cytotoxic values obtained and the state of the art on iron compounds currently present in literature will be given; cisplatin as well will be used as reference to better understand the activity of the systems under study.
The quantification of the release of CO was assessed through UV spectroscopy to evaluate the amount of carbon monoxide captured by myoglobin.
In light of the promising results obtained in vitro, some experiments were carried on searching a rationale behind the cytotoxic behaviour. The results obtained through the study of the interaction of selected dinuclear systems with DNA and a model protein (BSA) will be discussed. The possible redox activity was evaluated through cyclic voltammetry in aqueous solution, looking for a possible correlation between IC50 values and the reductive and/or oxidative potential.
The redox chemistry of a model vinyliminium compound was deeply investigated both from a chemical and an electrochemical point of view. The monoelectronic reduction almost selectively lead to a mononuclear product with a formal abstraction of a “Fe-Cp” unit. Unexpectedly, the formation of the Fe(II) mononuclear product from a Fe(II)-Fe(II) dimeric precursor occur without harming the bridging ligand. Alongside this pathway several intermediates were characterized by using spectroelectrochemistry, IR spectroscopy, magnetic measurements, EPR spectroscopy and single crystal X-ray diffraction. DFT calculations have been used to give insights into the reaction intermediates and to support experimental results.
In this work of thesis, several diiron cyclopentadienyl/carbonyl compounds were assessed for their anticancer potential for the first time. As a preliminary observation, both the main classes of complexes investigated throughout this thesis, that is aminocarbyne- and vinyliminium-functionalized dinuclear compounds present some promising features, such as easy availability from commercial precursors in gram scale, appreciable solubility in water, and indefinite stability in air and in water media.
The largely investigated reactivity of these category of compounds has been further explored, in terms of electrophilic and reductive behaviour, and stability towards water solutions. Interestingly, it has been found that the monoelectron reduction of a model vinyliminium compound triggers the re-organization of the C3 chain in a monoiron structures, through the straightforward, controlled release of Cp and atomic Fe units. This rearrangement is the key to the functionalization of the vinyliminium skeleton.
The preliminary IC50 results suggest that minor variations in substituents and ligands may determine dramatic effects on the antiproliferative activity in vitro. Although this activity seems to be related substantially to the lipophilic character of the organic structures tethered to the [Fe2Cp2(CO)2] frame, it is interesting to note that the combination of appropriate ligands with a net cationic charge of the complex may provide strong cytotoxic activity maintaining some water solubility. Moreover, a substantial selectivity of the compounds towards cancerous cells respect to a non-cancerous model cell line has been detected in correspondence to some structures. In particular, the large availability of commercial alkynes, and the possibility of easily functionalizing them, encourages further research on cationic vinyliminium complexes. Studies aimed to rationalize the mode of action of the investigated compounds are in progress.
In general, this pioneering work will hopefully pave the way for a deeper investigation on the potentialities of organometallic diiron compounds, in the view of finding alternatives to classical platinum-based drugs.