The aim of this Thesis was the prepatation of new water-soluble Ru(II) complexes for the synthesis of metal conjugates. We decided to use 1,3,5-triaza-7-phosphoadamantene (PTA) for give water solubility to perform a systematic investigation of the reactivity of this ligand with well-known neutral Ru(II) complexes, such as Ru-dmso and Ru-dmso-CO compounds. Chapters 2 and 3 describe in detail the results of this study. Moreover, all the new compounds prepared were reacted with 2,2′-bipirydine, used as model for diimmine linkers. These aspects are extensively described in Chapters 2 and 4 of this Thesis. Finally, since mainly organometallic Ru(II)-PTA complexes have been tested as potential anticancer agents, an explorative investigation of the in vitro anticancer properties, as well as protein and DNA binding ability of trans- and cis-RuX2(PTA)4 (X = Cl, Br) and of the Ru(III)-PTA complex, trans-[RuCl4(PTAH)2]Cl, was performed (Chapter 5). In addition to the above-described main project, during the three years of Ph D I was involved in other side-projects in the field of bioinorganic chemistry, whose results are included in this Thesis. The topics of these side-projects are briefly introduced here, whereas a more exhaustive introduction will be found in the corresponding Chapters. In particular, during a six-month stage in the group of Prof. Nils Metzler-Nolte at the University of Bochum (Germany), new Ru(II)-peptide bioconjugates with potential antitumor activity were prepared and characterized. The group of Prof. Metzler-Nolte has a consolidate experience in the preparation, characterisation and utilisation of novel metal-bioconjugates with peptides or other biomolecules. Particularly interesting is the use of receptor-binding peptides, such as neurotensin and ocreotide, an analogue of somatostatin. Such peptides have a high affinity for receptors that are overexpressed in several tumors so they can be used positively to target cancer cells. We decided to prepare novel bioconjugates using Ru(II) precursors prepared in Trieste and the neurotensin synthesized in Bochum. In particular, we were interested to assess the individual properties of two stereoisomeric conjugates, obtained – in principle – by linking neurotensin to the two Ru(II) complexes of the cppH linker (cppH = 2-(2′-pyridyl)pyrimidine-4-carboxylic acid) that are linkage isomers: trans,cis-RuCl2(CO)2(cppH-κNp) and trans,cis-RuCl2(CO)2(cppH-κNo). Details of this project are reported in Chapter 6 and 7. As part of a collaborative project with the group of Dr. Anna Renfrew from the University of Sidney (Australia), we prepared a series of complexes of the type [Ru([9]aneS3)(chel)(py)](Cl)2, where chel is a chelating diimine ligand in aqueous solution when illuminated with blue light (λ = 420 nm). Since the photo-generated aqua species [Ru([9]aneS3)(bpy)(OH2)]2+ showed a substantial lack of cytotoxicity (against the MDA-MB-231 human mammary carcinoma cell line) we suggested that Ru(II) compounds of this type might be suitable agents for the light-triggered release of coordinated drugs (photo-uncaging). This strategy belongs to the so-called Photoactivated Chemotherapy (PACT), a phototherapy approach in which a kinetically inert and biologically non-active prodrug is irreversibly activated by irradiation with visible light that – for example – induces the cleavage of a photolabile protecting group or an isomerization. Our aim was that of establishing if, in the future, complexes of this series, bearing a pharmacologically active molecule in the place of pyridine, can be realistically used within this strategy. Renfrew’s group, in fact, is studying the photo-triggered release of CHS-828. This cyanoguanidine, which has shown interesting properties as a potential anticancer agent, behaves also as a ligand and binds to a metal center through the pyridine moiety. Chapter 8 describes the results of this project.

Preparation of New Water-Soluble Ru(II) Compounds for the Synthesis of Metal Conjugates / Battistin, Federica. - (2018 Feb 26).

Preparation of New Water-Soluble Ru(II) Compounds for the Synthesis of Metal Conjugates

BATTISTIN, FEDERICA
2018-02-26

Abstract

The aim of this Thesis was the prepatation of new water-soluble Ru(II) complexes for the synthesis of metal conjugates. We decided to use 1,3,5-triaza-7-phosphoadamantene (PTA) for give water solubility to perform a systematic investigation of the reactivity of this ligand with well-known neutral Ru(II) complexes, such as Ru-dmso and Ru-dmso-CO compounds. Chapters 2 and 3 describe in detail the results of this study. Moreover, all the new compounds prepared were reacted with 2,2′-bipirydine, used as model for diimmine linkers. These aspects are extensively described in Chapters 2 and 4 of this Thesis. Finally, since mainly organometallic Ru(II)-PTA complexes have been tested as potential anticancer agents, an explorative investigation of the in vitro anticancer properties, as well as protein and DNA binding ability of trans- and cis-RuX2(PTA)4 (X = Cl, Br) and of the Ru(III)-PTA complex, trans-[RuCl4(PTAH)2]Cl, was performed (Chapter 5). In addition to the above-described main project, during the three years of Ph D I was involved in other side-projects in the field of bioinorganic chemistry, whose results are included in this Thesis. The topics of these side-projects are briefly introduced here, whereas a more exhaustive introduction will be found in the corresponding Chapters. In particular, during a six-month stage in the group of Prof. Nils Metzler-Nolte at the University of Bochum (Germany), new Ru(II)-peptide bioconjugates with potential antitumor activity were prepared and characterized. The group of Prof. Metzler-Nolte has a consolidate experience in the preparation, characterisation and utilisation of novel metal-bioconjugates with peptides or other biomolecules. Particularly interesting is the use of receptor-binding peptides, such as neurotensin and ocreotide, an analogue of somatostatin. Such peptides have a high affinity for receptors that are overexpressed in several tumors so they can be used positively to target cancer cells. We decided to prepare novel bioconjugates using Ru(II) precursors prepared in Trieste and the neurotensin synthesized in Bochum. In particular, we were interested to assess the individual properties of two stereoisomeric conjugates, obtained – in principle – by linking neurotensin to the two Ru(II) complexes of the cppH linker (cppH = 2-(2′-pyridyl)pyrimidine-4-carboxylic acid) that are linkage isomers: trans,cis-RuCl2(CO)2(cppH-κNp) and trans,cis-RuCl2(CO)2(cppH-κNo). Details of this project are reported in Chapter 6 and 7. As part of a collaborative project with the group of Dr. Anna Renfrew from the University of Sidney (Australia), we prepared a series of complexes of the type [Ru([9]aneS3)(chel)(py)](Cl)2, where chel is a chelating diimine ligand in aqueous solution when illuminated with blue light (λ = 420 nm). Since the photo-generated aqua species [Ru([9]aneS3)(bpy)(OH2)]2+ showed a substantial lack of cytotoxicity (against the MDA-MB-231 human mammary carcinoma cell line) we suggested that Ru(II) compounds of this type might be suitable agents for the light-triggered release of coordinated drugs (photo-uncaging). This strategy belongs to the so-called Photoactivated Chemotherapy (PACT), a phototherapy approach in which a kinetically inert and biologically non-active prodrug is irreversibly activated by irradiation with visible light that – for example – induces the cleavage of a photolabile protecting group or an isomerization. Our aim was that of establishing if, in the future, complexes of this series, bearing a pharmacologically active molecule in the place of pyridine, can be realistically used within this strategy. Renfrew’s group, in fact, is studying the photo-triggered release of CHS-828. This cyanoguanidine, which has shown interesting properties as a potential anticancer agent, behaves also as a ligand and binds to a metal center through the pyridine moiety. Chapter 8 describes the results of this project.
26-feb-2018
ALESSIO, ENZO
30
2016/2017
Settore CHIM/03 - Chimica Generale e Inorganica
Università degli Studi di Trieste
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