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Preparation of New Water-Soluble Ru(II) Compounds for the Synthesis of Metal Conjugates
Full text linkThe 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
Neutral 1,3,5-Triaza-7-phosphaadamantane-Ruthenium(II) Complexes as Precursors for the Preparation of Highly Water-Soluble Derivatives
Full text linkThe monodentate phosphane ligand 1,3,5-triaza-7-phosphaadamantane (PTA) imparts excellent water solubility to its complexes. We aimed to prepare precursors with one or more PTA coligands for solubility and one or more labile ligands for facile replacement by a linker. For this purpose, we investigated the reactivity of the neutral isomers trans- and cis-RuCl2(PTA)4 (1 and 2) towards 2,2′-bipyridine (bpy), as a model chelating diimine linker. The new derivatives mer-[Ru(bpy)Cl(PTA)3]Cl (9) and fac-[Ru(bpy)Cl(PTA)3]Cl (10) were prepared and characterized. We also found that PTA reacts rapidly with cis,fac-RuCl2(dmso-O)(dmso-S)3 (11) and trans-RuCl2(dmso-S)4 (13) under mild conditions through the replacement
of pairs of mutually trans dmso ligands with high selectivity, even when in stoichiometric defect. Thus, 11 affords cis,cis,trans-RuCl2(dmso-S)2(PTA)2 (12), whereas 13 gives 1. The two dmso ligands of 12 can be replaced selectively by chelating diimines such as bpy to afford the less symmetrical all-cis product cis,cis-Ru(bpy)Cl2(PTA)2 (16)
The Insertion of Ruthenium into Porphyrins Revisited and Improved: Proof of Concept Results with a Ruthenium(II) Monocarbonyl Compound, and the Spectacular Effect of Propionic Acid
Full text linkThis contribution, that readdresses the insertion of the Ru(II)–CO fragment into model porphyrins (i.e. ruthenation), has a Janus character, with one speculative and one practical side. As a proof of concept we demonstrate that ruthenation of a porphyrin can be performed under relatively mild conditions using the Ru(II) monocarbonyl complex [Ru(CO)(dmso)5][PF6]2 that – besides CO – features exclusively labile dmso ligands. Even though this finding might seem trivial, it is only the second example that uses a Ru(II) carbonyl for porphyrin ruthenation, the first one having been reported almost 50 years ago and then neglected. From a practical point of view, we show the spectacular effect of propionic acid as solvent for performing the ruthenation of neutral and anionic model porphyrins with Ru3(CO)12 (1). This process turned out to be extremely efficient and advantageous in terms of both reaction rates and yields (e.g. 100% ruthenation of TPP in 30 min at 140°C) compared to the procedures described in the literature
Investigating the reactivity of neutral water-soluble Ru(ii)–PTA carbonyls towards the model imine ligands pyridine and 2,2′-bipyridine
No full textAs a continuation of our strategy for preparing new Ru(II) precursors to be exploited as building blocks in the construction of metal-mediated supramolecular assemblies with improved solubility in water, here we describe the reactivity of selected neutral Ru(II)–PTA carbonyls (PTA = 1,3,5-triaza-7-phosphaadamantane) towards the model imine ligands pyridine (py) and 2,2′-bipyridine (bpy) and the preparation and characterization of several neutral and cationic water-soluble derivatives: trans,trans,trans-[RuCl2(CO)(py)(PTA)2] (7), cis,cis,trans-[RuCl2(CO)2(py)(PTA)] (9), cis,trans-[Ru(bpy)Cl(CO)(PTA)2]Cl (10), mer-[Ru(bpy)(CO)(PTA)3](Cl)2 (12), cis,trans-[Ru(bpy)(CO)2Cl(PTA)]Cl (13), cis,trans-[Ru(bpy)(CO)2(PTA)2](NO3)2 (14NO3). In addition, we found that light-induced isomerization in some bpy compounds could be induced. The following species, either side-products isolated in low yield or compounds obtained exclusively in solution, were also unambiguously identified: cis,cis,trans-[RuCl2(CO)(py)(PTA)2] (8), trans-[RuCl2(bpy)(CO)(PTA)] (11), cis,cis-[Ru(bpy)Cl(CO)(PTA)2]Cl (15) and cis,cis-[Ru(bpy)(CO)2Cl(PTA)]Cl (16). The X-ray structures of 7, 11·H2O, and 12·7H2O are also reported. All compounds are new and – with few exceptions – show a good solubility in water
(2L)] Complexes (2L=2py or bpy): From Theoretical Calculations to a 2+2 Metallacycle of Pyridylporphyrins
No full textTreatment of the Ru(II) precursor cis,cis,trans-[RuCl2(dmso-S)2(PTA)2] (1, PTA=1,3,5-triaza-7-phosphaadamantane) with 2,2’-bipyridine (bpy) in refluxing ethanol selectively affords cis,cis-[Ru(bpy)Cl2(PTA)2] (2), whereas with pyridine (py), under the same conditions, it gives trans,cis,cis-[RuCl2(PTA)2(py)2] (6). The slightly less stable stereoisomer of 2, cis,trans-[Ru(bpy)Cl2(PTA)2] (3), is obtained selectively through a different
synthetic route. Isomers 2 and 3 are thermally stable, but cleanly equilibrate upon irradiation of an aqueous solution of either one with blue light. Intrigued by the stereoisomeric outcome in the preparations of this homogeneous set of complexes, we also investigated 2, 3, and 6 (and the monopyridine complex trans,mer-[RuCl2(py)(PTA)3] (7)) through a topological analysis of the electron density map using the quantum theory of atoms in molecules (QTAIM). The wealth of acquired experimental and calculated data allow us to discuss the stereochemical preferences of the [RuCl2(PTA)2(2 L)] complexes (2 L=bpy or 2py) in terms of electronic and steric contributions. The results of this speculative study on model
complexes are transferable to similar systems. As an example, our findings from the reactivity of 1 towards pyridine allowed us to prepare the 2+2 pyridylporphyrin metallacycle trans,cis,cis-[RuCl2(PTA)2(4’-cisDPyP)]2 (10, 4’-cisDPyP=5,10-(4’-pyridyl)-15,20-(phenyl)-porphyrin), whose X-ray molecular structure is also reported
(15)N NMR spectroscopy unambiguously establishes the coordination mode of the diimine linker 2-(2'-pyridyl)pyrimidine-4-carboxylic acid (cppH) in Ru(II) complexes
Full text linkWe investigated the reactivity of three Ru(II) precursors - trans,cis,cis-[RuCl2(CO)2(dmso-O)2], cis,fac-[RuCl2(dmso-O)(dmso-S)3], and trans-[RuCl2(dmso-S)4] - towards the diimine linker 2-(2'-pyridyl)pyrimidine-4-carboxylic acid (cppH) or its parent compound 4-methyl-2-(2'-pyridyl)pyrimidine ligand (mpp), in which a methyl group replaces the carboxylic group on the pyrimidine ring. In principle, both cppH and mpp can originate linkage isomers, depending on how the pyrimidine ring binds to ruthenium through the nitrogen atom ortho (N(o)) or para (N(p)) to the group in position 4. The principal aim of this work was to establish a spectroscopic fingerprint for distinguishing the coordination mode of cppH/mpp also in the absence of an X-ray structural characterization. By virtue of the new complexes described here, together with the others previously reported by us, we successfully recorded (1)H,(15)N-HMBC NMR spectra at natural abundance of the (15)N isotope on a consistent number of fully characterized Ru(ii)-cppH/mpp compounds, most of them being stereoisomers and/or linkage isomers. Thus, we found that (15)N NMR chemical shifts unambiguously establish the binding mode of cppH and mpp - either through N(o) or N(p) - and can be conveniently applied also in the absence of the X-ray structure. In fact, coordination of cppH to Ru(ii) induces a marked upfield shift for the resonance of the N atoms directly bound to the metal, with coordination induced shifts (CIS) ranging from ca. -45 to -75 ppm, depending on the complex, whereas the unbound N atom resonates at a frequency similar to that of the free ligand. Similar results were found for the complexes of mpp. This work confirmed our previous finding that cppH has no binding preference, whereas mpp binds exclusively through N(p). Interestingly, the two cppH linkage isomers trans,cis-[RuCl2(CO)2(cppH-κN(p))] () and trans,cis-[RuCl2(CO)2(cppH-κN(o))] () were easily obtained in pure form by exploiting their different solubility properties
Ru(ii)-Peptide bioconjugates with the cppH linker (cppH = 2-(2'-pyridyl)pyrimidine-4-carboxylic acid): synthesis, structural characterization, and different stereochemical features between organic and aqueous solvents
Full text linkThree new Ru(ii) bioconjugates with the C-terminal hexapeptide sequence of neurotensin, RRPYIL, namely trans,cis-RuCl2(CO)2(cppH-RRPYIL-κNp) (7), [Ru([9]aneS3)(cppH-RRPYIL-κNp)(PTA)](Cl)2 (8), and [Ru([9]aneS3)Cl(cppH-RRPYIL-κNp)]Cl (11), where cppH is the asymmetric linker 2-(2'-pyridyl)pyrimidine-4-carboxylic acid, were prepared in pure form and structurally characterized in solution. The cppH linker is capable of forming stereoisomers (i.e. linkage isomers), depending on whether the nitrogen atom ortho (No) or para (Np) to the carboxylate on C4 in the pyrimidine ring binds the metal ion. Thus, one of the aims of this work was to obtain pairs of stereoisomeric conjugates and investigate their biological (anticancer, antibacterial) activity. A thorough NMR characterization clearly indicated that in all cases exclusively Np conjugates were obtained in pure form. In addition, the NMR studies showed that, whereas in DMSO-d6 each conjugate exists as a single species, in D2O two (7) or even three if not four (8 and 11) very similar stable species form (each one corresponding to an individual compound). Similar results were observed for the cppH-RRPYIL ligand alone. Overall, the NMR findings are consistent with the occurrence of a strong intramolecular stacking interaction between the phenol ring of tyrosine and the pyridyl ring of cppH. Such stacking interactions between aromatic rings are expected to be stronger in water. This interaction leads to two stereoisomeric species in the free cppH-RRPYIL ligand and in the bioconjugate 7, and is somehow modulated by the less symmetrical Ru coordination environments in 8 and 11, affording three to four very similar species
Water-Soluble Ruthenium(II) Carbonyls with 1,3,5-Triaza-7-phosphoadamantane
No full textAs a continuation of our strategy for preparing new Ru(II) precursors with improved water solubility through the introduction of highly water-soluble 1,3,5-triaza-7-phosphoadamantane (PTA) supporting ligands in the coordination sphere, in this work, we address the largely unexplored preparation of Ru(II)-PTA carbonyls. Two complementary synthetic approaches were used: (1) the treatment of a series of neutral Ru(II)-CO-dmso compounds of general formula RuCl2(CO) n(dmso)4- n ( n = 1-3, 1-5) with PTA; (2) the reaction of Ru(II)-PTA complexes with CO. Through the first approach, we obtained and fully characterized seven novel neutral compounds bearing from one to three PTA ligands per Ru atom, namely, the four monocarbonyls, cis, cis, trans-RuCl2(CO)(dmso-S)(PTA)2 (6), trans-RuCl2(CO)(PTA)3 (7), cis, mer-RuCl2(CO)(PTA)3 (8), and trans, trans, trans-RuCl2(CO)(OH2)(PTA)2 (10), and the three dicarbonyls, trans, trans, trans-RuCl2(CO)2(PTA)2 (11), [RuCl2(CO)2(PTA)]2 (12), and cis, cis, trans-RuCl2(CO)2(PTA)2 (13). The less stable, and thus more elusive, species fac-RuCl2(CO)(PTA)3 (9) and cis, cis, cis-RuCl2(CO)2(PTA)2 (14) were also unambiguously identified but could not be obtained in pure form and fully characterized. The complementary synthetic approach, that involved the treatment of the trans- and cis-RuCl2(PTA)4 (15, 16) isomers with CO, afforded only one new Ru(II)-PTA carbonyl, the cationic species cis-[RuCl(CO)(PTA)4]Cl (17). In general, the choice of the solvent was very relevant for obtaining the products with high yield and purity. We were unable to isolate Ru(II)-PTA compounds with more than two carbonyls. The thermodynamically preferred species have CO trans to Cl and two mutually trans PTAs, and only in the dinuclear compound 12 there is a single PTA per Ru atom. Compounds 7 and 17 feature the unprecedented trans-Ru(CO)(PTA) fragment. The X-ray structures of cis, cis, cis-RuCl2(CO)2(dmso)2 (3), 6-8, 10, 11, 13, and 17 are also reported. All compounds are new, are air-stable, and show a good solubility in water ( S from 10 to 165 g·L-1) and, most often, also in chloroform
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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