Anticancer organometallic Complexes of Ru (II) (Doctoral thesis)

Τσώλης, Θεόδωρος

The synthesis of Ru(II) organometallic ‘piano stool’ compounds has recently evolved into an important research field , due to the cytotoxic properties they exhibit. These compounds bind to DNA both through aromatic interactions with the ligands and via coordination, by directly bonding with the nucleic bases, following the hydrolysis of the Ru-Cl bond. In this work, compounds of the general formula [(η6-arene)Ru(N-N’)Cl]PF6 have been synthesized, where arene = benzene or cymene and (N-N’) aromatic diimines with a systematically increasing aromatic plateau. The synthesis of the ‘piano stool’ compounds was achieved through the reaction of the dimeric complex [Ru(η6-arene)(μ-Cl)Cl]2 with the chelating ligand N-N’. The complexes where isolated and characterized by NMR techniques (1H NMR, and 13C NMR), mass spectrometry and X-ray diffraction. All the prepared compounds adopt the ‘piano stool’ geometry with a bidentate chelate ligand N-N’, an arene and a chloride occupying the remaining positions of the metal center. The complexes [Ru(η6-bz)(pqx)Cl]Cl, [Ru(η6-bz)(pbqx)Cl]Cl, [Ru(η6-cym)(pqx)Cl]Cl and [Ru(η6-cym)(pbqx)Cl]Cl were tested against various cancer cell lines, exhibiting remarkable cytotoxicity, with observed IC50 values of less than 1 μM. The compounds [Ru(η6-cym)(pqx)Cl]Cl and [Ru(η6-cym)(pbqx)Cl]Cl were found to be stable in aqueous media without being hydrolyzed, preserving their saturated coordination sphere (η6-arene, N-N’, Cl). However, it was discovered that they both interact with the hexamer, with the outer side of the chelating ligand N-N’, causing elongation or disruption of the oligonucleotide Watson-Crick (W-C) hydrogen bonds. Since the arene does not take part in the interaction, as it lies on the opposite side, it can be concluded that their cytotoxic activity could be owed to this type of interaction. The study of the hydrolysis of the complexes [Ru(η6-cym)(N-N’)Cl]Cl, where N-N’: pqn, pqx and pbqx, was performed by 1H NMR spectroscopy and HR-ESI mass spectroscopy at 298 K, after removal of the counter chloride. The rate constants (k) and the half-lives (t1/2) of the hydrolysis reactions were calculated from the integration of selected signals and the construction of the diagram [((Ru-H2O)] = f(t)}. The t1/2 of the complex with pqx was found to be less than that of the complex with pbqx, indicating that the additional aromatic ring of pbqx plays an important role in the rate of the hydrolysis reaction. The complexes [(η6-arene)Ru(N-N’)(9MeG-N7)](PF6)2, where arene: bz or p-cym and N-N’: pqn, pqx, pbqx, bpm or bpy, were synthesized by the subtraction of the coordinated chloride with AgNO3 from the precursor complexes [(η6-arene)Ru(N-N’)Cl]PF6, followed by the reaction of the resulting solution with excess of 9-MeG. The complexes where isolated and characterized by 1H NMR spectroscopy and HR-ESI mass spectroscopy. NMR spectroscopic techniques lead to the conclusion that the strong shielding effect on 9-MeGH8 is due to the orientation of the purine ring in such a way that the imidazole H8 faces the aromatic ring of the diimine ligands. The heterometallic complexes [(η6-arene)ClRu(μ-bpm)MCl2)]PF6, where M: Pt ή Pd, were synthesized by the reaction of cis-Pt(dmso)2Cl2 or cis-Pd(CH3CN)2Cl2 with the [(η6-arene)Ru (bpm)Cl]Cl. The complexes were characterized by NMR measurements (1Η NMR & 195Pt NMR) and Electrospray Ionisation Mass Spectrometry (ESI-MS). The heterometallic complex [(η6-cym)ClRu(μ-bpm)PtCl2)]PF6 got cleaved in DMSO, which resulted in four distinct products. The same was observed when reacting with 9MeG. In particular, following the coordination of 9MeG to the platinum site, the bimetallic complex was cleaved, and mainly the compound [Pt(bpm)(9MeG-N7)Cl]+ was generated. All the synthesized heterometallic complexes are under investigation with regard to their anticancer properties.
Alternative title / Subtitle: σύνθεση χαρακτηρισμός και μηχανισμός δράσης τους
synthesis, characterization and mechanism of action
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Θετικών Επιστημών. Τμήμα Χημείας
Subject classification: Οργανομεταλλικές ενώσεις
Keywords: Ρουθήνιο,Οργανομεταλλικά,Αντικαρκινικά,Σύμπλοκα,Αρένια,9-μεθυλογουανίνη,Ολιγονουκλεοτίδιο,Ετερομεταλλικά,Λευκόχρυσος,Φασματοσκοπία NMR,Φασματομετρία μάζας (HR-ESI-MS),Ruthenium,Organometallic,Anticancer,Complexes,Arene,9-methylguanine,Oligonucleotide,Heterometallic,Platimun,NMR and Mass spectrometry (HR-ESI-MS)
Appears in Collections:Διδακτορικές Διατριβές

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