Object

Alternative title:

Synthesis, physicochemical and structural characterization of ruthenium, rhodium and iridium complexes with potential cytotoxic properties

Abstract:

The interdisciplinary - bioinorganic chemistry, which is developing intensively within coordination chemistry, deals with studies on the use of metal compounds in biological systems, thus serving to solve modern problems of medical therapy and pharmacology, among others through the synthesis of new drugs. Application possibilities of coordination compounds in medicine result both from the type of central metal ion, ligands and structural features. Bearing in mind the above and a detailed literature review, I formulated the following as the main goal of my dissertation: Synthesis, physicochemical and structural characterization of ruthenium, rhodium and iridium complexes with potential cytotoxic properties The choice of the central atoms of ruthenium, rhodium and iridium for the design of new compounds was inspired by both, the ability to form complexes with diverse structures and to obtain new compounds with potential anticancer properties. Taking into account the fact that also the ligands play an important role in generating biological activity of the resulting complexes, heteroaromatic N,N-, N,O-, C,N-donor ligands were used in the designed syntheses of compounds with potential anticancer properties: 4,4',5,5'-tetramethyl-2,2'-bisimidazole (Me4biIm), 2,2'-bisimidazole (BiIm), 2-(2'-pyridyl)benzimidazole, 3,5-dimethyl-1-phenylpyrazole (DMFPz), di-(2-pyridyl)ketone (Py2CO) and thiophene-2-carboxylic acid (Thi-S-2-COOH). In order to realize the research task set out in the dissertation. I synthesized 13 new coordination compounds which are presented in three groups: • half-sandwich Ru(II), Rh(III), Ir(III) complexes: {[RuCl(Me4biIm)(η6-p-cymen)]PF6}2·H2O(1), {[RuCl(BiIm)(η6-p-cymen)]PF6}2·H2O(2), [(η6-p-cymen)RuCl(Py2CO)]PF6 (3); [(η5-Cp)RhCl(BiIm)]PF6 (4), [(η5-Cp)RhCl(Py2CO)]PF6 (5), [(η5-Cp)IrCl(BiIm)]PF6 (6), [(η5-Cp)IrCl(Py2CO)]PF6 (7), [(η5-Cp)IrCl(DMFPz)] (8). • dimeric Ru(II), Rh(II), Ir(III) complexes: (Et3NH)2[Rh2(μ2-Thi-S-2-COO)4Cl2] (9), [((η6-p-cymen)Ru)2(μ-Cl)3)]PF6 (10), [Ir2(μ2-DMFPz)4Cl2] (11). • anionic Ir(III) complexes: NH4[IrCl4(Py2CO)] · H2O (12), (Me2NH2)[IrCl4PyBIm] · H2O (13). These complexes were characterized in detail using the following physicochemical methods: CHNS, FT-IR, UV-Vis, 1H, 13C, 15N NMR; X-Ray structural analysis on monocrystal and Hirshfeld surface analysis (HS). The obtained and fully characterized ruthenium, rhodium and iridium complexes served as material for biological studies planned on the basis of selected model systems: (1) Studies on the influence of the type of central metal ion on cytotoxic properties based on studies on Ru(II), Rh(III), Ir(III) half-sandwich complexes with the same heteroaromatic ligand. (2) Identification of relationships between cytotoxicity and the structure and composition of potential chemotherapeutic agents on the basis of studies on binuclear Ru(II), Rh(II), Ir(III) complexes. (3) Studies on the relationship between the type of heteroaromatic ligand and cytotoxic properties of the complex based on selected iridium(III) compounds.
The above problems were solved by: • determination of antiproliferative activity by in vitro cytotoxic tests (SRB, MTT) of tested complexes against selected tumour lines (LoVo, MV-4-11, MCF-7, HL-60, K562, CEM) • determination of ability of tested complexes to penetrate cell membranes by identification of log P parameter value (shake-flask method); • determination of the mode of complex-DNA interactions and with selected transport proteins (albumin) using UV-Vis spectroscopy and circular dichroism (CD); • comparative analysis between the affinity of the analysed complexes and cisplatin for glutathione (GSH), using UV-Vis technique and additionally for selected complexes mass spectrometry; • evaluation of biocatalytic reactivity of selected iridium(III) complexes towards NADH by UV-Vis technique. The biological studies on the obtained half-sandwich complexes Ru(II) (2), Rh(III) (4), Ir(III) (6) with the same heteroaromatic ligand indicate that the central ion influences the properties of potential chemotherapeutics. Namely, against HL-60 cell line the value of IC50 parameter decreases in the series: Rh(III) > Ir(III) > Ru(II) complex. However, against the MV-4-11 cell line the activity changes in the series: Rh(III) complex < Ru(II) < Ir(III). Moreover, a correlation between the structure and composition of the obtained binuclear Ru(II) (10), Rh(II) (9), Ir(III) (11) complexes and in vitro cytotoxic properties of potential chemotherapeutics was demonstrated. The complex (Et3NH)2[Rh2(μ2-Thi-S-2-COO)4Cl2] (9), was found to be active against MV-4-11 (IC50 = 4.02 ± 1.08 μM), LoVo (IC50 = 11.71 ± 5.38 μM) among the tested dimers. The transformed data indicate that the dimer may be a particularly promising chemotherapeutic agent for therapy against myeloid leukemia cancer cells (MV-4-11). Studies carried out on model systems on the influence of the type of heteroaromatic ligand: BiIm, Py2CO, DMFPz on the cytotoxic properties of half -sandwich iridium(III) complexes showed that the main differences in activity are due to the type of donor atoms of the tested ligands. Complex 8 containing C,N-donor ligand (3,5-dimethyl-1-phenylpyrazole) showed the best in vitro antiproliferative activity as IC50 is 5.6 ± 0.98 μM, 12.3 ± 1.03 μM, 21.2 ± 3.21 μM against CEM, K562, MCF-7 cancer cell lines, respectively. In addition, complex with C,N-donor ligand showed the best biocatalytic properties in NADH oxidation reaction. In conclusion, the objectives outlined in the PhD dissertation have been achieved.

Additional notes:

Streszcz. ang. ; Zawiera bibliografię ; Zawiera ilustracje kolorowe

Identifier:

oai:bibliotekacyfrowa.ujk.edu.pl:4769

Computer catalogue:

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Language:

pol

Degree name:

doktor

Date obtained:

28.09.2022

Degree grantor:

Uniwersytet Jana Kochanowskiego w Kielcach

Supervisor:

Barszcz, Barbara ; Masternak, Joanna Grażyna (1982- ). Promotor pomocniczy

Field:

Dziedzina nauk ścisłych i przyrodniczych

Scientific disciplines:

Nauki chemiczne

Faculty:

Wydział Nauk Ścisłych i Przyrodniczych

Type:

rozprawa doktorska

Access rights:

tylko w Oddziale Informacji Naukowej

Publication status:

niepublikowana