Comparative solution equilibrium studies of antitumor ruthenium(η6-p-cymene) and rhodium(η5-C5Me5) complexes of 8-hydroxyquinolines

Dömötör, Orsolya and Pape, Veronika F. S. and May, N. V. and Szakács, Gergely and Enyedy, Éva Anna (2017) Comparative solution equilibrium studies of antitumor ruthenium(η6-p-cymene) and rhodium(η5-C5Me5) complexes of 8-hydroxyquinolines. DALTON TRANSACTIONS, 46 (13). pp. 4382-4396. ISSN 1477-9226

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Abstract

Complex formation processes of [ Ru(η 6 - p - cymene) (H 2 O) 3 ] + and [ Rh( η 5 - C 5 Me 5 )(H 2 O) 3 ] + organometallic cations with 8 - hydroxyquinoline (HQ) ligands were studied in aqueous solution by the combined use of 1 H NMR spectroscopy, UV - visible spectrophotometry and pH - potentiometry. Solution stability, chloride ion affinity and lipophilicity of the complexes were characterized together with the in vitro cytotoxicity against a pair of cancer cell lines, responsive and resistant to classic chemotherapy. The solid phase structure of the [Rh( η 5 - C 5 Me 5 )( 8 - quinolinolato )(Cl)] complex was characterized by s ingle - crystal X - ray diffraction analysis. In addition to the unsubstituted HQ its 7 - (1 - piperidinylmethyl) (PHQ) and 5 - sulfonate ( HQS) derivatives were involved. PHQ has a significant preference for targeting multidrug resistant cancer cell lines , while HQS served as a water soluble model compound. The equilibrium studies revealed the formation of mono [M(L)(H 2 O)] complexes with prominently high solution stability, which predominate at physiological pH even in the micromolar concentration range , and f ormation of mixed hydroxido [M(L)(OH)] complexes was characterized by relatively high p K a values (8.5 – 10.3). In comparison to the Rh(η 5 - C 5 Me 5 ) species the complex ation process with Ru(η 6 - p - cymene) is much slower, and both the p K a values and the H 2 O/Cl − co - ligand exchange constants are lower by 1 - 1.5 orders of magnitude. The stability order obtained for these organometallic complexes is as follows: HQS > HQ > PHQ. Cytotoxicity of the ligands and their Ru(η 6 - p - cymene) and Rh(η 5 - C 5 Me 5 ) complexes was investigated against MES - SA (human uterine sarcoma) cell line and its multidrug resistant counterpart (MES - SA/Dx5). HQ and its complexes show similar cytotoxicity in both cell lines. In contrast, PHQ and its Rh(η 5 - C 5 Me 5 ) complex are more potent against MES - SA/Dx5 cells, while this selectivity could not be observed for the Ru(η 6 - p - cymene) complex.

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