Synthesis and characterization of an 8-hydroxyquinoline–proline hybrid, and its complex formation with half-sandwich organometallic cations: aqueous chemistry, lipophilicity, cellular uptake and anticancer activity.

Five Ru(II)( 6 -toluene) complexes formed with 2-picolinic acid and its various derivatives have been synthesized and characterized. X-ray structures of four complexes are also

Herein we describe the synthesis, characterization, and anticancer activity of novel p-cymeneruthenium(II) complexes containing methyl, ethyl, n-propyl, and n-butyl esters of (S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid. The results of IR, UV/Vis, ESIMS, (1)H, and (13)C NMR characterization reveal that ligand coordination occurs through nitrogen donor atoms of the ester ligands, with the organoruthenium moiety being kept in complex. These ruthenium(II) complexes are cytotoxic toward various cancer cell lines including leukemic HL-60, K562, and REH cells (IC(50): 1.0-20.2 μM), with the n-butyl ester complex being the most effective. It causes apoptotic cell death associated with mitochondrial depolarization, caspase activation, phosphatidylserine exposure, and DNA fragmentation. Importantly, the n-butyl ester complex is more effective against leukemic patients' blood mononuclear cells relative to those from healthy control subjects, thus indicating a fairly selective antileukemic action of Ru(II)-based compounds.

We investigated the cytotoxicity of recently synthesized (S,S)-ethylendiamine-N,N'-di-2-(3-cyclohexyl)propanoic acid esters toward human leukemic cell lines and healthy blood mononuclear cells. Cell viability was assessed by acid phosphatase assay, apoptosis, and differentiation were analyzed by flow cytometry and electron microscopy, while intracellular localization of apoptosis-inducing factor (AIF) was determined by immunoblotting. It was demonstrated that methyl, ethyl, and n-propyl esters were toxic to HL-60, REH, MOLT-4, KG-1, JVM-2, and K-562 leukemic cell lines, while the nonesterified parental compound and n-butyl ester were devoid of cytotoxic action. The ethyl ester exhibited the highest cytotoxic activity (IC₅₀ 10.7 μM-45.4 μM), which was comparable to that of the prototypical anticancer drug cisplatin. The observed cytotoxic effect in HL-60 cells was associated with an increase in superoxide production and mitochondrial membrane depolarization, leading to apoptotic cell death characterized by phosphatidylserine externalization and DNA fragmentation in the absence of autophagic response. DNA fragmentation preceded caspase activation and followed AIF translocation from mitochondria to nucleus, which was indicative of caspase-independent apoptotic cell death. HL-60 cells treated with subtoxic concentration of the compound displayed morphological signs of granulocytic differentiation (nuclear indentations and presence of cytoplasmic primary granules), as well as an increased expression of differentiation markers CD11b and CD15. The cyclohexyl analogues of ethylenediamine dipropanoic acid were also toxic to peripheral blood mononuclear cells of both healthy controls and leukemic patients, the latter being more sensitive. Our data demonstrate that the toxicity of the investigated cyclohexyl compounds against leukemic cell lines is mediated by caspase-independent apoptosis associated with oxidative stress, mitochondrial dysfunction, and AIF translocation.

Please cite this article as: J.P. Mészáros, J.M. Poljarevic, G.T. Gál, et al., Comparative solution and structural studies of half-sandwich rhodium and ruthenium complexes bearing curcumin and acetylacetone, Journal of Inorganic Biochemistry, https://doi.ABSTRACT Half-sandwich organometallic complexes of curcumin are extensively investigated as anticancer compounds. Speciation studies were performed to explore the solution stability of curcumin complexes formed with [Rh( 5 -C5Me5)(H2O)3] 2+ . Acetylacetone (Hacac), as the simplest -diketone ligand bearing (O,O) donor set, was involved for comparison and its Ru( 6 -p-cymene), Ru( 6 -toluene) complexes were also studied. 1 H NMR, UV-visible and pH-potentiometric titrations revealed a clear trend of stability constants of the acac complexes: Ru( 6 -p-cymene) > Ru( 6 -toluene) > Rh( 5 -C5Me5). Despite this order, the highest extent of complex formation is seen for the Rh( 5 -C5Me5) complexes at pH 7.4. Formation constant of [Rh( 5 -C5Me5)(H2curcumin)(H2O)] + reveals similar solution stability to that of the acac complex. Additionally, structures of two complexes were determined by Xray crystallography. The in vitro cytotoxicity of curcumin was not improved by the complexation with these organometallic cations. Highlights ► Solution stability of Ru(arene) and Rh(C5Me5) complexes of acac and curcumin ► Acac is used as curcumin binding model ► X-ray crystal structures of two complexes and comparison with analogous structures ► Antiproliferative activity against multidrug resistant human cancer cell lines ► Human serum albumin binding and interaction with cell culture medium components

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Two non-steroidal antiinflammatory drugs indomethacin and mefenamic acid were coordinated to Ru(ii)–arenes to afford four new complexes.

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