New ruthenium(II) bipyridyl complex : synthesis, crystal structure and cytotoxicity

A new Ru(II) bipyridyl complex with O-4-hydrogenpyridine-2,4-dicarboxylate was synthesized and characterized by IR, NMR and mass spectrometry, X-ray diffraction analysis and elemental analysis. The electrochemical characteristics of the complex were investigated by cyclic voltammetry, revealing Ru(II)/Ru(III) electron transfer in the positive range of potentials. On the opposite potential side, multiple partially reversible peaks were dominant, representing subsequent reductions of the bulky bipyridyl moiety. The cytotoxic activity of the complex was tested in two human cancer cell lines: A549 (lung cancer) and K562 (leukemia) as well as non-tumor MRC-5 cells, by MTT assays. The IC50 values were >300 and 177.63+/-2.28 mu M for the A549 and K562 cells, respectively

Antibacterial activity of polypiridinearene ruthenium(II) complexes

Few studies concerning antibacterial activity of ruthenium complexes have been published but all of them have been performed on small limited number of strains 1,2. In this study complex 1 ([(η6-toluene)Ru(ppf)Cl]PF6) and complex 2 ([(η6-p-cymene)Ru(ppf)Cl]PF6) where ppf is pyrido[2′,3′:5,6]pyrazino[2,3-f][1,10]phenanthrolinewere investigated as antibacterial agents. Previous study proved the cytotoxicity of these compounds 3. The structural difference between 1 and 2 reflected through the presence or absence of isopropyl group onto one of the ligand (toluene), resulted in significant different activity against melanoma cells 3. Five strains of Gram-positive bacteria (C. sporagenes, M. flavus, B. subtilis, S. lutea and S. aureus), and four strains of Gram-negative bacteria (S. enteritidis, P. vulgaris, P. aeruginosa and E. coli) were used for study of antibacterial activity of 1 and 2. While 2 did not show activity against most strains, complex 1 showed good results against all strains, but the best against Clostridium sporagenes and Proteus vulgaris. The obtained antibacterial activity of the complexes was in accordance with the nuclease activity obtained by plasmid DNA cleavage study. Complex 2 showed higher damaging effect to supercoiled DNA, than complex 1. Minor structural modifications of arene moiety resulted in major difference in activity of the complexes

(Electro)chemical and antimicrobial characterization of novel Ru(II) bipyridine complexes with acetylpyridine analogs

Three ruthenium-bipyridine complexes (1–3) carrying acetylpyridine ligand unit were synthesized in methanol via the reaction of [RuCl2(bpy)2] with corresponding acetylpyridine (2-, 3-, and 4-acpy). Obtained complexes were characterized by (1H and 13C) NMR and IR spectroscopy, MS spectrometry, UV‒vis spectrophotometry, and cyclic voltammetry. Their structural characterization revealed bidentate coordination mode for 2-acpy while 3- and 4-acpy acted as monodentate ligands. The electrochemical profile of newly synthesized compounds was investigated by cyclic voltammetry which confirmed their electrochemical activity. Voltammetric responses within the −1.20 < Ep < 1.50 V range of potentials were summarized in two major events: Ru(II)→Ru(III) oxidation spotted at app. ΔEp = 0.65 V and successive reductions of bpy units located from ‒0.79 V to 0.47 V (vs. Ag/AgCl (3 M) electrode). The DNA-binding activity of the complexes was evaluated by both UV‒vis spectrophotometry and cyclic voltammetry indicating DNA-intercalation with a slight contribution of electrostatic interactions. Furthermore, antimicrobial activity was tested against bacterial and fungal strains, for which moderate activity was observed. Assessment of in vitro toxicity against freshly hatched nauplii of Artemia salina as well as radical scavenging capacity was evaluated. The test compounds showed neither toxicity nor antioxidant activity

Novel methylene bridged ethylenediamine-type ligands: Synthesis and spectral characterization

Herein we report the synthesis of two new organic compounds, diisobutyl- and diisopentyl N,N′-methylene-(S,S)-ethylenediamine-N,N′-di-2-(3-cyclohexyl)propanoate. A one-pot procedure was carried out by adding the reducing agent and carbonyl compound into the methanol solution of the parent compounds (iso-butyl and iso-pentyl esters of (S,S)-ethylenediamine-N,N′-di-2-(3-cyclohexyl)propanoic acid) in appropriate stoichiometric ratios. The compounds were fully characterized by infrared, ESI-MS, 1D (1H, 13C) and 2D (COSY, HSQC, HMBC) NMR spectroscopy and elemental analysis. The spectral data confirm the presence of -CH2- group introduced between nitrogen atoms of the ethylenediamine moiety revealing neutral form of potential bidentate ligand. [Projekat Ministarstva nauke Republike Srbije, br. 172035. The authors also acknowledge the support of the FP7 RegPot project FCUB ERA GA No. 256716. The EC does not share responsibility for the content of the article

Cytotoxic and cytoselective profile of novel ruthenium(II)-arene complexes with (fluoro substituated) picolinic acid

Background: Ruthenium containing compounds represent the most promising alternative to platinum-based chemotherapeutics whose therapeutic value has been limited by significant side effects. Advantageous features such as good aqueous solubility and relatively inert arene ligand make them very attractive for structural optimizations aimed for improved in vivo potency. Material and Methods: Reported complexes were obtained in a reaction of [Ru(η6-benzene)Cl(μ-Cl)]2 or [Ru(η6-toluene)Cl(μ-Cl)]2 with picolinic acid or 6-fluoropicolinic acid in a 1:2 molar ratio in ethanol and characterized by IR and NMR spectroscopy and MS spectrometry. Results: The cytotoxic profile was investigated by the colorimetric MTT assay, in a panel of human non-malignant cell line (MRC-5), and cancer cell lines (A549, HTB177, PC3, A375, HeLa, HCT116, MDA-MB-453). The complexes carrying picolinic acid, displayed moderate antiproliferative effect particularly toward colorectal carcinoma (HCT116) and cervix adenocarcinoma cells (HeLa). The highest activity and cytoselectivity was observed for complex with [Ru(η6-benzene)Cl(μ-Cl)]2 toward HCT116 cells: it was capable of reducing viability of HCT116 cells 1.5 times more efficiently (IC50 = 27.5 μM), than of the MRC-5 cells (IC50 = 41.3 μM). Conclusion: The complex with improved activity and selectivity is candidate for further investigations regarding its binding modes, sites, and affinities

Cytotoxic Pt(IV) and Ru(II) complexes containing a biologically relevant edda-type ligand: A comparative study of their thermal properties

The thermal behaviour of a Pt(IV) and a Ru(II) complex coordinated to O,O'-di-n-butyl-(S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoate has been investigated using thermogravimetry (TG) and differential scanning calorimetry (DSC). The study included investigation of the thermal decomposition of these complexes in the temperature range of 30 to 590°C and evaluation of activation energy for the first decomposition steps. For both metal complexes, broad DSC peaks indicated complex thermal transformation processes. The two-step decomposition of the Pt(IV) complex started at 175 and ended at about 418°C, leaving elemental platinum as a final residue. On the other hand, the Ru(II) analogue decomposed in three stages. Thermal degradation was evident beginning at 144°C and suggested the decomposition of a coordinated ligand as dominant process. For this complex, the proposed final residue was RuO2. Kinetic parameters for the first decomposition step were obtained by means of multi-heating rates method, in this case the Kissinger-Akahira-Sunose (KAS) method. The mean activation energy calculated for 0.2 < α < 0.8 were 122.0 kJ mol−1 for the Pt(IV) and 118.9 kJ mol−1 for the Ru(II) complex and decreased constantly, characteristic of a multi-step process. [Projekat Ministarstva nauke Republike Srbije, br. 172035, 172055 i br. 172018

Drug combination study of novel oxorhenium(V) complexes

Three Re(V) complexes of structural formulas [ReOCl2L(PPh3)], where L is pyridine-2-carboxylic acid (C1), 3-methyl-pyridine-2-carboxylic acid (C2) and 6-methyl-pyridine-2-carboxylic acid (C3) were synthesized andcharacterized using NMR, IR spectroscopy and mass spectrometry. Crystal structures of all three complexes havebeen additionally confirmed by X-ray analysis. The biological activity has been investigated in the panel of tumorcell lines A549, PANC-1, MDA-MB-231, MCF-7, LS-174, EAhy.926 and one in non-tumor cell line MRC-5. OnlyC1 showed dose-dependent cytotoxic potential, particularly toward triple-negative breast adenocarcinoma cellsMDA-MB-231 with IC50 68.90 ± 1.73 μM and pancreatic adenocarcinoma cells PANC-1 with IC50 69.84 ± 2.3μM. Both cell lines are characterized by a highly invasive and resistant phenotype. Drug combination studies inPANC-1 cells with C1 and Verapamil hydrochloride (VRP), which is the established inhibitor of efflux transporterP-glycoprotein (Pgp), revealed enhancement of antiproliferative action of the complex in a dose-dependentmanner, and slight arrest of cell cycle in the S phase. Also, a depletion of the glutathione (GSH) level by Lbuthionine-sulfoximine (L-BSO) at sub-toxic concentrations (100 μM) caused an increase of activity of C1 to theIC50 57.67 ± 6.51 (μM). A morphological analysis in PANC-1 cells by dual acridine orange/ethidium bromidestaining, revealed apoptotic potential of complex C1 and a slower kinetic of cell death induction, suggesting adifferent mechanism of action compared to cisplatin.This is the peer-reviewed version of the following article: Petrović, T.; Gligorijević, N.; Belaj, F.; Aranđelović, S.; Mihajlović-Lalić, L. E.; Grgurić-Šipka, S.; Poljarević, J. Drug Combination Study of Novel Oxorhenium(V) Complexes. Journal of Inorganic Biochemistry 2022, 231, 111807. [https://doi.org/10.1016/j.jinorgbio.2022.111807]

Co(III), Ni(II), and Cu(II) complexes with tetradentate Schiff base ligand: Synthesis, Characterization, Electrochemical Behavior, Binding assessment and In vitro cytotoxicity activity

Two new Schiff base cobalt(III) ([Co(LH)Cl2], 1) and nickel(II) ([Ni(LH)ClO4], 2) complexes with a diimine-dioxime ligand, (4,9-diaza-3,10-diethyl-3,9-dodecadiene-2,11-dione bis oxime (LH2)), were synthesized and characterized. The compounds were obtained in MeOH from corresponding metal salts and LH2 in molar ratio 1:1 and further characterized by mass spectrometry, IR spectroscopy, electrochemistry, and elemental analysis. Previously reported copper(II) analog, ([Cu2(LH)2]·(ClO4)2, 3) was joined to 1 and 2, and the three metal analogs, 1-3, were further investigated in terms of their electrochemical behavior. The binding studies of the complexes with deoxyribonucleic acid (DNA) and human serum albumin (HSA) were carried out using both spectrophotometric and electrochemical methods. All three complexes exhibit binding affinity towards the DNA chain through intercalative interaction. The binding reaction with HSA showed for 1 and 3 complexes decrease in the peak current obtained in the case of complexes before the addition of HSA, while resulted compound obtained from Ni complex – HSA possesses the same electroactivity as starting complex. Furthermore, the cytotoxicity of LH2 as well as its metal complexes, and cisplatin were evaluated on CT-26 mouse colon carcinoma and human LS174T cancer cell lines employing MTT assay. The copper(II) complex exhibited very promising anticancer activity compared with cisplatin

Ruthenium(II) bipyridine complexes : from synthesis and crystal structures to electrochemical and cytotoxicity investigation

Complexes 1-4, [Ru(L)(bpy)(2)]PF6, where bpy=2,2-bipyridine; HL=3-methylpyridine-2-carboxylic acid (HL1), 6-methylpyridine-2-carboxylic acid (HL2), 5-bromopyridine-2-carboxylic acid (HL3) and 6-bromopyridine-2-carboxylic acid (HL4), were synthesized and characterized. The electrochemical character of the complexes was investigated by cyclic voltammetry revealing two reversible reduction waves in the negative range of potentials, most likely due to a reduction of the bipyridine moiety. Cytotoxicity studies by MTT assay for 72h of drug action revealed that 2-4 exhibited moderate activity in cervical human tumor cells (HeLa). Complex 2 exhibited low activity in colon cancer LS-174 cells (180 +/- 10), while all complexes were devoid of activity in lung cancer A549 and non-tumor MRC-5 cells, up to 200M. Combinational studies of the most active complex 2, with pharmacological modulators of cell redox status, L-buthionine-sulfoximine (L-BSO) or N-acetyl-L-cysteine (NAC), showed that when L-BSO potentiated, 2 induced a sub-G1 peak of the cell cycle in the HeLa cell line. UV-vis and cyclic voltammetry were performed in order to investigate the binding mode of 2 to DNA and suggested intercalation for the complex-DNA interaction. [GRAPHICS