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Novel ruthenium(III) complexes of general formula Na[RuCl2(L1-3-N,O)2] where L(1-3)denote deprotonated Schiff bases (HL1-HL3) derived from 5-substituted salicyladehyde and alkylamine (propyl- or butylamine) were prepared and characterized based on elemental analysis, mass spectra, infrared, electron spin/paramagnetic resonance (ESR/EPR) spectroscopy, and cyclovoltammetric study. Optimization of five isomers of complex C1 was done by DFT calculation. The interaction of C1-C3 complexes with DNA (Deoxyribonucleic acid) and BSA (Bovine serum albumin) was investigated by electron spectroscopy and fluorescence quenching. The cytotoxic activity of C1-C3 was investigated in a panel of four human cancer cell lines (K562, A549, EA.hy926, MDA-MB-231) and one human non-tumor cell line (MRC-5). Complexes displayed an apparent cytoselective profile, with IC50values in the low micromolar range from 1.6 ± 0.3 to 23.0 ± 0.1 µM. Cisplatin-resistant triple-negative breast cancer cells MDA-MB-231 displayed the highest sensitivity to complexes, with Ru(III) compound containing two chlorides and two deprotonated N-propyl-5-chloro-salicylidenimine (hereinafter C1) as the most potent (IC50= 1.6 µM), and approximately ten times more active than cisplatin (IC50= 21.9 µM). MDA-MB-231 cells treated for 24 h with C1 presented with apoptotic morphology, as seen by acridine orange/ethidium bromide staining, while 48 h of treatment induced DNA fragmentation, and necrotic changes in cells, as seen by flow cytometry analysis. Drug-accumulation study by inductively coupled plasma mass spectrometry (ICP-MS) demonstrated markedly higher intracellular accumulation of C1 compared with cisplatin.

Despite extensive research on the anticancer properties of Ru complexes with dipyrido[3,2-a:2′,3′-c]phenazine (dppz) ligands, their in vivo efficacy is rarely investigated. Aiming to understand whether the coordination of certain half-sandwich Ru(II)-arene fragments might improve the therapeutic potential of dppz ligands, we prepared a series of Ru(II)-arene complexes with the general formula [(η6-arene)Ru(dppz-R)Cl]PF6, where the arene fragment was benzene, toluene, or p-cymene and R was -NO2, -Me, or -COOMe. All compounds were fully characterized by 1H and 13C NMR spectroscopy and high- resolution ESI mass-spectrometry, and their purity was verified by elemental analysis. The electrochemical activity was investigated using cyclic voltammetry. The anticancer activity of dppz ligands and their respective Ru complexes was assessed against several cancer cell lines, and their selectivity toward cancer cells was assessed using healthy MRC5 lung fibroblasts. The substitution of benzene with a p-cymene fragment resulted in a more than 17-fold increase of anticancer activity and selectivity of Ru complexes and significantly enhanced DNA degradation in HCT116 cells. All Ru complexes were electrochemically active in the biologically accessible redox window and were shown to markedly induce the production of ROS in mitochondria. The lead Ru-dppz complex significantly reduced tumor burden in mice with colorectal cancers without inducing liver and kidney toxicity. Supplementary material: [https://cherry.chem.bg.ac.rs/handle/123456789/5900]

Metal-based compounds are rarely good antimicrobial compounds. Here we report synthesis, chemical characterization and antimicrobial potency of fourteen Ru(II) arene complexes with pyridine-based ligands. The structures and purity of synthesized compounds were confirmed using 1H and 13C NMR spectroscopy, IR spectroscopy, MS, and EA. A micro-well dilution assay was used to determine the minimum inhibitory concentration (MIC), and minimum bactericidal concentration. of evaluated compounds. Streptomycin and chloramphenicol were used as a positive control. The best activity of all tested bacteria was observed against E. coli, with a MIC value of 1.25 mg/mL, for complexes with 2,4- i 2,5-pyridinedicarboxylic ligands. Also, all synthesized complexes showed the same activity against C. Albicans. Kompleksi metala retko se koriste kao potencijalni antimikrobni agensi. U ovom radu smo prikazali sintezu, hemijsku karakterizaciju i antimikrobnu aktivnost 14 arenskih Ru(II) kompleksa sa piridinskim ligandima. Strukturu i čistoću dobijenih jedinjenja potvrdili smo koristeći 1H, 13C NMR i IC spektroskopiju, MS i EA. Mikrodilucioni esej je korišćen za određivanje minimalne inhibitorne koncentracije (MIC) i minimalne baktericidne koncentracije sintetisanih jedinjenja. Streptomicin i hloramfenikol su korišćeni kao standard. Najbolja aktivnost prema ispitivanim sojevima bakterija zapažena je na soju E. coli, sa MIC vrednošću 1,25 mg/mL, kompleksa sa 2,4- i 2,5-piridindikarboksilnim ligandima. Svi sintetisani kompleksi pokazali su podjednako dobru aktivnost prema C. Albicans.

Discover a new class of ruthenium-based complexes that were investigated as potential antimicrobial agents: dinuclear polypyridil ruthenium(II) complexes exhibited excellent growth inhibition, and Ru(II) arene complexes with acetyl pyridine ligands exhibited moderate antimicrobial activity in the panel of bacteria1. Here we have synthesized 14 new Ru(II) arene complexes with pyridine-based ligands and examined their antimicrobial potency, trying to correlate their structure and biological activity. Reported complexes were obtained in a reaction of [Ru(η6-benzene)Cl(μ-Cl)]2 or [Ru(η6-toluene)Cl(μ-Cl)]2 with halogen derivatives of picolinic acid or pyridine dicarboxylic acids in a 1:2 molar ratio in ethanol. The complexes were soluble in DMSO and water. Their structural characterization included IR and NMR spectroscopy and MS spectrometry, and purity was confirmed by elemental analysis. In this report, we demonstrate the activities of these novel compounds against six typical gram-negative and two gram-positive bacteria. A micro-well dilution assay was used to determine the minimum inhibitory concentration (MIC), and minimum bactericidal concentration. Streptomycin and chloramphenicol, commercial antibiotics, were used as a positive control. The best activity of all tested bacteria was observed against E. coli, with a MIC value of 1.25 mg/mL, for C3, C6, and C10 complexes. Also, all synthesized complexes showed the same activity against C. albicans.

Rhenium complexes merit particular attention in the area of metallodrug design due to rhenium’s broad spectrum of oxidation states and consequently, the possibility to design compounds of a great structural diversity. Thus, the synthesis, chemical characterization and antitumor activity in vitro of the three Re(V) complexes is described. Novel compounds were obtained via reaction of [ReOCl3(PPh3)2] with corresponding ligands (pyridine-2-carboxylic acid, 3-methylpyridine-2-carboxylic acid and 6-methylpyridine- 2-carboxylic acid) in acetonitrile at 78 °C for 3h. The complexes were fully characterized using NMR, IR, MS and elemental analysis. Their octahedral geometry with bidentate N^O ligand was confirmed by X-ray diffraction analysis. Antiproliferative effect was determined by MTT assay and only the complex with pyridine-2-carboxylic acid (1) showed dose-dependent cytotoxic potential, particularly toward triple-negative breast adenocarcinoma cells MDA-MB-231 with IC50 68.90 ± 1.73 μM and pancreatic adenocarcinoma cells PANC-1 with IC50 69.8 ± 2.3 μM. Drug combination studies in PANC-1 cells with 1 and Verapamil hydrochloride (VRP) showed slight arrest of cell cycle in the S phase and also it increase its antiproliferative potential to IC50 51.4 ± 2.8 μM. Part of the research included a depletion of the glutathione (GSH) level by L-buthionine-sulfoximine (L-BSO) at sub-toxic concentrations (100 μM) in PANC-1 cells which caused an increase of activity of 1 to the IC50 57.67 ± 6.51 μM. Book of Abstracts

Ruthenium complexes are of significant interest in the treatment of malignancies. Ru(II) complexes with N-alkylphenothiazines (chlorpromazine, trifluoperazine, and thioridazine) were used in the study of possible apoptosis pathways in K562 cells. Spectrophotometrically extracellular LDH was quantified and immunochemical expression of COX-2, t-JNK, p-JNK and -actin after SDS electrophoresis was determined. The Ru(II) complex with trifluoperazine at a concentration of 10 μM reduced t-JNK expression, inhibited COX-2 by about 42%, significantly increased the amount of extracellular LDH compared to the untreated K562 cells and thus confirmed apoptosis. U cilju pronalaženja adekvatne terapije u lečenju maligniteta kompleksi rutenijuma pokazali su zavidan potencijal. Kompleksi Ru(II) sa N-alkilfenotiazinima, hlorpromazinom, trifluoperazinom i tioridazinom, korišćeni su u ispitivanju mogućih puteva apoptoze u K562 ćelijama. Ispitivana je spektrofotometrijski ekstracelularna LDH, ekspresija COX-2, t-JNK, p-JNK i β-aktina imunohemijski nakon SDS elektroforeze. Kompleks Ru(II) sa trifluoperazinom u koncentraciji od 10 µM smanjuje ekspresiju t-JNK, inhibira COX-2 oko 42%, značajno povećava količinu ekstracelularne LDH u odnosu na netretirane K562 ćelije i time potvrdjuje apoptozu ovih ćelija.

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.

Editorial: The Golden Future in Medicinal Chemistry: Perspectives and Resources From Old and New Gold-Based Drug Candidates