Also published as: Sabatella M, Pioli M, Maji M, Juszczak M, Vinoda Rani M, Mariadason, J M, Gallardo M, Böhme M, Kasprzak M, Alfiean M, Zalibera M, Mitrović M, Bartholomä M, Yue M, Ren M, Osmak M, Tian M, Jakubaszek M, Brook M, Gouveia M, Aldrovandi M, Dénes M, Woldeselassie M, Harlos M, Schaier M, Klajner M, Qian M, Schlame M, Albanell-Fernández M, Harkiolaki M, Lucas M, Nomura M, Zeng M, Acharya M, Dickerson M, Hektoen, M, Walczyk M, Muralisankar M, Lekka M, Font-Bardia M, Ionta M, Nieddu M, Nabissi M, Palaniandavar M, Sztiller-Sikorska M, Porchia M, Zheng M, Ranjani M, Aatif A M, Abinaya M, Feelisch M, Devocelle M, Assfalg M, Zienkiewicz-Machnik M, Cecchini M, Subramani M, Lari M, Zoldakova M, Mozzicafreddo M, Milczarek M, Olivar-Villanueva M, Hernaez M, Sá M, Rothemund M, Vilaseca M, Feizi-Dehnayebi M, Ouyang M, Liu M, Bortoluzzi M, Piccioli M, Dürst M, Kostić M, Sedić M, Káplár M, Ahn M, Contel M, Vraneš M, Holtgrewe M, Lv M, Delibašić M, Vaquero M, Dow M, Patra M, Kou M, Lo Bello M, Bian M, Shen M, Dalla Pozza M, Li M, Fogagnolo M, Bosch M, Bazett M, Hadiji M, Muir M, Qin M, Meyer M, Chorilli M, Panigati M, Singh M, Kerou M, Grazul M, Schmid M, Zhang M, Conrad M, Shaloski M, Concepción Gimeno M, Lanznaster M, Međedović M, Xie M, Gao M, Dulović M, Haghdoost M, Miñana M, Hirahara M, Capdevila M, Sanaú M, Létourneau M, Chikuma M, Martínez-Estévez M, Matiková-Mal'arová M, Magrane M, Abovsky M, Rojo de la Vega M, Caraglia M, Sattler M, Folgueira M, Shukla M, Dontenwill M, Camacho-Artacho M, Verma M, Lesser, M, El Sibai M, Sarkar M, Peruzzini M, Chen M, Zou M, Kokoschka M, Martins M, Kandawa-Shultz M, Rusz M, Lange M, Yu M, Markuliak M, Dodds M, Reithofer M, Chesi M, Xiangjun M, Nechay M, Kotlyar M, Helena Garcia M, Guelfi M, Berecka M, Milovanović M, Shee M, Gladkikh M, Savic M, Khater M, Seldin M, Wills M, Myint M, Živanović M, Korb M, Abid M, Zhou M, Feuermann M, Taghizadeh Shool M, Koester M, Bruno, Peter M, Guevara M, Planas M, Block M, Mastore M, Papadakis M, Pellegrino M, Tancredi M, Cocchietto M, Mohanraj M, Zain Aldin M, Arif M, Guerrero M, Aleksandrova M, Borsari M, Huang M, Malček M, Kaplanis M, Zhong M, Lapins M, Park M, Rúbio, Guilherme M D M, Vojtek M, Gazvoda M, Girek M, Piccolo M, Kubanik M, Tharaud M, Shao M, Pan M, Azam M, Nakai M, Pruess M, Siegler M, Piškor M, Jordà-Redondo M, Knopp M, Qasim Warraich M, Bicho M, Mauro M, Ohtsuji M, Piccolella M, Korkmaz M, Yang M, Tang M, Khawar Rauf M, Massi M, Paravatou-Petsotas M, Preiner M, Kaiser M, Karpiel M, Danyel M, Lavaud M, Koronkiewicz M, Sidhoum M, Hanif M, Brabender M, Fernandez M, Peretz M, Matera M, Lin M, Matković M, Łomzik M, Zhao M, Cohen M, Groessl M, Pozzato M, Corsini M, Dobroschke M, Bubrin M, Haukka M, P M, Hammad M, Wagner M, Grätzel M, Raftari M, Lehvaslaiho M, Spehr M, Micksche M, Falasca M, Hannink M, Grigalunas M, Sameni M, Velusamy M, Oleszak M, Carcelli M, Momcilovic M, Kosanić M, Trichet M, Duan M, Trifuoggi M, Gelbcke M, Salamini-Montemurri M, Novak M, de Souza Oliveira M, Xia M, Sun M, He M, Mohanty M, Lutz M, Hejl M, Juhas M, Kim M, Navarro M, Pfeffer M, Więckowska-Szakiel M, Salome M, Krenn M, Melchart M, Yamamoto M, Pongratz M, Jovanović M, Koukouvitaki M, Brown, Lewis M, Fan M, Spink M, Hollenstein M, Chhabra M, Abul Farah M, Zeller M, Ali M, Salmain M, Buczkowska M, Nikhil M, Tourte M, Digman M, Bacac M, Babin M, Paulpandi M, Hu M, Rincón M, Clémancey M, Crestani M, Skreta M, Nieger M, Alagesan M, López Torres M, Scarpi-Luttenauer M, Albrecht M, Murali M, Lesiów M, Dotou M, Pavlović M, Negi M, Dharmasivam M, Richert M, Wühr M, Azmanova M, González-Bártulos M, Angeletti M, Milenković M, Soudani M, Fandzloch M, Cargile M, Sajid Ali M, Tampere M, Casals M, Ganeshpandian M, Pernar M, Hetu M, Machuqueiro M, Lepoivre M, Soula M, Yao M, Iglesias M, Marloye M, Hooshmand M, Tuohan M, M M, Skocic M, Butinar M, Erby M, Riisom M, Monari M, Ibarrola-Villava M, Tanić M, Pizurica M, Chakrabarti M, Koch M, Grujović M, Đorđić Crnogorac M, Scaccaglia M, Wang M, Goldberg M, Audano M, Orts-Arroyo M, Zegke M, Nieminen M, Galanski M, Bette M, Monsalve M, Martínez M, Storch M, Cieslak M, Frik M, El-Sibai M, Ferrer M, Redrado M, Musthafa M, Płotek M, Pérez-Manrique M, Rossi M, Ravi M, Schmidlehner M, Pinto M, Dodson M, Goicuría M, Martínez-Alonso M, Eknæs, M, Řezáčová M, Cuccioloni M
Chemotherapy remains one of the dominant treatments to cure cancer. However, due to the many inherent drawbacks, there is a search for new chemotherapeutic drugs. Many classes of compounds have been i Show more
Chemotherapy remains one of the dominant treatments to cure cancer. However, due to the many inherent drawbacks, there is a search for new chemotherapeutic drugs. Many classes of compounds have been investigated over the years to discover new targets and synergistic mechanisms of action including multicellular targets. In this work, we designed a new chemotherapeutic drug candidate against cancer, namely, [Ru(DIP)2(sq)](PF6) (Ru-sq) (DIP = 4,7-diphenyl-1,10-phenanthroline; sq = semiquinonate ligand). The aim was to combine the great potential expressed by Ru(II) polypyridyl complexes and the singular redox and biological properties associated with the catecholate moiety. Experimental evidence (e.g., X-ray crystallography, electron paramagnetic resonance, electrochemistry) demonstrates that the semiquinonate is the preferred oxidation state of the dioxo ligand in this complex. The biological activity of Ru-sq was then scrutinized in vitro and in vivo, and the results highlight the promising potential of this complex as a chemotherapeutic agent against cancer. Show less
Ispinesib is a potent inhibitor of kinesin spindle protein (KSP), which has been identified as a promising target for antimitotic anticancer drugs. Herein, we report the synthesis of half-sandwich com Show more
Ispinesib is a potent inhibitor of kinesin spindle protein (KSP), which has been identified as a promising target for antimitotic anticancer drugs. Herein, we report the synthesis of half-sandwich complexes of Ru, Os, Rh, and Ir bearing the ispinesib-derived N,N-bidentate ligands (R)- and (S)-2-(1-amino-2-methylpropyl)-3-benzyl-7-chloroquinazolin-4(3H)-one and studies on their chemical and biological properties. Using the enantiomerically pure (R)- and (S)-forms of the ligand, depending on the organometallic moiety, either the SM,R or RM,S diastereomers, respectively, were observed in the molecular structures of the Ru- and Os(cym) (cym = η6-p-cymene) compounds, whereas the RM,R or SM,S diastereomers were found for the Rh- and Ir(Cp*) (Cp* = η5-pentamethylcyclopentadienyl) derivatives. However, density functional theory (DFT) calculations suggest that the energy difference between the diastereomers is very small, and therefore a mixture of both will be present in solution. The organometallics exhibited varying antiproliferative activity in a series of human cancer cell lines, with the complexes featuring the (R)-enantiomer of the ligand being more potent than the (S)-configured counterparts. Notably, the Rh and Ir complexes demonstrated high KSP inhibitory activity, even at 1 nM concentration, which was independent of the chirality of the ligand, whereas the Ru and especially the Os derivatives were much less active. Show less
The Ru(ii) complex of an imidazole-mesalazine Schiff base is a unique example showing growth inhibition of 3D-colon cancer stem cell spheroids and bulk colon cancer cells at lower dosage than salinomy Show more
The Ru(ii) complex of an imidazole-mesalazine Schiff base is a unique example showing growth inhibition of 3D-colon cancer stem cell spheroids and bulk colon cancer cells at lower dosage than salinomycin or oxaliplatin. Unlike oxaliplatin which increases the expression of stemness genes (SOX2, KLF4, HES1 and Oct4), these complexes maintain a tight regulation. Show less
PtII complexes are commonly used to treat cancer. To reduce their side effects and improve their pharmacological properties, PtIV complexes are being developed as prodrug candida Show more
PtII complexes are commonly used to treat cancer. To reduce their side effects and improve their pharmacological properties, PtIV complexes are being developed as prodrug candidates that are activated by reduction in cancer cells. Concomitantly, RuII polypyridine complexes have gained much attention as photosensitizers for use in photodynamic therapy due to their attractive characteristics. In this article, a novel PtIV -RuII conjugate, which combines cancer activated chemotherapy with PDT, is presented. Upon entering the cancer cell, the PtIV centre is reduced to PtII and the axial ligands including the RuII complex and phenylbutyrate are released. As each component has its individual targets, the conjugate exerts a multi-target and multi-action effect with (photo-)cytotoxicity values upon irradiation up to 595 nm in the low nanomolar range in various (drug resistant) 2D monolayer cancer cells and 3D multicellular tumour spheroids. Show less
The reaction of 2-{2-(benzo[1,3]dioxol-5-yl)- diazo}-4-methylphenol (HL) with [Ru(PPh3)3Cl2] in ethanol resulted in the carbonylated ruthenium complex [RuL(PPh3Show more
The reaction of 2-{2-(benzo[1,3]dioxol-5-yl)- diazo}-4-methylphenol (HL) with [Ru(PPh3)3Cl2] in ethanol resulted in the carbonylated ruthenium complex [RuL(PPh3)2(CO)] (1), wherein metal-assisted decarbonylation via in situ ethanol dehydrogenation is observed. When the reaction was performed in acetonitrile, however, the complex [RuL(PPh3)2(CH3CN)] (2) was obtained as the main product, probably by trapping of a common intermediate through coordination of CH3CN to the Ru(II) center. The analogous reaction of HL with [Ir(PPh3)3Cl] in ethanol did not result in ethanol decarbonylation and instead gave the organoiridium hydride complex [IrL(PPh3)2(H)] (3). Unambiguous evidence for the generation of CO via ruthenium-assisted ethanol oxidation is provided by the synthesis of the 13C-labeled complex, [Ru(PPh3)2L(13CO)] (1A) using isotopically labeled ethanol, CH313CH2OH. To summarize all the evidence, a ruthenium-assisted mechanistic pathway for the decarbonylation and generation of alkane via alcohol dehydrogenation is proposed. In addition, the in vitro antiproliferative activity of complexes 1-3 was tested against human cervical (HeLa) and human colorectal adenocarcinoma (HT-29) cell lines. Complexes 1-3 showed impressive cytotoxicity against both HeLa (half-maximal inhibitory concentration (IC50) value of 3.84-4.22 μM) and HT-29 cancer cells (IC50 values between 3.3 and 4.5 μM). Moreover, the complexes were comparatively less toxic to noncancerous NIH-3T3 cells. Show less
The synthesis and characterization of two half-sandwich complexes of Ru(II) and Ir(III) with thiabendazole as ancillary ligand and their DNA binding ability were investigated using experimental and co Show more
The synthesis and characterization of two half-sandwich complexes of Ru(II) and Ir(III) with thiabendazole as ancillary ligand and their DNA binding ability were investigated using experimental and computational methods. 1H NMR and acid-base studies have shown that aquo-complexes are the reactive species. Kinetic studies show that both complexes bind covalently to DNA through the metal site and non covalently through the ancillary ligand. Thermal stability studies, viscosity, circular dichroism measurements and quantum chemical calculations have shown that the covalent binding causes breaking of the H-bonding between base pairs, bringing about DNA denaturation and compaction. Additionally, molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations shed light into the binding features of the Ru(II) and Ir(III) complexes and their respective enantiomers toward double-helical DNA, highlighting the important role played by the NˆN ancillary ligand once the complexes are covalently linked to DNA. Moreover, metal quantification in the nucleus of SW480 colon adenocarcinoma cells were carried out by inductively coupled plasma-mass spectrometry (ICP-MS), both complexes are more internalized than cisplatin after 4 h of exposition. However, in spite of the dramatic changes in the helicity of the DNA secondary structure induced by these complexes and their nuclear localization, antiproliferative studies have revealed that both, Ru(II) and Ir(III) complexes, cannot be considered cytotoxic. This unexpected behavior can be justified by the fast formation of aquo-complexes, which may react with components of the cell culture medium or the cytoplasm compartment in such a way that they may become deactivated before reaching DNA. Show less
A series of mono and bimetallic ruthenium(II) arene complexes bearing diamine (Ru1-6) were prepared and fully characterized by 1H, 13C, 19F, and 31Show more
A series of mono and bimetallic ruthenium(II) arene complexes bearing diamine (Ru1-6) were prepared and fully characterized by 1H, 13C, 19F, and 31P NMR spectroscopy and elemental analysis. The crystal structure of the bimetallic complex (Ru5) was determined by X-ray crystallography. Monometallic analogues (Ru1-3) were synthesized to investigate the contributions of ruthenium and the other organic groups (aren, ethylenediamine, butyl) to the activity. The electrochemical behaviors of mono and bimetallic complexes were obtained from the relationship between cyclic voltammetry (CV) and the biological activities of the compounds. The cytotoxic activities of the complexes (Ru1-6) were tested against wide-scale cancer cell lines, namely HeLa, MDA-MB-231, DU-145, LNCaP, Hep-G2, Saos-2, PC-3, and MCF-7, and normal cell lines 3T3-L1 and Vero. Diamine Ru(II) arene complexes have unique biological characteristics and they are promising models for new anticancer drug development. MTT analysis reveals that each synthesized Ru complex showed cytotoxic activity towards the different cancer cells. In particular, three Ru complexes (Ru3, Ru5 and Ru6) showed less toxic effects on the cancer cells than the others. These novel Ru complexes affected both cancer and normal cell lines. As they had a toxic effect on the cells, the dosage applied should be tested before being used for in vivo applications. Cytotoxicity tests have shown that the bimetallic complex Ru6 was effective on all cancer cells. The effect of bimetallic enhancement on cancer cell lines, the systematic variation of the intermetallic distance and the ligand donor properties of the mono and bimetallic complexes were explored based on the cytotoxic activity. The interaction with FS-DNA and the stability/aquation of the complexes (Ru3 and Ru6) were investigated with 1H NMR spectroscopy. The binding modes between the complexes (Ru3 and Ru6) and DNA were investigated via UV-Vis spectroscopy. Show less
The combination of more than one bioactive moiety in a multitargeted anticancer agent may result in synergistic activity of its components. Using this concept, bioorganometallic compounds were designe Show more
The combination of more than one bioactive moiety in a multitargeted anticancer agent may result in synergistic activity of its components. Using this concept, bioorganometallic compounds were designed to feature a metal center, a 2-pyridinecarbothioamide (PCA), and a hydroxamic acid, which is found in the anticancer drug vorinostat (SAHA). The organometallics showed inhibitory activity in the nanomolar range against histone deacetylases (HDACs) as the key target for SAHA. In particular, the Rh complex was a potent inhibitor of HDAC6 over HDAC1 and HDAC8. Whereas this complex was highly cytotoxic in human cancer cells, it showed low toxicity in hemolysis studies and zebrafish, demonstrating the role of the metal center. For this complex a slightly reduced expression of vascular endothelial growth factor receptor 2 (VEGFR2) was established, which was upregulated by SAHA. This finding indicates that the new organometallics display different modes of action than their bioactive components. Show less
Three iridium(III) complexes [Ir(ppy)2(CPIP)](PF6) (Ir-1, ppy = 2-phenylpyridine, CPIP = 2-(4-chlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy)2(DCPIP)](P Show more
Three iridium(III) complexes [Ir(ppy)2(CPIP)](PF6) (Ir-1, ppy = 2-phenylpyridine, CPIP = 2-(4-chlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline), [Ir(ppy)2(DCPIP)](PF6) (Ir-2, DCPIP = 2-(3,4-dichlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(ppy)2(TCPIP)](PF6) (Ir-3, TCPIP = 2,3,5-trichlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized. The complexes Ir-1, Ir-2 and Ir-3 were encapsulated in liposomes to form Ir-1-Lipo, Ir-2-Lipo and Ir-3-Lipo. Morphology, size distribution, and zeta potential of liposomes were examined by transmission electron microscopy (TEM) and Zetasizer. The cytotoxic activity in vitro of Ir-1, Ir-2 and Ir-3 against cancer A549, HTC-116, HepG2, BEL-7402, Eca-109, B16, HeLa SGC-7901 and normal NIH3T3 cells was evaluated by 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) method. Ir-2 and Ir-3 show no cytotoxic activity against the selected cancer cells, and Ir-1 displays moderate cytotoxic effect on the cell growth in A549 cells. However, Ir-1, Ir-2 and Ir-3 were encapsulated in liposomes, the cytotoxic activity was greatly enhanced. In particular, Ir-1-Lipo and Ir-2-Lipo can effectively inhibit the cell growth in A549 cells with a low IC50 value of 3.1 ± 0.3 and 1.2 ± 0.4 μM. The apoptosis was assayed by flow cytometry. Ir-1, Ir-2 and Ir-3 reveal weak apoptotic effect, whereas Ir-1-Lipo, Ir-2-Lipo and Ir-3-Lipo induce an apoptotic percentage of 55.6%, 69.3% and 16.7% in A549 cells, respectively. Specially, in the assay of antitumor activity in vivo, the inhibiting percentage of tumor growth induced by Ir-2 is 27.65%, while inhibiting percentage of tumor growth caused by Ir-2-Lipo is 57.45%. Obviously, the liposomes can enhance anticancer activity in vitro and in vivo compared with the complexes. The results show that the iridium(III) complexes encapsulated liposomes induce apoptosis in A549 cells through ROS-mediated lysosome-mitochondria dysfunction pathway and target the microtubules. Show less
A series of half-sandwich structural iridium(III) phenanthroline (Phen) complexes with halide ions (Cl- , Br- , I- ) and pyridine leaving groups ([(η5 -CpShow more
A series of half-sandwich structural iridium(III) phenanthroline (Phen) complexes with halide ions (Cl- , Br- , I- ) and pyridine leaving groups ([(η5 -CpX )Ir(Phen)Z](PF6 )n , Cpx : electron-rich cyclopentadienyl group, Z: leaving group) have been prepared. Target complexes, especially the Cpxbiph (biphenyl-substituted cyclopentadienyl)-based one, showed favourable anticancer activity against human lung cancer (A549) cells; the best one (Ir8) was almost five times that of cisplatin under the same conditions. Compared with complexes involving halide ion leaving groups, the pyridine-based one did not display hydrolysis but effectively caused lysosomal damage, leading to accumulation in the cytosol, inducing an increase in the level of intracellular reactive oxygen species and apoptosis; this indicated an anticancer mechanism of oxidation. Additionally, these complexes could bind to serum albumin through a static quenching mechanism. The data highlight the potential value of half-sandwich iridium(III) phenanthroline complexes as anticancer drugs. Show less
The organoiridium complex Ir[(C,N)2(O,O)] (1) where C, N = 1-phenylisoquinoline and O,O = 2,2,6,6-tetramethyl-3,5-heptanedionate is a promising photosensitiser for Photo-Dynamic Therapy (PD Show more
The organoiridium complex Ir[(C,N)2(O,O)] (1) where C, N = 1-phenylisoquinoline and O,O = 2,2,6,6-tetramethyl-3,5-heptanedionate is a promising photosensitiser for Photo-Dynamic Therapy (PDT). 1 is not toxic to cells in the dark. However, irradiation of the compound with one-photon blue or two-photon red light generates high levels of singlet oxygen (1O2) (in Zhang et al. Angew Chem Int Ed Engl 56 (47):14898-14902 https://doi.org/10.1002/anie.201709082,2017), both within cell monolayers and in tumour models. Moreover, photo-excited 1 oxidises key proteins, causing metabolic alterations in cancer cells with potent antiproliferative activity. Here, the tomograms obtained by cryo-Soft X-ray Tomography (cryo-SXT) of human PC3 prostate cancer cells treated with 1, irradiated with blue light, and cryopreserved to maintain them in their native state, reveal that irradiation causes extensive and specific alterations to mitochondria, but not other cellular components. Such new insights into the effect of 1O2 generation during PDT using iridium photosensitisers on cells contribute to a detailed understanding of their cellular mode of action. Show less
The potential chemotherapeutic properties coupled to photochemical transitions make the family of fac-[Re(CO)3(N,N)X]0/+ (N,N = a bidentate diimine such as 2,2'-bipyridine (bpy); Show more
The potential chemotherapeutic properties coupled to photochemical transitions make the family of fac-[Re(CO)3(N,N)X]0/+ (N,N = a bidentate diimine such as 2,2'-bipyridine (bpy); X = halide, H2O, pyridine derivatives, PR3, etc.) complexes of special interest. We have investigated reactions of the aqua complex fac-[Re(CO)3(bpy)(H2O)](CF3SO3) (1) with potential anticancer activity with the amino acid L-cysteine (H2Cys), and its derivative N-acetyl-L-cysteine (H2NAC), as well as the tripeptide glutathione (H3A), under physiological conditions (pH 7.4, 37 °C), to model the interaction of 1 with thiol-containing proteins and enzymes, and the impact of such coordination on its photophysical properties and cytotoxicity. We report the syntheses and characterization of fac-[Re(CO)3(bpy)(HCys)]·0.5H2O (2), Na(fac-[Re(CO)3(bpy)(NAC)]) (3), and Na(fac-[Re(CO)3(bpy)(HA)])·H2O (4) using extended X-ray absorption spectroscopy, IR and NMR spectroscopy, electrospray ionization spectrometry, as well as the crystal structure of {fac-[Re(CO)3(bpy)(HCys)]}4·9H2O (2 + 1.75 H2O). The emission spectrum of 1 displays a variance in Stokes shift upon coordination of L-cysteine and N-acetyl-L-cysteine. Laser excitation at λ = 355 nm of methanol solutions of 1-3 was followed by measuring their ability to produce singlet oxygen (1O2) using direct detection methods. The cytotoxicity of 1 and its cysteine-bound complex 2 was assessed using the MDA-MB-231 breast cancer cell line, showing that the replacement of the aqua ligand on 1 with L-cysteine significantly reduced the cytotoxicity of the Re(I) tricarbonyl complex. Probing the cellular localization of 1 and 2 using X-ray fluorescence microscopy revealed an accumulation of 1 in the nuclear and/or perinuclear region, whereas the accumulation of 2 was considerably reduced, potentially explaining its reduced cytotoxicity. Replacing the aqua ligand with cysteine in the antitumor active fac-[Re(CO)3(bpy)(H2O)](CF3SO3) complex significantly reduced its cellular accumulation and cytotoxicity against the MDA-MB-213 breast cancer cell line, shifted its maximum emission to considerably higher energies, and decreased its fluorescence quantum yield. Show less
The synthesis and structural characterization of a newly synthesized mononuclear rhodium(iii) complex, Rhtrz, with a ligand (2,2,6-bis((4S,7R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol- Show more
The synthesis and structural characterization of a newly synthesized mononuclear rhodium(iii) complex, Rhtrz, with a ligand (2,2,6-bis((4S,7R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine) and a ligand of 1,2,4-triazole, are presented in this paper. The kinetic interactions of the Rhtrz complex with essential biomolecules such as 5-GMP, L-Met, and GSH were examined. The study of the biological interactions was focused on the binding properties of the Rhtrz complex with CT-DNA and serum albumin. These interactions were investigated using UV-vis spectrophotometry, fluorescence spectroscopy, viscosity measurements, thermal denaturation studies, and electrophoresis. Fluorescence competition experiments with site-markers for BSA were used to locate the binding site of the Rhtrz-complex to the BSA. Molecular docking studies were carried out to obtain detailed binding information of the complex with CT-DNA, BSA, and HSA. Furthermore, the apparent distance between the donor (HSA) and acceptor (Rhtrz) was determined using fluorescence resonance energy transfer (FRET). The thermodynamic properties and relative stabilities of the Rhtrz complex were examined, constructing the two model equation by DFT calculations (B3LYP(CPCM)/LANL2DZp). In vitro cytotoxicity and redox status on the human epithelial colorectal cancer cell line (HCT-116) and healthy human fibroblast cell line (MRC-5) were also investigated. Show less
Two novel ruthenium(II) polypyridyl complexes, namely, [Ru(dmp)2(CAPIP)](ClO4)2 (Ru(II)-1) and [Ru(dmp)2(CFPIP)](ClO4)2 (Ru(II)-2), wh Show more
Two novel ruthenium(II) polypyridyl complexes, namely, [Ru(dmp)2(CAPIP)](ClO4)2 (Ru(II)-1) and [Ru(dmp)2(CFPIP)](ClO4)2 (Ru(II)-2), which respectively contain (E)-2-(2-(furan-2-yl)vinyl)-1H-imidazo[4,5-f][1,10]phen-anthroline (CAPIP) and (E)-2-(4-fluorostyryl)-1H-imidazo[4,5-f][1,10]phenanthroline. (CFPIP), were first designed and characterized (dmp = 2,9-dimethyl-1,10-phenanthroline). DNA binding experiments indicated that Ru(II) complexes interact with CT DNA through intercalative mode. In addition, the complexes Ru(II)-1 and Ru(II)-2, showed remarkable cell cytotoxicity, giving the respective IC50 values of 4.1 ± 1.4 μM and 6.1 ± 1.4 μM on the A549 cancer cells. These values indicated higher activity than CAPIP, CFPIP, cisplatin (8.2 ± 1.4 μM) and other corresponding Ru(II) polypyridyl complexes. Furthermore, the Ru(II) complexes could arrive the cytoplasm through the cell membrane and accumulate in the mitochondria. Significantly, complexes Ru(II)-1 and Ru(II)-2 induced A549 cells apoptosis was mediated by increase of ROS levels and dysfunction of mitochondria, and resulted in cell cycle arrest and increased anti-migration activity on A549 cells. Overall, these results indicated that complexes Ru(II)-1 and Ru(II)-2 could be suitable candidates for further investigation as a chemotherapeutic agent in the treatment of tumors. Show less
Development of new chemotherapeutic agents to treat microbial infections and recurrent cancers is of pivotal importance. Metal based drugs particularly ruthenium complexes have the uniqueness and desi Show more
Development of new chemotherapeutic agents to treat microbial infections and recurrent cancers is of pivotal importance. Metal based drugs particularly ruthenium complexes have the uniqueness and desired properties that make them suitable candidates for the search of potential chemotherapeutic agents. In this study, two mixed ligand Ru(III) complexes [Ru(Cl)2(SB)(Phen] (RC-1) and [Ru(Cl)2(SB)(Bipy)] (RC-2) were synthesised and characterized by elemental analysis, IR, UV-Vis, 1H, 13C NMR spectroscopic techniques and their molecular structure was confirmed by X-ray crystallography. Antibacterial activity evaluation against two Gram-positive (S. pneumonia and E. faecalis) and four Gram-negative strains (P. aurogenosa, K. pneumoniae, S. enterica, and E. coli) revealed their moderate antibacterial activity with MIC value of ≥250 μg/mL. Anticancer activity evaluation against a non-small lung cancer cell line (H1299) revealed the tremendous anticancer activity of these complexes which was further validated by DNA binding and docking results. DNA binding profile of the complexes studied by UV-Visible and fluorescence spectroscopy showed an intercalative binding mode with CT-DNA and an intrinsic binding constant in the range of 3.481-1.015× 105 M-1. Both the complexes were also found to exert weak toxicity to human erythrocytes by haemolytic assay compared to cisplatin. Potential of these complexes as anticancer agents will be further delineated by in vivo studies. Show less
A series of nanomaterials based on mesoporous silica have been synthesised and functionalised with a photoactive polypyridyl ruthenium(ii) complex, namely [Ru(bipy)2-dppz-7-hydroxymethyl][PF6]2 (bipy Show more
A series of nanomaterials based on mesoporous silica have been synthesised and functionalised with a photoactive polypyridyl ruthenium(ii) complex, namely [Ru(bipy)2-dppz-7-hydroxymethyl][PF6]2 (bipy = 2,2'-bipyridine, dppz = dipyrido[3,2-a:2',3'-c]phenazine), by various methods. The functionalisation reactions were based on the covalent binding to different ligands attached to the pores of the mesoporous nanoparticles and a simple physisorption using polyamino-functionalised mesoporous silica nanoparticles. The resulting nanostructured systems have been characterised by XRD, XRF, BET, SEM and TEM, observing the incorporation of the metallodrug onto the nanostructured silica in a different way depending on the synthetic method used in the loading reactions. In our studies, we have also observed that functionalisation with the metallodrug causes changes in the structural and textural features of the materials. The phototherapeutic activity of the ruthenium-functionalised materials in HeLa cervical cancer cells has been tested and the preliminary results are presented herein. Show less
Ruthenium(ii) complexes are lately of great scientific interest due to their chemotherapeutic potential as anticancer and antimicrobial agents. Here we present the synthesis of new pyrazole carbothioa Show more
Ruthenium(ii) complexes are lately of great scientific interest due to their chemotherapeutic potential as anticancer and antimicrobial agents. Here we present the synthesis of new pyrazole carbothioamide derivatives and their four arene-ruthenium complexes. The title compounds were characterized with the application of IR, NMR, mass spectrometry, elemental analysis and X-ray diffraction. Additionally, for new complexes DFT calculations were done. Their antimicrobial activity (MIC, MBC/MFC) was examined in vitro against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Pseudomonas aeruginosa, Proteus vulgaris and Candida albicans. Their cytotoxic effects, using the MTT assay, against three cancer cell lines: HL-60, NALM-6, WM-115 and normal human foreskin fibroblasts (HFF-1) were also investigated. The influence of the new arene-ruthenium(ii) complexes on the DNA structure was also tested. From our results, compound 2d showed higher cytotoxicity against melanoma cell line WM-115 than cisplatin. Strong biostatic and biocidal activity of the tested complexes against Gram-positive bacteria, including S. aureus, S. epidermidis and E. faecalis was demonstrated. The new arene-ruthenium(ii) compounds could not only inhibit proliferation of cancer cells, but also protect patients against malignant wound infections. Show less
(p-Cymene)-ruthenium bioconjugates ML (1) and ML2 (2), bearing phosphane ligands substituted with chiral or non-chiral amino acid esters, L, were synthetized and characterized by instrument Show more
(p-Cymene)-ruthenium bioconjugates ML (1) and ML2 (2), bearing phosphane ligands substituted with chiral or non-chiral amino acid esters, L, were synthetized and characterized by instrumental methods (NMR, CD, MS) and DFT calculations (using the wB97xD functional). Cytotoxic activity of complexes 1 and 2 was investigated by using human cervical carcinoma cell line (HeLa) and MTT assay. Four (2pG, 2pA, 2mG and 2mA) out of ten synthesized ruthenium complexes showed significant toxicity, with IC50 values of 5-30 μM. Evaluation of the potential biomolecular targets of bioconjugates 2 by UV-Vis, fluorescence and CD spectroscopy revealed no measurable interaction with DNA, but micromolar affinity for proteins. The cytotoxicity of bioconjugates 2 is in correlation with their BSA binding constants, i. e. bioconjugates with lower IC50 values show higher binding affinities towards BSA. Compound 2mG with value of IC50 16 μM was selected for further biological characterization. The higher level of toxicity towards tumor compared to normal cell lines indicates its selective activity, important characteristic for potential medical use. It was detected 2mG caused increase of cells in the S phase of cell cycle and consequential decrease of cells in G0/G1 phase. Additionally, 2mG caused dose- and time-dependent increase of SubG0/G1 cell population, suggesting its ability to induce programmed cell death. Further investigation determined autophagy as the mode of cell death. The role of GSH in HeLa cells response to investigated organometallic ruthenium complexes was confirmed using specific regulators of GSH synthesis, buthionine sulfoximine and N-acetyl-cysteine. Pre-treatment of cells with ethacrynic acid and probenecid emphasized the role of GSH in detoxification of 2mG compound. The amount of total ruthenium accumulation in the cell did not correlate with toxicity of 2pG, 2pA, 2mG and 2mA, suggesting structure dependent differences in either cell uptake or kinetics of ruthenium complexes detoxification. We speculate that ruthenium complexes bind protein-based biomolecules further triggering cell death. Based on the gained knowledge, the synthesis and development of more tumor-specific ruthenium-based complexes as potential anticancer drugs can be expected. Show less
Six novel ruthenium(III) complexes of general formula [RuCl3(L)3] (1,3,5) and [RuCl3(H2O)(L)2] (2,4,6), where L stands for three different triazo Show more
Six novel ruthenium(III) complexes of general formula [RuCl3(L)3] (1,3,5) and [RuCl3(H2O)(L)2] (2,4,6), where L stands for three different triazolopyrimidine-derived ligands, are reported. The compounds have been structurally characterized (IR, EPR, SCXRD), and their magnetic moments have been determined. The single-crystal X-ray diffraction study revealed a slightly distorted octahedral geometry of the Ru(III) complexes with mer configuration in 1 and 5, and fac configuration in 3. In 2 and 4, three chloride ions are in mer configuration and the two triazolopyrimidines are oriented trans mutually with the water molecule playing the role of the sixth ligand. All complexes have been thoroughly screened for their in vitro cytotoxicity against human breast cancer cell line MCF-7, human cervical cancer cell line HeLa, and L929 murine fibroblast cells, uncovering among others that the most lipophilic complexes 5 and 6, containing the bulky ligand dptp (5,7-diphenyl-1,2,4-triazolo[1,5-a]pyrimidine), display high cytotoxic activity against MCF-7, and HeLa cells. Moreover, it was also revealed that during the interaction of the complexes 1-6 with the cancer MCF-7 cell line, reactive oxygen species are released intracellularly, which could indicate that they are involved in cell apoptosis. Furthermore, extensive studies have been carried out to reveal the mechanism by which complexes 1-6 interact with DNA, albumin, and apotransferrin. The biological studies were complemented by detailed kinetic studies of the hydrolysis of the complexes in the pH range 5-8, to determine the stability of the complexes in solution. Six novel ruthenium(III) complexes with triazolopyrimidine derivatives demonstrated the potential for use as anticancer agents by maintaining the toxic effect on MCF-7 and HeLa cells. Show less
A range of novel cyclometalated ruthenium(II) and iridium(III) complexes with a steroidal backbone based on androsterone were synthesized and characterized by NMR spectroscopy and X-ray crystallograph Show more
A range of novel cyclometalated ruthenium(II) and iridium(III) complexes with a steroidal backbone based on androsterone were synthesized and characterized by NMR spectroscopy and X-ray crystallography. Their cytotoxic properties in RT112 and RT112 cP (cisplatin-resistant) cell lines as well as in MCF7 and somatic fibroblasts were compared with those of the corresponding nonsteroidal complexes and the noncyclometalated pyridyl complexes as well as with cisplatin as reference. All steroidal complexes were more active in RT112 cP cells than cisplatin, whereby the cyclometalated pyridinylphenyl complexes based on 5c showed high cytotoxicity while maintaining low resistant factors of 0.33 and 0.50. Show less
Ruthenium(II) polypyridyl complexes have displayed some promising biological responses against a variety of cancers and have emerged as a potential candidate that can show significant antitumor activi Show more
Ruthenium(II) polypyridyl complexes have displayed some promising biological responses against a variety of cancers and have emerged as a potential candidate that can show significant antitumor activity. Three ruthenium(II) polypyridyl complexes were biologically evaluated in vitro against the A549 cancer cell line. The complexes were selected based on initial DNA intercalation studies and MTT viability screening and were selected based on the most promising candidates, the [Ru(bpy)2o-CPIP].2PF6 (complex 1), [Ru(phen)2o-CPIP].2PF6 (complex 2) and [Ru(biq)2o-CPIP].2PF6 (complex 3). Confocal cellular uptake studies confirmed the intracellular transport of complexes into A549. Cytoplasmic and the nucleic accumulation of the complex 1 and 2 was seen while no fluorescent microscopy was performed for complex 3 due to instrumental limitations. Cellular cytotoxicity was investigated with the aid of the Alamar blue assay. The complexes displayed concentration and time dependent inhibitory effects yielding IC50 values from 5.00 to 32.75 µM. Complex 1 exhibit highest cytotoxicity with IC50 value of 5.00 ± 1.24 µM. All of the complexes have shown a significant effect in the reduction of intracellular reactive oxygen species (ROS) levels. Finally, the complexes have shown a transient effect on the cell cycle by arresting it at G0/G1 phase except for complex 2 [Ru(phen)2o-CPIP].2PF6 which has shown the significant G0/G1 arrest. Show less
Benzoylthiourea derivatives feature several donor atoms capable of coordinating to metal centers. We report here a series of Ru(η6 -p-cymene) complexes employing benzoylthiourea derivatives Show more
Benzoylthiourea derivatives feature several donor atoms capable of coordinating to metal centers. We report here a series of Ru(η6 -p-cymene) complexes employing benzoylthiourea derivatives as ligands. Such ligands often coordinate to metal centers through their S and O donor atoms. We isolated complexes where the ligands were mono- or bidentately coordinated to Ru involving the S donor atom and surprisingly in bidentate coordination mode a deprotonated thiourea nitrogen resulting in a 4-membered ring structure around the metal center. DFT calculations were used to explain the differences in coordination behavior. These were complemented by stability studies and biological investigations of the compounds as anticancer agents. Several of the synthesized derivatives exhibited significant cell growth inhibitory activity, with the complexes featuring bidentate ligands being more potent than their monodentate counterparts. This can be explained by the higher stability of the former under the conditions employed in cell culture assays. Show less
Three new ruthenium(II)-arene complexes with pyrido[2',3':5,6]pyrazino[2,3-f][1, 10]phenanthroline (ppf) of general formula: C1 ([(ƞ6-benzene)Ru(ppf)Cl]PF6, C2 ([(ƞ6-t Show more
Three new ruthenium(II)-arene complexes with pyrido[2',3':5,6]pyrazino[2,3-f][1, 10]phenanthroline (ppf) of general formula: C1 ([(ƞ6-benzene)Ru(ppf)Cl]PF6, C2 ([(ƞ6-toluene)Ru(ppf)Cl]PF6) and C3 ([(ƞ6-p-cymene)Ru(ppf)Cl]PF6) have been synthesized. The structures of complexes were determined by elemental analysis, IR, ESI-MS, as well as with 1H and 13C NMR spectroscopy. Cytotoxic activity has been evaluated in three different human neoplastic cell lines (A549, A375, LS 174T) and in one human non-tumor cell line (MRC-5), by the MTT assay. Complexes C1-C3 showed IC50 values in the micromolar range below 100 µM. Complex C3, carrying ƞ6-p-cymene as the arene ligand, exhibited cytoselective activity toward human malignant melanoma A375 cells (IC50 = 15.8 ± 2.7 µM), and has been selected for further analyses of its biological effects. Drug-accumulation study performed in the A375 cells disclosed that C3 possess lower ability of entering the cells compared to cisplatin and distributes approximately equally in the cytosol and membrane/organelle fraction of cells. Investigations in the 3D model of A375 cells, disclosed different effects of the complex C3 and cisplatin on growth of multicellular tumor spheroids (MCTSs). While the size of cisplatin-treated MCTSs decreased with time, MCTSs treated with C3 continued to growth. Differences in structural organization and biological activity of this type of ruthenium(II)-arene complexes versus cisplatin in A375 malignant melanoma cells pointed out their different modes of action, and necessity for further biological studies and optimizations for potential applications. Show less
The use of Photodynamic Therapy (PDT) for the treatment of several kinds of cancer as well as bacterial, fungal or viral infections has received increasing attention during the last decade. However, t Show more
The use of Photodynamic Therapy (PDT) for the treatment of several kinds of cancer as well as bacterial, fungal or viral infections has received increasing attention during the last decade. However, the currently clinically approved photosensitizers (PSs) have several drawbacks, including photobleaching, slow clearance from the organism and poor water solubility. To overcome these shortcomings, many efforts have been made in the development of new types of PSs, such as Ru(II) polypyridyl complexes. Nevertheless, most studied Ru(II) polypyridyl complexes have a low absorbance in the spectral therapeutic window. In this work, we show that, by carefully selecting substituents on the polypyridyl complex, it is possible to prepare a complex absorbing at a much higher wavelength. Specifically, we report on the synthesis as well as in-depth experimental and theoretical characterisation of a Ru(II) polypyridyl complex (complex 3) combining a shift in absorbance towards the spectral therapeutic window with a high 1O2 production. To overcome the absence or poor selectivity of most approved PSs into targeted cells/bacteria, they can be linked to targeting moieties. In this line, compound 3 was designed with reactive aldehyde groups, which can be used as a highly versatile synthetic precursor for further conjugation. As a proof of concept, 3 was reacted with benzylamine and the stability of the resulting conjugate 4 was investigated in DMSO, PBS and cell media. 4 showed an impressive ability to act as a PDT PS with no measurable dark cytotoxicity and photocytotoxicity in the low micromolar range against cancerous HeLa cells from 450 nm up to 540 nm. Show less
Due to acquired resistance or limitations of the currently approved drugs against cancer, there is an urgent need for the development of new classes of compounds. Among others, there is an increasing Show more
Due to acquired resistance or limitations of the currently approved drugs against cancer, there is an urgent need for the development of new classes of compounds. Among others, there is an increasing attention towards the use of Ru(II) polypyridyl complexes. Most studies in the literature were made on complexes based on the coordination of N-donating bidentate ligands to the ruthenium core whereas studies on 2,2':6', 2″-terpyridine (terpy) coordinating ligands are relatively scare. However, several studies have shown that [Ru(terpy)2]2+ derivatives are able bind to DNA through various binding modes making these compounds potentially suitable as chemotherapeutic agents. Additionally, light irradiation of these compounds was shown to enable DNA cleavage, highlighting their potential use as photosensitizers (PSs) for photodynamic therapy (PDT). In this work, we present the systematic investigation of the potential of 7 complexes of the type [Ru(terpy)(terpy-X)]2+ (X = H (1), Cl (2), Br (3), OMe (4), COOH (5), COOMe (6), NMe2 (7)) as potential chemotherapeutic agents and PDT PSs. Importantly, six of the seven complexes were found to be stable in human plasma as well as photostable in acetonitrile upon continuous light irradiation (480 nm). The determination of the distribution coefficient logP values for the 7 complexes revealed their good water solubility. Complex 7 was found to be cytotoxic in the micromolar range in the dark as well as to have some phototoxicity upon light exposure at 480 nm in non-cancerous retinal pigment epithelium (RPE-1) and cancerous human cervical carcinoma (HeLa) cells. SYNOPSIS: The systematic investigation of the potential of 7 complexes of the type [Ru(terpy)(terpy-X)]2+ (terpy: 2,2':6', 2″-terpyridine; X = H (1), Cl (2), Br (3), OMe (4), COOH (5), COOMe (6), NMe2 (7)) as potential chemotherapeutic agents and photosensitizers for photodynamic therapy is presented. Show less
We herein report the synthesis, characterization and anticancer activity of BTPIP (2-(4-(benzo[b]thiophen-2-yl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its four ruthenium(II) polypyridyl com Show more
We herein report the synthesis, characterization and anticancer activity of BTPIP (2-(4-(benzo[b]thiophen-2-yl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its four ruthenium(II) polypyridyl complexes [Ru(NN)2(BTPIP)](ClO4)2 (N-N = bpy = 2,2'-bipyridine, Ru(II)-1; phen = 1,10-phenanthroline, Ru(II)-2; dmb = 4,4'-dimethyl-2,2'-bipyridine, Ru(II)-3; dmp = 2,9-dimethyl-1,10-phenanthroline, Ru(II)-4). The DNA binding behaviors reveal that the complexes bind to calf thymus DNA by intercalation. Cytotoxicity of the complexes against A549, HepG-2, SGC-7901 and Hela cells were evaluated in vitro. Complexes Ru(II)-1, Ru(II)-2, Ru(II)-3, Ru(II)-4 show moderate activity on the cell proliferation in A549 cells with IC50 values of 9.3 ± 1.2, 12.1 ± 1.6, 10.3 ± 1.6, 8.9 ± 1.2 μM, respectively. Apoptosis assessment, intracellular mitochondrial membrane potential (MMP), location in mitochondria, reactive oxygen species (ROS), cell invasion assay and cell cycle arrest were also performed to explore the mechanism of this action. When the concentration of the ruthenium(II) complexes is increased, the amount of reactive oxygen species increases obviously and the mitochondrial membrane potential decreases dramatically in A549 cells. Most importantly, the ruthenium(II) polypyridyl complexes could arrive the cytoplasm through the cell membrane and accumulate in the mitochondria. These results showed that the ruthenium(II) complexes could induce apoptosis in A549 cells through an ROS-mediated mitochondrial dysfunction pathway. Show less
Four trimethoxy- and dimethoxyphenylamine-based Schiff base (L1-L4)-bearing RuII-p-cymene complexes (1-4) of the chemical formula [RuII(η6-pShow more
Four trimethoxy- and dimethoxyphenylamine-based Schiff base (L1-L4)-bearing RuII-p-cymene complexes (1-4) of the chemical formula [RuII(η6-p-cymene)(L)(Cl)] were synthesized, isolated in pure form, and structurally characterized using single-crystal X-ray diffraction and other analytical techniques. The complexes showed excellent in vitro antiproliferative activity against various forms of cancer that are difficult to cure, viz., triple negative human metastatic breast carcinoma MDA-MB-231, human pancreatic carcinoma MIA PaCa-2, and hepatocellular carcinoma Hep G2. The 1H nuclear magnetic resonance data in the presence of 10% dimethylformamide-d7 or dimethyl sulfoxide-d6 in phosphate buffer (pD 7.4, containing 4 mM NaCl) showed that the complexes immediately generate the aquated species that is stable for at least 24 h. Electrospray ionization mass spectrometry data showed that they do not bind with guanine nitrogen even in the presence of 5 molar equivalents of 9-EtG, during a period of 24 h. The best complex in the series, 1, exhibits an IC50 of approximately 10-15 μM in the panel of tested cancer cell lines. The complexes do not enhance the production of reactive oxygen species in the cells. Docking studies with a tubulin crystal structure (Protein Data Bank entry 1SAO ) revealed that 1 and 3 as well as L1 and L3 have a high affinity for the interface of the α and β tubulin dimer in the colchicine binding site. The immunofluorescence studies showed that 1 and 3 strongly inhibited microtubule network formation in MDA-MB-231 cells after treatment with an IC20 or IC50 dose for 12 h. The cell cycle analysis upon treatment with 1 showed that the complexes inhibit the mitotic phase because the arrest was observed in the G2/M phase. In summary, 1 and 3 are RuII half-sandwich complexes that are capable of disrupting a microtubule network in a dose-dependent manner. They depolarize the mitochondria, arrest the cell cycle in the G2/M phase, and kill the cells by an apoptotic pathway. Show less
Fine-tuning of the properties of a recently reported 1,3-indandione-based organoruthenium complex is attempted to optimize the stability under physiological conditions. Previous work has shown its cap Show more
Fine-tuning of the properties of a recently reported 1,3-indandione-based organoruthenium complex is attempted to optimize the stability under physiological conditions. Previous work has shown its capacity of inhibiting topoisomerase IIα; however, fast aquation leads to undesired reactions and ligand cleavage in the blood stream before the tumor tissue is reached. Exchange of the chlorido ligand for six different N-donor ligands resulted in new analogs that were stable at pH 7.4 and 8.5. Only a lowered pH level, as encountered in the extracellular space of the tumor tissue, was capable of aquating the complexes. The 50% inhibitory concentration (IC50) values in three human cancer cell lines differed only slightly, and their dependence on the utilized leaving group was smaller than what would be expected from their differences in cellular accumulation, but in accordance with the very minor variation revealed in measurements of the complexes' lipophilicity. Show less
Organoruthenium complexes are potent alternatives for platinum-based complexes because of their superior anticancer activity. In this investigation, a series of new Ru(II)-arene complexes with triaryl Show more
Organoruthenium complexes are potent alternatives for platinum-based complexes because of their superior anticancer activity. In this investigation, a series of new Ru(II)-arene complexes with triarylamine-thiosemicarbazone hybrid ligands with higher anticancer activity than cisplatin are reported. The molecular structure of the ligands and complexes was confirmed spectroscopically and supported by single-crystal X-ray crystallography. These complexes adopted a three-leg piano stool geometry. All the Ru(II)-arene complexes were systematically investigated for their in vitro cytotoxicity against human cervical (HeLa S3), lung (A549) cancer, and human normal lung (IMR-90) cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Interestingly, a pyrrolidine-attached Ru(II)-benzene complex exhibited superior activity against cancer cells with low IC50 values, and colony formation study showed complete inhibition at 5 and 10 μM concentration. Furthermore, morphological changes assessed by acridine orange and propidium iodide staining revealed that the cell death occurred by apoptosis. In addition, the interaction between synthesized Ru(II)-arene complexes and DNA/protein was explored by absorption and emission spectroscopy methods. These synthesized new organoruthenium complexes can be used for developing new metal-based anticancer drugs. Show less