A new copper(II) complex containing long-chain aliphatic hydrazide and 1,10-phenanthroline upregulates ADP hydrolysis in triple-negative breast cancer cells.

Copper can be opportunely complexed to modulate oncogenic pathways, being a promising strategy for cancer treatment. Herein, three new copper(II) complexes containing long-chain aliphatic hydrazides and 1,10-phenanthroline (1,10-phen), namely, [Cu(octh)(1,10-phen)(H2O)](NO3)21, [Cu(dech)(1,10-phen)(H2O)](NO3)22 and [Cu(dodh)(1,10-phen)(H2O)](NO3)2.H2O 3 (where octh = octanoic hydrazide, dech = decanoic hydrazide, dodh = dodecanoic hydrazide) were successfully prepared and characterized by several physical-chemical methods. Furthermore, X-ray structural analysis of complex 2 indicated that the geometry around the copper(II) ion is distorted square-pyramidal, in which hydrazide and 1,10-phenanthroline act as bidentate ligands. A water molecule in the apical position completes the coordination sphere of the metal ion. All new copper(II) complexes were cytotoxic to breast cancer cell lines (MCF7, MDA-MB-453, MDA-MB-231, and MDA-MB-157) and selective when compared to the non tumor lineage MCF-10A. In particular, complex 2 showed half-maximal inhibitory concentration (IC50) values ranging between 2.7 and 13.4 µM in MDA-MB231 cells after 24 and 48 h of treatment, respectively. Furthermore, this complex proved to be more selective for tumor cell lines when compared to doxorubicin and docetaxel. Complex 2 inhibited the clonogenicity of MDA-MB231 cells, increasing adenosine diphosphate (ADP) hydrolysis and upregulating ecto-nucleoside triphosphate diphosphohydrolase 1 (ENTPD1) transcriptional levels. In this sense, we suggest that the inhibitory effect on cell proliferation may be related to the modulation of adenosine monophosphate (AMP) levels. Thus, a novel copper(II) complex with increased cytotoxic effects and selectivity against breast cancer cells was obtained, contributing to medicinal chemistry efforts toward the development of new chemotherapeutic agents.

Dissolving Microneedle-Based Cascade-Activation Nanoplatform for Enhanced Photodynamic Therapy of Skin Cancer.

Purpose: Photodynamic therapy (PDT) has been an attractive strategy for skin tumor treatment. However, the hypoxic microenvironment of solid tumors and further O2 consumption during PDT would diminish its therapeutic effect. Herein, we developed a strategy using the combination of PDT and hypoxia-activated bioreductive drug tirapazamine (TPZ). Methods: TPZ was linked to DSPE-PEG-NHS forming DSPE-PEG-TPZ to solve leakage of water-soluble TPZ and serve as an antitumor agent and monomer molecule further forming the micellar. Chlorin e6 (Ce6) was loaded in DSPE-PEG-TPZ forming DSPE-PEG-TPZ@Ce6 (DPTC). To further improve tumor infiltration and accumulation, hyaluronic acid was adopted to make DPTC-containing microneedles (DPTC-MNs). Results: Both in vitro and in vivo studies consistently demonstrated the synergistic antitumor effect of photodynamic therapy and TPZ achieved by DPTC-MNs. With laser irradiation, overexpressions of PDT tolerance factors NQO1 and HIF-1α were inhibited by this PDT process. Conclusion: The synergistic effect of PDT and TPZ significantly improved the performance of DPTC-MNs in the treatment of melanoma and cutaneous squamous cell carcinoma and has good biocompatibility.

Re(I)[2-aryl-1H-imidazo[4,5-f][1,10]phenanthroline] tricarbonyl chloride complexes for selective cancer therapy via a potential DNA damage mechanism.

Recently, achieving selective cancer therapy with trifling side effects has been a great challenge in the eradication of cancer. Thus, to amplify the cytoselective approach of complexes, herein, we developed a series of Re(I)[2-aryl-1H-imidazo[4,5-f][1,10]phenanthroline] tricarbonyl chloride complexes and screened their potency against HeLa and MCF-7 cell lines together with the evaluation of their toxicity towards a normal kidney cell line (HEK-293). On meticulous investigation, complex [ReI(CO)3Cl(K2-N,N-(2c))] (3c) was found to be the most potent anticancer entity among other complexes. Complex 3c also showed competency to induce apoptosis in MCF-7 cells through G2/M phase cell-cycle arrest in association with the generation of ample reactive oxygen species (ROS), eventually leading to DNA intercalation and internucleosomal cleavage. The order of the cytotoxicity of these complexes depended on their lipophilic character and the electron-withdrawing halogen substitution at the para-position of the phenyl ring in the imidazophenanthroline ligand.

Self-Assembled Molecular Complexes of 1,10-Phenanthroline and 2-Aminobenzimidazoles: Synthesis, Structure Investigations, and Cytotoxic Properties.

Three new molecular complexes (phen)3(2-amino-Bz)2(H+)(BF4-)·3H2O 5, (phen)3(2-amino-5(6)-methyl-Bz)2(H+)(BF4-)·H2O 6, and (phen)(1-methyl-2-amino-Bz)(H+)(BF4-) 7, were prepared by self-assembly of 1,10-phenanthroline (phen) and various substituted 2-aminobenzimidazoles. Confirmation of their structures was established through spectroscopic methods and elemental analysis. The X-ray diffraction analysis revealed that the crystal structure of 7 is stabilized by the formation of hydrogen bonds and short contacts. In addition, the molecular geometry and electron structure of molecules 5 and 6 were theoretically evaluated using density functional theory (DFT) methods. According to the DFT B3LYP/6-311+G* calculations, the protonated benzimidazole (Bz) units act as NH hydrogen bond donors, binding two phenanthrolines and a BF4- ion. Non-protonated Bz unit form hydrogen bonds with the N-atoms of a third molecule phen. The molecular assembly is held together by π-π stacking between benzimidazole and phenanthroline rings, allowing for N-atoms to associate with water molecules. The complexes were tested in vitro for their tumor cell growth inhibitory effects on prostate (PC3), breast (MDA-MB-231 and MCF-7), and cervical (HeLa) cancer cell lines using MTT-dye reduction assay. The in vitro cytotoxicity analysis and spectrophotometric investigation in the presence of ct-DNA, showed that self-assembled molecules 5-7 are promising DNA-binding anticancer agents warranting further in-depth exploration.

DNA Interaction with Coordination Compounds of Cd(II)containing 1,10-Phenanthroline.

The experimental study of the DNA interaction with three cadmium coordination compounds [Cd(phen)3](CH3CO2)2, [Cd(phen)2(H2O)2](CH3CO2)2, and [Cd2(phen)4(H2O)2](CH3CO2)4 was carried out using spectrophotometry, viscosity, and dynamic light scattering methods. The role of the solution ionic strength (concentration of NaCl) was analyzed. All compounds can penetrate (fully or partly) to the major or minor DNA grooves. It was shown that, in addition to the important role of electrostatic interactions in the formation of the complex, intercalation of the 1,10-phenanthroline ligand occurs for compounds [Cd(phen)2(H2O)2](CH3CO2)2 and [Cd2(phen)4(H2O)2](CH3CO2)4. Compound [Cd(phen)3](CH3CO2)2 binds to DNA externally. The coordination bond between cadmium and DNA was formed in DNA complexes with [Cd2(phen)4(H2O)2](CH3CO2)4. Preliminary computer modeling of the DNA interaction with the compounds used was performed.

Manganese(II), copper(II) and silver(I) complexes containing 1,10-phenanthroline/1,10-phenanthroline-5,6-dione against Candida species.

Background: New chemotherapeutics are urgently required to treat Candida infections caused by drug-resistant strains. Methods: The effects of 16 1,10-phenanthroline (phen)/1,10-phenanthroline-5,6-dione/dicarboxylate complexed with Mn(II), Cu(II) and Ag(I) were evaluated against ten different Candida species. Results: Proliferation of Candida albicans, Candida dubliniensis, Candida famata, Candida glabrata, Candida guilliermondii, Candida kefyr, Candida krusei, Candida lusitaniae, Candida parapsilosis and Candida tropicalis was inhibited by three of six Cu(II) (MICs 1.52-21.55 µM), three of three Ag(I) (MICs 0.11-12.74 µM) and seven of seven Mn(II) (MICs 0.40-38.06 µM) complexes. Among these [Mn2(oda)(phen)4(H2O)2][Mn2(oda)(phen)4(oda)2].4H2O, where oda = octanedioic acid, exhibited effective growth inhibition (MICs 0.4-3.25 µM), favorable activity indexes, low toxicity against Vero cells and good/excellent selectivity indexes (46.88-375). Conclusion: [Mn2(oda)(phen)4(H2O)2][Mn2(oda)(phen)4(oda)2].4H2O represents a promising chemotherapeutic option for emerging, medically relevant and drug-resistant Candida species.

Candida species are widespread fungi that can cause a variety of infections in humans, and some of them exhibit resistance profile to existing antifungal drugs. Consequently, it is imperative to discover novel treatments for these clinically relevant human infections. Complexes are chemical compounds containing metal ion components that are well-known for their antimicrobial properties, including antifungal activity. In the present study, we investigated the effects of 16 novel complexes against ten medically relevant Candida species, including some strains resistant to commonly used clinical antifungals. Our findings revealed that all complexes containing manganese and silver metals effectively inhibited the growth of all Candida species tested, albeit to varying extents. Some of these complexes exhibited superior antifungal activity and lower toxicity to mammalian cells compared to traditional antifungals, such as fluconazole. In conclusion, these new complexes hold promise as a potential novel approach for treating fungal infections, especially those caused by drug-resistant Candida strains.

Modification of Glassy Carbon Electrodes with Complexes of Manganese(II) with Some Phenanthroline Derivatives Immobilized in Nafion Layer.

Manganese(II) complexes with phenanthroline derivatives modified with different substituents were synthesized and incorporated into Nafion layers covering the surfaces of glassy carbon electrodes and were studied electrochemically. Formal potentials and apparent diffusion coefficients were calculated and discussed. The suitability for electrocatalytic oxidation of ascorbic acid and glycolic acid was examined. The surfaces of modified electrodes were characterized using atomic force microscopy.

Ternary Phenolate-Based Thiosemicarbazone Complexes of Copper(II): Magnetostructural Properties, Spectroscopic Features and Marked Selective Antiproliferative Activity against Cancer Cells.

The new diprotic ligand 3,5-di-tert-butylsalicylaldehyde 4-ethyl-3-thiosemicarbazone, abbreviated H2(3,5-t-Bu2)-sal4eT, exists as the thio-keto tautomer and adopts the E-configuration with respect to the imine double bond, as evidenced by single-crystal X-ray analysis and corroborated by spectroscopic characterisation. Upon treatment with Cu(OAc)2·H2O in the presence of either 2,9-dimethyl-1,10-phenanthroline (2,9-Me2-phen) or 1,10-phenanthroline (phen) as a co-ligand in MeOH, this thiosemicarbazone undergoes conformational transformation (relative donor-atom orientations: syn,anti → syn,syn) concomitantly with tautomerisation and double deprotonation to afford the ternary copper(II) complexes [Cu{(3,5-t-Bu2)-sal4eT}(2,9-Me2-phen)] (1) and [Cu2{3,5-t-Bu2)-sal4eT}2(phen)] (2). Crystallographic elucidation has revealed that complex 1 is a centrosymmetric dimer of mononuclear copper(II) complex molecules brought about by intermolecular H-bonding. The coordination geometry at the copper(II) centre is best described as distorted square pyramidal in accordance with the trigonality index (τ = 0.14). The co-ligand adopts an axial-equatorial coordination mode; hence, there is a disparity between its two Cu-N coordinate bonds arising from weakening of the apical one as a consequence of the tetragonal distortion. The axial X-band ESR spectrum of complex 1 is consistent with retention of this structure in solution. Complex 2 is a centrosymmetric dimer of dinuclear copper(II) complex molecules exhibiting intermolecular H-bonding and π-π-stacking interactions. The two copper(II) centres, which are 4.8067(18) Å apart and bridged by the thio-enolate nitrogen of the quadridentate thiosemicarbazonate ligand, display two different coordination geometries, one distorted square planar (τ4 = 0.082) and the other distorted square pyramidal (τ5 = 0.33). Such dinuclear copper(II) thiosemicarbazone complexes, which are crystallographically characterised, are extremely rare. In vitro, complexes 1 and 2 outperform cisplatin as antiproliferative agents in terms of potency and selectivity towards HeLa and MCF-7 cancer cell lines.

Analyses of the Antibiofilm Activity of o-Phenanthroline Monohydrate against Enterococcus faecalis and Staphylococcus aureus and the Mechanisms Underlying These Effects.

Enterococcus faecalis and Staphylococcus aureus exhibit robust biofilm formation capabilities, the formation of which is closely linked to pathogenicity and drug resistance, thereby resulting in host infection and treatment failure. o-Phenanthroline monohydrate (o-Phen) and its derivatives demonstrate a wide range of antibacterial and antifungal activities. In this study, we aimed to explore the antibiofilm activity of o-Phen to E. faecalis and S. aureus and provide insights into the molecular mechanisms for combating biofilm resistance. We demonstrated that o-Phen possesses significant antibacterial and antibiofilm properties against E. faecalis and S. aureus, inducing alterations in bacterial morphology, compromising cell membrane integrity, and exhibiting synergistic effects with ß-lactam antibiotics at sub-MIC concentrations. The adhesion ability and automatic condensation capacity of, and synthesis of, extracellular polymers by E. faecalis cells were reduced by o-Phen, resulting in the inhibition of biofilm formation. Importantly, transcriptome analysis revealed 354 upregulated and 456 downregulated genes in o-Phen-treated E. faecalis. Differentially expressed genes were enriched in 11 metabolism-related pathways, including amino acid metabolism, pyrimidine metabolism, and glycolysis/gluconeogenesis. Moreover, the oppA, CeuA, and ZnuB genes involved in the ABC transport system, and the PBP1A penicillin-binding protein-coding genes sarA and mrcA were significantly downregulated. The multidrug efflux pump system and membrane permeability genes mdtG and hlyD, and bacterial adhesion-related genes, including adcA and fss2 were also downregulated, while mraZ and ASP23 were upregulated. Thus, o-Phen is anticipated to be an effective alternative drug for the treatment of E. faecalis and S. aureus biofilm-associated infections.

1,10-phenanthroline inhibits sumoylation and reveals that yeast SUMO modifications are highly transient.

The steady-state levels of protein sumoylation depend on relative rates of conjugation and desumoylation. Whether SUMO modifications are generally long-lasting or short-lived is unknown. Here we show that treating budding yeast cultures with 1,10-phenanthroline abolishes most SUMO conjugations within one minute, without impacting ubiquitination, an analogous post-translational modification. 1,10-phenanthroline inhibits the formation of the E1~SUMO thioester intermediate, demonstrating that it targets the first step in the sumoylation pathway. SUMO conjugations are retained after treatment with 1,10-phenanthroline in yeast that express a defective form of the desumoylase Ulp1, indicating that Ulp1 is responsible for eliminating existing SUMO modifications almost instantly when de novo sumoylation is inhibited. This reveals that SUMO modifications are normally extremely transient because of continuous desumoylation by Ulp1. Supporting our findings, we demonstrate that sumoylation of two specific targets, Sko1 and Tfg1, virtually disappears within one minute of impairing de novo sumoylation. Altogether, we have identified an extremely rapid and potent inhibitor of sumoylation, and our work reveals that SUMO modifications are remarkably short-lived.

Synthesis, characterization, and cancer cell-selective cytotoxicity of mixed-ligand cobalt(III) complexes of 8-hydroxyquinolines and phenanthroline bases.

Transition metal complexes exhibiting selective toxicity towards a broad range of cancer types are highly desirable as potential anticancer agents. Herein, we report the synthesis, characterization, and cytotoxicity studies of six new mixed-ligand cobalt(III) complexes of general formula [Co(B)2(L)](ClO4)2 (1-6), where B is a N,N-donor phenanthroline base, namely, 1,10-phenanthroline (phen in 1, 2), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq in 3, 4), and dipyrido[3,2-a:2',3'-c]phenazine (dppz in 5, 6), and L is the monoanion of 8-hydroxyquinoline (HQ in 1, 3, 5) and 5-chloro-7-iodo-8-hydroxyquinoline (CQ in 2, 4, 6). The X-ray single crystal structures of complexes 1 and 2 as PF6- salts revealed a distorted octahedral CoN5O coordination environment. Complexes demonstrated good stability in an aqueous buffer medium and in the presence of ascorbic acid as a reductant. Cytotoxicity studies using a panel of nine cancer cell lines showed that complex 6, with the dppz and CQ ligands, was significantly toxic against most cancer cell types, yielding IC50 values in the range of 2 to 14 µM. Complexes 1, 3, and 5, containing the HQ ligand, displayed lower toxicity compared to their CQ counterparts. The phenanthroline complexes demonstrated marginal toxicity towards the tested cell lines, while the dpq complexes exhibited moderate toxicity. Interestingly, all complexes demonstrated negligible toxicity towards normal HEK-293 kidney cells (IC50 > 100 µM). The observed cytotoxicity of the complexes correlated well with their lipophilicities (dppz > dpq > phen). The cytotoxicity of complex 6 was comparable to that of the clinical drug cisplatin under similar conditions. Notably, neither the HQ nor the CQ ligands alone demonstrated noticeable toxicity against any of the tested cell lines. The Annexin-V-FITC and DCFDA assays revealed that the cell death mechanism induced by the complexes involved apoptosis, which could be attributed to the metal-assisted generation of reactive oxygen species. Overall, the dppz complex 6, with its remarkable cytotoxicity against a broad range of cancer cells and negligible toxicity toward normal cells, holds significant potential for cancer chemotherapeutic applications.

Effects of the tetravanadate [V4O12]4- anion on the structural, magnetic, and biological properties of copper/phenanthroline complexes.

The aim to access linked tetravanadate [V4O12]4- anion with mixed copper(II) complexes, using α-amino acids and phenanthroline-derived ligands, resulted in the formation of four copper(II) complexes [Cu(dmb)(Gly)(OH2)]2[Cu(dmb)(Gly)]2[V4O12]·9H2O (1) [Cu(dmb)(Lys)]2[V4O12]·8H2O (2), [Cu(dmp)2][V4O12]·C2H5OH·11H2O (3), and [Cu(dmp)(Gly)Cl]·2H2O (4), where dmb = 4,4'-dimethioxy-2,2'-bipyridine; Gly = glycine; Lys = lysine; and dmp = 2,9-dimethyl-1,10-phenanthroline. The [V4O12]4- anion is functionalized with mixed copper(II) units in 1 and 2; while in 3, it acts as a counterion of two [Cu(dmp)]2+ units. Compound 4 crystallized as a unit that did not incorporate the vanadium cluster. All compounds present magnetic couplings arising from Cu⋯O/Cu⋯Cu bridges. Stability studies of water-soluble 3 and 4 by UV-Vis spectroscopy in cell culture medium confirmed the robustness of 3, while 4 appears to undergo ligand scrambling over time, resulting partially in the stable species [Cu(dmp)2]+ that was also identified by electrospray ionization mass spectrometry at m/z = 479. The in vitro cytotoxicity activity of 3 and 4 was determined in six cancer cell lines; the healthy cell line COS-7 was also included for comparative purposes. MCF-7 cells were more sensitive to compound 3 with an IC50 value of 12 ± 1.2 nmol. The tested compounds did not show lipid peroxidation in the TBARS assay, ruling out a mechanism of action via reactive oxygen species formation. Both compounds inhibited cell migration at 5 µM in wound-healing assays using MCF-7, PC-3, and SKLU-1 cell lines, opening a new window to study the anti-metastatic effect of mixed vanadium-copper(II) systems.

Phenanthroline relaxes uterine contractions induced by diverse contractile agents by decreasing cytosolic calcium concentration.

Uterine contractions during labor and preterm labor are influenced by a complex interplay of factors, including hormones and inflammatory mediators. This complexity may contribute to the limited efficacy of current tocolytics for preterm labor, a significant challenge in obstetrics with 15 million cases annually and approximately 1 million resulting deaths worldwide. We have previously shown that the myometrium expresses bitter taste receptors (TAS2Rs) and that their activation leads to uterine relaxation. Here, we investigated whether the selective TAS2R5 agonist phenanthroline can induce relaxation across a spectrum of human uterine contractions and whether the underlying mechanism involves changes in intracellular Ca2+ signaling. We performed experiments using samples from pregnant women undergoing scheduled cesarean delivery, assessing responses to various inflammatory mediators and oxytocin with and without phenanthroline. Our results showed that phenanthroline concentration-dependently inhibited contractions induced by PGF2α, U46619, 5-HT, endothelin-1 and oxytocin. Furthermore, in hTERT-infected human myometrial cells exposed to uterotonics, phenanthroline effectively suppressed the increase in intracellular Ca2+ concentration induced by PGF2α, U46619, oxytocin, and endothelin-1. These results suggest that the selective TAS2R5 agonist may not only significantly reduce uterine contractions but also decrease intracellular Ca2+ levels. This study highlights the potential development of TAS2R5 agonists as a new class of uterine relaxants, providing a novel avenue for improving the management of preterm labor.

Treatment with 1, 10 Phenanthroline-5-Amine Reduced Amyloid Burden in a Mouse Model of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent age-related dementia, and, despite numerous attempts to halt or reverse its devastating progression, no effective therapeutics have yet been confirmed clinically. However, one class of agents that has shown promise is certain metal chelators. OBJECTIVE: For the novel assessment of the effect of oral administration of 1,10-phenanthroline-5-amine (PAA) on the severity of amyloid plaque load, we used a transgenic (Tg) mouse model with inserted human autosomally dominant (familial) AD genes: amyloid-ß protein precursor (AßPP) and tau. METHODS: AßPP/Tau transgenic mice that model AD were allotted into one of two groups. The control group received no treatment while the experimental group received PAA in their drinking water starting at 4 months of age. All animals were sacrificed at 1 year of age and their brains were stained with two different markers of amyloid plaques, Amylo-Glo+ and HQ-O. RESULTS: The control animals exhibited numerous dense core plaques throughout the neo- and allo- cortical brain regions. The experimental group treated with PAA, however, showed 62% of the amyloid plaque burden seen in the control group. CONCLUSIONS: Oral daily dosing with PAA will significantly reduce the amyloid plaque burden in transgenic mice that model AD. The underlying mechanism for this protection is not fully known; however, one proposed mechanism involves inhibiting the "metal-seeding" of Aß.

Phenanthroline and Schiff Base associated Cu(II)-coordinated compounds containing N, O as donor atoms for potent anticancer activity.

As an inherent metal ion, copper has been the subject of investigation for developing a novel antitumoral compound that exhibits fewer adverse effects. Copper serves as a cofactor in multiple enzymes, generates reactive oxygen species (ROS), facilitates tumour evolution, metastasis and angiogenesis and has been detected at elevated concentrations in the serum and tissues of various human cancer types. In the given setting, utilising two methodologies in developing novel Copper-based pharmaceuticals for anti-cancer applications is standard practice. These approaches involve either the sequestration of unbound Copper ions or the synthesis of Copper complexes that induce cellular apoptosis. In the past four decades, the latter system has been used, leading to numerous reviews that have examined the anticancer characteristics of a wide range of Copper complexes. These analyses have consistently demonstrated that multiple factors frequently influence the efficacy of these compounds. This review examines the possible anticancer properties of copper and Cu(II) complexes that incorporate Schiff base ligands containing 1,10-phenanthroline. The present study will comprehensively analyse the examined cell lines and mechanistic research associated with each complex.

8-hydroxyquinoline-N-oxide copper(II)- and zinc(II)-phenanthroline and bipyridine coordination compounds: Design, synthesis, structures, and antitumor evaluation.

Fourteen novel tumor-targeting copper(II) and zinc(II) complexes, [Cu(ONQ)(QD1)(NO3)]·CH3OH (NQ3), [Cu(ONQ)(QD2)(NO3)] (NQ2), [Cu(NQ)(QD2)Cl] (NQ3), [Cu(ONQ)(QD1)Cl] (NQ4), [Cu(ONQ)(QD3)](NO3) (NQ5), [Cu(ONQ)(QD3)Cl] (NQ6), [Zn(ONQ)(QD4)Cl] (NQ7), [Zn(ONQ)(QD1)Cl] (NQ8), [Zn(ONQ)(QD5)Cl] (NQ9), [Zn(ONQ)(QD2)Cl] (NQ10), [Zn(ONQ)(QD6)Cl] (NQ11), [Zn(ONQ)(QD7)Cl] (NQ12), and [Zn(ONQ)(QD3)Cl] (NQ13) supported on 8-hydroxyquinoline-N-oxide (H-ONQ), 2,2'-dipyridyl (QD1), 5,5'-dimethyl-2,2'-bipyridyl (QD2), 1,10-phenanthroline (QD3), 4,4'-dimethoxy-2,2'-bipyridyl (QD4), 4,4'-dimethyl-2,2'-bipyridyl (QD5), 5-chloro-1,10-phenanthroline (QD6), and bathophenanthroline (QD7), were first synthesized and characterized using various spectroscopic techniques. Furthermore, NQ1-NQ13 exhibited higher antiproliferative activity and selectivity for cisplatin-resistant SK-OV-3/DDP tumor cells (CiSK3) compared to normal HL-7702 cells based on results obtained from the cell counting Kit-8 (CCK-8) assay. The complexation of copper(II) ion with QD2 and ONQ ligands resulted in an evident increase in the antiproliferation of NQ1-NQ6, with NQ6 exhibiting the highest antitumor potency against CiSK3 cells compared to NQ1-NQ5, H-ONQ, QD1-QD7, and NQ7-NQ13 as well as the reference cisplatin drug with an IC50 value of 0.17 ± 0.05 µM. Mechanistic studies revealed that NQ4 and NQ6 induced apoptosis of CiSK3 cells via mitophagy pathway regulation and adenosine triphosphate (ATP) depletion. Further, the differential induction of mitophagy decreased in the order of NQ6 > NQ4, which can be attributed to the major impact of the QD3 ligand with a large planar geometry and the Cl leaving group within the NQ6 complex. In summary, these results confirmed that the newly synthesized H-ONQ copper(II) and zinc(II) coordination metal compounds NQ1-NQ13 exhibit potential as anticancer drugs for cisplatin-resistant ovarian CiSK3 cancer treatment.

Targeted liposomes encapsulated iridium(III) compound greatly enhance anticancer efficacy and induce cell death via ferroptosis on HepG2 cells.

In this study, ligands 2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline (PIP), 2-(2-nitrophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline (NPIP), 2-(2-nitronaphthalen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (NNIP) and their iridium(III) metal compounds [Ir(ppy)2(PIP)](PF6) (ppy = 2-phenylpyridine, 1a), [Ir(ppy)2(NPIP)](PF6) (1b), [Ir(ppy)2(NNIP)](PF6) (1c) were designed and synthesized. The anti-cancer activities of 1a, 1b and 1c on BEL-7402, HepG2, SK-Hep1 and non-cancer LO2 were detected using MTT method. 1a shows moderate, 1b and 1c display low or no anti-cancer activities. To elevate the anti-cancer effectiveness, encapsulating the compounds 1a, 1b and 1c into the ordinary or targeted liposomes to produce 1alip, 1blip, 1clip, or targeted 1aTlip, 1bTlip and 1cTlip. The IC50 values of 1alip, 1blip, 1clip, 1aTlip, 1bTlip and 1cTlip against HepG2 cells are 7.9 ± 0.1, 8.6 ± 0.2, 16.9 ± 0.5, 5.9 ± 0.2, 7.3 ± 0.1 and 9.7 ± 0.7 µM, respectively. Specifically, the anti-tumor activity assays in vivo found that the inhibitory rates are 23.24 % for 1a, 61.27 % for 1alip, 76.06 % for 1aTlip. It is obvious that the targeted liposomes entrapped iridium(III) compound greatly enhance anti-cancer efficacy. Additionally, 1alip, 1blip and 1clip or targeted 1aTlip, 1bTlip and 1cTlip can effectively restrain the cell colony and proliferation in the G0/G1 period. 1alip, 1blip, 1clip, 1aTlip, 1bTlip and 1cTlip can increase reactive oxygen species (ROS) concentration, arouse a decline in the mitochondrial membrane potential and promote Ca2+ release. RNA-sequence was applied to examine the signaling pathways. Taken together, the liposomes or targeted liposomes encapsulated compounds trigger cell death by way of apoptosis, autophagy, ferroptosis, disruption of mitochondrial function and PI3K/AKT/mTOR signaling pathways.

Ru(II) Phenanthroline-Based Oligothienyl Complexes as Phototherapy Agents.

Ru(II) polypyridyl complexes have gained widespread attention as photosensitizers for photodynamic therapy (PDT). Herein, we systematically investigate a series of the type [Ru(phen)2(IP-nT)]2+, featuring 1,10-phenanthroline (phen) coligands and imidazo[4,5-f][1,10]phenanthroline ligands tethered to n = 0-4 thiophene rings (IP-nT). The complexes were characterized and investigated for their electrochemical, spectroscopic, and (photo)biological properties. The electrochemical oxidation of the nT unit shifted by -350 mV as n = 1 → 4 (+920 mV for Ru-1T, +570 mV for Ru-4T); nT reductions were observed in complexes Ru-3T (-2530 mV) and Ru-4T (-2300 mV). Singlet oxygen quantum yields ranged from 0.53 to 0.88, with Ru-3T and Ru-4T being equally efficient (∼0.88). Time-resolved absorption spectra of Ru-0T-1T were dominated by metal-to-ligand charge-transfer (3MLCT) states (τTA = 0.40-0.85 µs), but long-lived intraligand charge-transfer (3ILCT) states were observed in Ru-2T-4T (τTA = 25-148 µs). The 3ILCT energies of Ru-3T and Ru-4T were computed to be 1.6 and 1.4 eV, respectively. The phototherapeutic efficacy against melanoma cells (SK-MEL-28) under broad-band visible light (400-700 nm) increases as n = 0 → 4: Ru-0T was inactive up to 300 µM, Ru-1T-2T were moderately active (EC50 ∼ 600 nM, PI = 200), and Ru-3T (EC50 = 57 nM, PI > 1100) and Ru-4T (EC50 = 740 pM, PI = 114,000) were the most phototoxic. The activity diminishes with longer wavelengths of light and is completely suppressed for all complexes except Ru-3T and Ru-4T in hypoxia. Ru-4T is the more potent and robust PS in 1% O2 over seven biological replicates (avg EC50 = 1.3 µM, avg PI = 985). Ru-3T exhibited hypoxic activity in five of seven replicates, underscoring the need for biological replicates in compound evaluation. Singlet oxygen sensitization is likely responsible for phototoxic effects of the compounds in normoxia, but the presence of redox-active excited states may facilitate additional photoactive pathways for complexes with three or more thienyl groups. The 3ILCT state with its extended lifetime (30-40× longer than the 3MLCT state for Ru-3T and Ru-4T) implicates its predominant role in photocytotoxicity.

Necrosis-Inducing High-Valent Oxo-Rhenium(V) Complexes with Potent Antitumor Activity: Synthesis, Aquation Chemistry, Cisplatin Cross-Resistance Profile, and Mechanism of Action.

Chemotherapy with the cytotoxic platinum (Pt) drugs cisplatin, carboplatin, and oxaliplatin is the mainstay of anticancer therapy in the clinic. The antitumor activity of Pt drugs originates from their ability to induce apoptosis via covalent adduct formation with nuclear DNA. While the phenomenal clinical success is highly encouraging, resistance and adverse toxic side effects limit the wider applicability of Pt drugs. To circumvent these limitations, we embarked on an effort to explore the antitumor potential of a new class of oxo-rhenium(V) complexes of the type [(N∧N)(EG)Re(O)Cl] (where EG = ethylene glycolate and N∧N = bipyridine, Bpy (1); phenanthroline, Phen (2); 3,4,7,8-tetramethyl-phenanthroline, Me4Phen (3)). Investigation of speciation chemistry in aqueous media revealed the formation of [(N∧N)Re(O)(OH)3] as the biologically active species. Complex 3 was found to be the most potent among the three, with IC50 values ranging from 0.1 to 0.4 µM against a panel of cancer cells, which is 5-70-fold lower when compared with cisplatin. The higher potency of 3 is attributed to its higher lipophilicity, which enhanced cellular uptake. Importantly, complex 3 efficiently overcomes cisplatin resistance in ovarian, lung, and prostate cancer cells. In addition to reporting the aquation chemistry and identifying the active species in aqueous media, we performed in-depth in vitro mechanistic studies, which revealed that complex 3 preferentially accumulates in mitochondria, depletes mitochondrial membrane potential, and upregulates intracellular reactive oxygen species (ROS), leading to ER stress-mediated necrosis-mediated cancer cell death.

Structural and solution speciation studies on selected [Cu(NN)(OO)] complexes and an investigation of their biomimetic activity, ROS generation and their cytotoxicity in normoxic, hypoxic and anoxic environments in MCF-7 breast cancer-derived cells.

Reactive oxygen species(ROS) generation with subsequent DNA damage is one of the principle mechanisms of action assigned to copper-based anticancer complexes. The efficacy of this type of chemotherapeutic may be reduced in the low oxygen environment of tumours. In this study the cytotoxicity of three complexes, [Cu(dips)(phen)] (1), [Cu(ph)(phen)]·2H2O (2) and [Cu(ph)(bpy)]·H2O (3) (disp: 3,5-diisopropylsalicylate, phen: 1,10- phenanthroline, ph: phthalate, bpy: 2,2'-bipyridyl) were assessed for anticancer activity in the breast-cancer derived MCF-7 line under normoxic, hypoxic and anoxic conditions. In an immortalised keratinocyte HaCaT cell line, the cytotoxicity of complexes 2 and 3 was significantly reduced under both normoxic and hypoxic conditions, whilst the cytotoxicity of complex 1 was increased under hypoxic conditions. The ability of the complexes to generate ROS in the MCF-7 cell line was evaluated as was their ability to act as superoxide dismutase(SOD) and catalase mimics using a yeast cell assay. ROS generation was significant for complexes 2 and 3, less so for complex 1 though all three complexes had SOD mimetic ability. Given the ternary nature of the complexes, solution speciation studies were undertaken but were only successful for complex 3, due to solubility issues with the other two complexes. The concentration distribution of various species, formed in aqueous solution, was evaluated as a function of pH and confirmed that complex 3 is the dominant species at physiological pH in the mM concentration range. However, as its concentration diminishes, it experiences a progressive dissociation, leading to the formation of binary complexes of bpy alongside unbound phthalate.