Three novel complexes of deprotonated diflunisal (dif) with neocuproine (neo) were synthesized and characterized via elemental, spectral (UV-vis, FTIR, fluorescence, and mass spectrometry), and single-crystal X-ray diffraction analyses. Although the compounds shared a similar composition of [MCl(dif)(neo)], where M represents Zn(II) (1), Co(II) (2) and Cu(II) (3), only 1 and 2 were isostructural, while 3 differed in both the molecular and supramolecular structures. In all three complex molecules, the central atom is coordinated by two nitrogen atoms of neo in a bidentate chelate mode, and one chlorido ligand and dif is bonded in either a monodentate mode via one oxygen atom of the carboxylate in 1 and 2 or in a bidentate chelate mode via both carboxylate oxygen atoms in 3. All three compounds demonstrated remarkable antiproliferative activity against human prostate (PC-3), colon (HCT116) and breast (MDA-MB-468) cancer cell lines with IC50 values in the nanomolar range, with the lowest values observed in the case of PC-3 and MDA-MB-468 with 2 (20.0 nM) and 3 (31.1 nM), respectively. Moreover, complex 2, as the most active, was further investigated for its potential to induce perturbations in the cell cycle of PC-3 cells. The results indicated an induction of caspase-independent apoptosis. The interaction of the complexes with genomic DNA isolated from the respective cancer cell lines was evaluated for the intercalative mode, with binding strength correlated with the antiproliferative activity against PC-3 and MDA-MB-468 cancer cell lines.

• MeSH
• apoptóza účinky léků   MeSH
• fenantroliny chemie   farmakologie   MeSH
• kobalt * chemie   farmakologie   MeSH
• komplexní sloučeniny * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• měď * chemie   farmakologie   MeSH
• molekulární modely MeSH
• nádorové buněčné linie MeSH
• proliferace buněk * účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv MeSH
• zinek * chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fenantroliny MeSH
• kobalt * MeSH
• komplexní sloučeniny * MeSH
• měď * MeSH
• neocuproine MeSH Prohlížeč
• protinádorové látky * MeSH
• zinek * MeSH

Current multiagent chemotherapy regimens have improved the cure rate in acute leukemia patients, but they are highly toxic and poorly efficient in relapsed patients. To improve the treatment approaches, new specific molecules are needed. The G-quadruplexes (G4s), which are noncanonical nucleic acid structures found in specific guanine-rich DNA or RNA, are involved in many cellular events, including control of gene expression. G4s are considered as targets for the development of anticancer agents. Heterocyclic molecules are well known to target and stabilize G4 structures. Thus, a new series of 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives (1a-i) was designed, synthesized, and evaluated against five human myeloid leukemia cell lines (K562, KU812, MV4-11, HL60, and U937). Their ability to stabilize various oncogene promoter G4 structures (c-MYC, BCL-2, and K-RAS) as well as the telomeric G4 was also determined through the fluorescence resonance energy transfer melting assay and native mass spectrometry. In addition, the more bioactive ligands 1g-i were tested for telomerase activity in HuT78 and MV4-11 protein extracts.

• Klíčová slova
• 1, 10-phenanthroline, FRET melting, G-quadruplex, G4 ligands, antiproliferative activity, leukemia,
• MeSH
• akutní myeloidní leukemie farmakoterapie   patologie   MeSH
• buňky K562 MeSH
• fenantroliny chemická syntéza   chemie   farmakologie   MeSH
• G-kvadruplexy účinky léků   MeSH
• HL-60 buňky MeSH
• lidé MeSH
• ligandy MeSH
• nádorové buněčné linie MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• racionální návrh léčiv MeSH
• rezonanční přenos fluorescenční energie MeSH
• telomerasa metabolismus   MeSH
• U937 buňky MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1,10-phenanthroline MeSH Prohlížeč
• fenantroliny MeSH
• ligandy MeSH
• protinádorové látky MeSH
• telomerasa MeSH

Hemochromatosis (iron overload) encompasses a group of diseases that are characterized by a toxic hyperaccumulation of iron in parenchymal organs. Currently, only few treatments for this disease have been approved; however, all these treatments possess severe side effects. In this study, a paradigm for hemochromatosis maintenance/preventive therapy is investigated: polymers with negligible systemic biological availability form stable complexes with iron ions in the gastrointestinal tract, which reduces the biological availability of iron. Macroporous polymer beads are synthesized with three different iron-chelating moieties (benzene-1,2-diol, benzene-1,2,3-triol, and 1,10-phenanthroline). The polymers rapidly chelate iron ions from aqueous solutions in vitro in the course of minutes, and are noncytotoxic and nonprooxidant. Moreover, the in vivo biodistribution and pharmacokinetics show a negligible uptake from the gastrointestinal tract (using 125 I-labeled polymer and single photon emission computed tomography/computed tomography), which generally prevents them from having systemic side effects. The therapeutic efficacy of the prepared polymers is successfully tested in vivo, and exhibits a significant inhibition of iron uptake from the gastrointestinal tract without any noticeable signs of toxicity. Furthermore, an in silico method is developed for the prediction of chelator selectivity. Therefore, this paradigm can be applied to the next-generation maintenance/preventive treatment for hemochromatosis and/or other diseases of similar pathophysiology.

• Klíčová slova
• SPECT, antioxidant, experimental therapy, hemochromatosis, iron metabolism, iron overload, maintenance therapy, polymeric chelator, preventive therapy, siderophore, uptake inhibitor,
• MeSH
• benzen chemie   farmakologie   MeSH
• chelátory železa chemie   farmakologie   MeSH
• fenantroliny chemie   farmakologie   MeSH
• gastrointestinální trakt účinky léků   MeSH
• hemochromatóza diagnostické zobrazování   farmakoterapie   patologie   MeSH
• lidé MeSH
• polymery chemie   farmakologie   MeSH
• teoretické modely * MeSH
• tomografie emisní počítačová MeSH
• železo metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1,10-phenanthroline MeSH Prohlížeč
• benzen MeSH
• chelátory železa MeSH
• fenantroliny MeSH
• polymery MeSH
• železo MeSH

Two novel Co(II) fenamato complexes containing bathocuproine (bcp), namely [Co(bcp)(flu)2] (1) and [Co(bcp)(nif)2] (2) (flu = flufenamato, nif = niflumato) were synthesized and characterized by elemental analysis, single-crystal X-ray structure analysis as well as absorption and fluorescence spectroscopy. Investigation of their molecular structure revealed that both complexes are isostructural and form analogous complex molecules, with a Co(II) atom hexacoordinated by two nitrogen atoms of bcp and four oxygen atoms of two chelate bonded flu (1) and nif (2) ligands in a distorted octahedral arrangement. Surprisingly, the results of cytotoxicity experiments on four cancer cell lines (HeLa, HT-29, PC-3 and MCF-7) have revealed that despite similar structure of the complexes, the nif complex exhibits significantly higher activity, being the most effective against the PC-3 cell line (IC50 (MTT) = 6.11 ± 1.95 μM). Further studies performed on PC-3 cell line have shown that the mechanism of the cytotoxic action of nif complex (2) might involve activation of autophagic processes and apoptosis, while for its flu analogue (1) apoptosis was detected.

• Klíčová slova
• Anti-cancer, Apoptosis, Cobalt(II) complexes, Flufenamic acid, NSAID, Niflumic acid,
• MeSH
• apoptóza účinky léků   MeSH
• autofagie účinky léků   MeSH
• fenantroliny chemická syntéza   farmakologie   MeSH
• kobalt chemie   MeSH
• komplexní sloučeniny chemická syntéza   farmakologie   MeSH
• kontrolní body fáze G1 buněčného cyklu účinky léků   MeSH
• kyselina flufenamová analogy a deriváty   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• protinádorové látky chemická syntéza   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bathocuproine MeSH Prohlížeč
• fenantroliny MeSH
• kobalt MeSH
• komplexní sloučeniny MeSH
• kyselina flufenamová MeSH
• ligandy MeSH
• protinádorové látky MeSH

The novel copper complex [Cu(phen)2(salubrinal)](ClO4)2 (C0SAL) has been synthesised and characterised. Copper(ii) is coordinated by salubrinal through the thionic group, as shown by the UV-Vis, IR, ESI-MS and tandem mass results, together with the theoretical calculations. The formed complex showed a DPPH radical scavenging ability higher than that of salubrinal alone. Studies on lipid oxidation inhibition showed that the C0SAL concentration, required to inhibit the enzyme, was lower than that of salubrinal. The inhibition of the enzyme could take place via allosteric modulation, as suggested by docking calculations. C0SAL showed a good cytotoxic activity on A2780 cells, 82 fold higher than that of the precursor salubrinal and 1.4 fold higher than that of [Cu(phen)2(H2O)](ClO4)2. Treatment with C0SAL in SKOV3 ovarian cancer cells induced expression of GRP-78 and DDIT3 regulators of ER-stress response. The cytotoxic effect of C0SAL was reverted in the presence of TUDCA, suggesting that C0SAL induces cell death through ER-stress. In A2780 cells treated with C0SAL γ-H2AX was accumulated, suggesting that DNA damage was also involved.

• MeSH
• antivirové látky farmakologie   MeSH
• cinnamáty farmakologie   MeSH
• fenantroliny farmakologie   MeSH
• kyselina taurochenodeoxycholová farmakologie   MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• měď farmakologie   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• peroxidace lipidů účinky léků   MeSH
• poškození DNA účinky léků   genetika   MeSH
• thiomočovina analogy a deriváty   farmakologie   MeSH
• transkripční faktor CHOP genetika   metabolismus   MeSH
• transmisní elektronová mikroskopie MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1,10-phenanthroline MeSH Prohlížeč
• antivirové látky MeSH
• cinnamáty MeSH
• fenantroliny MeSH
• kyselina taurochenodeoxycholová MeSH
• měď MeSH
• salubrinal MeSH Prohlížeč
• thiomočovina MeSH
• transkripční faktor CHOP MeSH
• ursodoxicoltaurine MeSH Prohlížeč

Conventional chemotherapy is mostly effective in the treatment of rapidly-dividing differentiated tumor cells but has limited application toward eliminating cancer stem cell (CSC) population. The presence of a very small number of CSCs may contribute to the development of therapeutic resistance, metastases, and relapse. Thus, treatment failure by developing novel anticancer drugs capable of effective targeting of CSCs is at present a major challenge for research focused on chemotherapy of cancer. Here, we show that Os(II) complex 2 [Os(η6-pcym)(bphen)(dca)]PF6 (pcym = p-cymene, bphen = bathophenanthroline, and dca = dichloroacetate), is capable of efficient and selective killing CSCs in heterogeneous populations of human breast cancer cells MCF-7 and SKBR-3. Notably, its remarkable submicromolar potency to kill CSCs is considerably higher than that of its Ru analog, [Ru(η6-pcym)(bphen)(dca)]PF6 (complex 1) and salinomycin, one of the most selective CSC-targeting compounds hitherto identified. Furthermore, Os(II) complex 2 reduces the formation, size, and viability of three-dimensional mammospheres which more closely reflect the tumor microenvironment than cells in traditional two-dimensional cultures. The antiproliferation studies and propidium iodide staining using flow cytometry suggest that Os(II) complex 2 induces human breast cancer stem cell death predominantly by necroptosis, a programmed form of necrosis. The results of this study demonstrate the promise of Os(II) complex 2 in treating human breast tumors. They also represent the foundation for further preclinical and clinical studies and applications of Os(II) complex 2 to comply with the emergent need for human breast CSCs-specific chemotherapeutics capable to treat chemotherapy-resistant and relapsed human breast tumors.

• MeSH
• apoptóza účinky léků   MeSH
• chloracetáty farmakologie   MeSH
• cymeny farmakologie   MeSH
• fenantroliny farmakologie   MeSH
• komplexní sloučeniny farmakologie   MeSH
• lidé MeSH
• lokální recidiva nádoru patologie   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky účinky léků   metabolismus   MeSH
• nádorové mikroprostředí účinky léků   MeSH
• nádory prsu farmakoterapie   patologie   MeSH
• nekroptóza účinky léků   MeSH
• nekróza metabolismus   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• osmium farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 4-cymene MeSH Prohlížeč
• bathophenanthroline MeSH Prohlížeč
• chloracetáty MeSH
• cymeny MeSH
• diammine(dichloroacetato)platinum(II) MeSH Prohlížeč
• fenantroliny MeSH
• komplexní sloučeniny MeSH
• organoplatinové sloučeniny MeSH
• osmium MeSH
• protinádorové látky MeSH

There is an ongoing need for the development of new cancer therapeutics that combine high cytotoxic efficiency with low side effects, and also override resistance to the first-line chemotherapeutics. Copper(ii)-phenanthroline complexes are promising compounds that were shown previously to induce an immediate cytotoxic response over a panel of tumor cell lines in vitro. The molecular mechanism, however, remained unresolved. In this work we performed a thorough study of the copper(ii)-phenanthroline complexes containing different imidazolidine-2-thione ligands in ovarian cancer cells, and revealed that these complexes induce endoplasmic reticulum (ER) stress and subsequently cell death mediated by the unfolded protein response. Alleviation of the ER-stress by tauroursodeoxycholic acid (TUDCA) attenuated the cytotoxic effects. In summary, we have identified a novel, ER-dependent, molecular mechanism mediating cytotoxic effects of copper(ii)-phenanthroline complexes.

• MeSH
• fenantroliny chemie   farmakologie   MeSH
• komplexní sloučeniny chemie   farmakologie   MeSH
• lidé MeSH
• měď chemie   farmakologie   MeSH
• nádorové buněčné linie MeSH
• nádory vaječníků farmakoterapie   metabolismus   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• signální dráha UPR účinky léků   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fenantroliny MeSH
• komplexní sloučeniny MeSH
• měď MeSH
• protinádorové látky MeSH

There is an urgent need to discover new, selective compounds to add to the limited arsenal of chemotherapeutics displaying selective toxicity for aggressive triple-negative breast cancer (TNBC) cells. The effect of two, recently developed metal-based half-sandwich complexes [Os(η6-pcym)(bphen)(dca)]PF6 (Os-dca) and [Ru(η6-pcym)(bphen)(dca)]PF6 (Ru-dca) [pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene); bphen = 4,7-diphenyl-1,10-phenanthroline (bathophenanthroline); dca = dichloroacetate] on triple-negative breast cancer cells MDA-MB-231 is reported. The complexes display selective toxicity in several tumor cells (at submicromolar concentrations), and a prominent effect is observed against highly progressive triple negative breast cancer MDA-MB-231 cells for Os-dca. The lower potency of Ru-dca in comparison with Os-dca is apparently connected with a relatively quick release of the dca ligand due to the hydrolysis of Ru-dca before this complex enters the cells. Remarkably, both Os-dca and Ru-dca reduce successfully metastasis-related properties of the triple-negative breast cancer cells such as migration, invasion, and re-adhesion. The anti-metastatic effects of Os-dca and Ru-dca are associated with their ability to suppress matrix metalloproteinase activity and/or production and reduce the expression of aquaporins. Further detailed mechanistic studies reveal that Os-dca reverses Warburg's effect and oncosis seems to be a prominent mode of cell death that predominates over apoptosis. As such, Os-dca can efficiently overcome the resistance of cancer cells to clinically-used apoptotic inducers cisplatin and carboplatin. The cytostatic and anti-metastatic properties of Os-dca in MDA-MB-231 provide a strong impetus for the development of new metal-based compounds to target hardly treatable human TNBC cells and displaying different modes of action compared to the antitumor metallodrugs in clinical use.

• MeSH
• fenantroliny chemie   farmakologie   MeSH
• komplexní sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• osmium chemie   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• ruthenium chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• triple-negativní karcinom prsu farmakoterapie   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• bathophenanthroline MeSH Prohlížeč
• fenantroliny MeSH
• komplexní sloučeniny MeSH
• osmium MeSH
• protinádorové látky MeSH
• ruthenium MeSH

A series of new 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives was synthesized, and the compounds were screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiparasitic activity with IC50 values in the μm range. The in vitro cytotoxicity of these molecules was assessed by incubation with human HepG2 cells; for some derivatives, cytotoxicity was observed at significantly higher concentrations than antiparasitic activity. The 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline 1h was identified as the most potent antimalarial candidate with ratios of cytotoxic-to-antiparasitic activities of 107 and 39 against a chloroquine-sensitive and a chloroquine-resistant strain of P. falciparum, respectively. As the telomeres of the parasite P. falciparum are the likely target of this compound, we investigated stabilization of the Plasmodium telomeric G-quadruplexes by our phenanthroline derivatives through a FRET melting assay. The ligands 1f and 1m were noticed to be more specific for FPf8T with higher stabilization for FPf8T than for the human F21T sequence.

• Klíčová slova
• G-quadruplex, antileishmanial activity, antimalarial activity, antitrypanosomal activity, phenanthroline,
• MeSH
• antiprotozoální látky chemická syntéza   metabolismus   farmakologie   MeSH
• buňky Hep G2 MeSH
• fenantroliny chemie   metabolismus   farmakologie   MeSH
• G-kvadruplexy MeSH
• Leishmania donovani účinky léků   růst a vývoj   MeSH
• lidé MeSH
• ligandy MeSH
• Plasmodium falciparum účinky léků   MeSH
• racionální návrh léčiv * MeSH
• tranzitní teplota MeSH
• Trypanosoma brucei brucei účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiprotozoální látky MeSH
• fenantroliny MeSH
• ligandy MeSH

We report on the preparation and thorough characterization of cytotoxic half-sandwich complexes [Ru(η⁶-pcym)(bphen)(dca)]PF₆ (Ru-dca) and [Os(η⁶-pcym)(bphen)(dca)]PF₆ (Os-dca) containing dichloroacetate(1-) (dca) as the releasable O-donor ligand bearing its own cytotoxicity; pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene), bphen = 4,7-diphenyl-1,10-phenanthroline (bathophenanthroline). Complexes Ru-dca and Os-dca hydrolyzed in the water-containing media, which led to the dca ligand release (supported by ¹H NMR and electrospray ionization mass spectra). Mass spectrometry studies revealed that complexes Ru-dca and Os-dca do not interact covalently with the model proteins cytochrome c and lysozyme. Both complexes exhibited slightly higher in vitro cytotoxicity (IC50 = 3.5 μM for Ru-dca, and 2.6 μM for Os-dca) against the A2780 human ovarian carcinoma cells than cisplatin (IC50 = 5.9 μM), while their toxicity on the healthy human hepatocytes was found to be IC50 = 19.1 μM for Ru-dca and IC50 = 19.7 μM for Os-dca. Despite comparable cytotoxicity of complexes Ru-dca and Os-dca, both the complexes modified the cell cycle, mitochondrial membrane potential, and mitochondrial cytochrome c release by a different way, as revealed by flow cytometry experiments. The obtained results point out the different mechanisms of action between the complexes.

• Klíčová slova
• cytotoxicity, dichloroacetate(1–), flow cytometry, half-sandwich, osmium, ruthenium,
• MeSH
• fenantroliny chemie   farmakologie   MeSH
• komplexní sloučeniny chemie   farmakologie   MeSH
• kyselina dichloroctová chemie   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• nádory vaječníků farmakoterapie   MeSH
• osmium chemie   MeSH
• proliferace buněk účinky léků   MeSH
• ruthenium chemie   MeSH
• uvolňování léčiv MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• bathophenanthroline MeSH Prohlížeč
• fenantroliny MeSH
• komplexní sloučeniny MeSH
• kyselina dichloroctová MeSH
• ligandy MeSH
• osmium MeSH
• ruthenium MeSH