- Copper(ii) complexes based on tripodal pyridyl amine derivatives as efficient anticancer agents
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The complexes [Cu(TPA)Cl]ClO4·?H2O (1-ClO4), [Cu(6-MeTPA)Cl]ClO4/PF6 (2-ClO4/2-PF6), [Cu(6-Me2TPA)Cl]PF6 (3-PF6), [Cu(BPQA)Cl]ClO4/PF6 (4-ClO4/4-PF6), [Cu(BPQA)Cl]ClO4/PF6 (4-ClO4/4-PF6), [Cu(BQPA)Cl]ClO4/PF6 (5-ClO4/PF6), [Cu(L1)Cl]ClO4/PF6 (6-ClO4/6-PF6), [Cu(L2)Cl]ClO4 (7-ClO4) and [Cu(L3)Cl]ClO4 (8-ClO4) have been synthesized and structurally characterized by spectroscopic techniques and single X-ray crystallography. The in vitro cytotoxicity of the prepared Cu(ii) complexes was evaluated against A2780 (ovarian), A2780R (cisplatin-resistant variant) and MCF7 (breast cancer) human cancer cell lines. Overall, the complexes revealed significant-to-moderate cytotoxicity, with the best results obtained for the complexes [Cu(BQPA)Cl]ClO4 (5-ClO4) and [Cu(BQPA)Cl]PF6 (5-PF6), showing IC50 values within the range of 4.7-10.8 μM. The ability of the most cytotoxic complexes to cleave DNA under different conditions and the mechanisms underlying this activity were assessed by means of agarose gel electrophoresis.
- Massoud, Salah S.,Louka, Febee R.,Tusa, Ada F.,Bordelon, Nicole E.,Fischer, Roland C.,Mautner, Franz A.,Van?o, Ján,Ho?ek, Jan,Dvo?ák, Zdeněk,Trávní?ek, Zdeněk
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- Identification of potent anticancer copper(ii) complexes containing tripodal bis[2-ethyl-di(3,5-dialkyl-1H-pyrazol-1-yl)]amine moiety
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A series of heteroleptic copper(ii) complexes of the composition [Cu(L1-5)Cl]X, where X = ClO4 and/or PF6 and [bis(2-ethyl-di(3,5-dimethyl-1H-pyrazol-1-yl))-(6-methyl-(2-pyridylmethyl))]amine (L1), [bis(2-ethyl-di(3,5-dimethyl-1H-pyrazol-1-yl))-(3,4-dimethoxy-(2-pyridylmethyl))]amine (L2), [bis(2-ethyl-di(3,5-dimethyl-1H-pyrazol-1-yl)-(2-quinolymethyl)]amine (L3), [bis(2-ethyl-di(3,5-dimethyl-1H-pyrazolyl)-(di(3,5-dimethyl-1H-pyrazol-1-yl-methyl))]amine (L4) and [bis(2-ethyl-di(3,5-dimethyl-1H-pyrazol-1-yl)-(5-methyl-3-phenyl-1H-pyrazol-1-yl-methyl)]amine (L5), were prepared and thoroughly characterized including single-crystal X-ray diffraction technique. The in vitro cytotoxicity of complexes against A2780, A2780R, HOS and MCF-7 human cancer cell lines was evaluated using the MTT test. The results revealed that complexes [Cu(L1)Cl]PF6 (1-PF6), [Cu(L2)Cl]ClO4 (2-ClO4) and [Cu(L3)Cl]PF6 (3-PF6) are the most effective, with IC50 values ranging from 1.4 to 6.3 μM, thus exceeding the cytotoxic potential of metallodrug cisplatin (IC50 values ranging from 29.9 to 82.0 μM). The complexes [Cu(L4)Cl]PF6 (4-PF6) and [Cu(L5)Cl]PF6 (5-PF6) showed only moderate cytotoxicity against A2780, with IC50 = 53.6 μM, and 33.8 μM, respectively. The cell cycle profile, time-resolved cellular uptake, interactions with small sulfur-containing biomolecules (cysteine and glutathione), intracellular ROS production, induction of apoptosis and activation of caspases 3/7 were also evaluated in the case of the selected complexes. It has been found that the best performing complexes 1 and 2 cause cell arrest in the G2/M phase and induce apoptosis via the increase in production of ROS, dominantly due to the overproduction of superoxide.
- Dial, Madison T.,Dvo?ák, Zdeněk,Fischer, Roland C.,Louka, Febee R.,Malek, Andrew J.,Malina, Tomá?,Massoud, Salah S.,Mautner, Franz A.,Trávní?ek, Zdeněk,Van?o, Ján
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p. 11521 - 11534
(2021/08/30)
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- Interplay Between Steric and Electronic Effects: A Joint Spectroscopy and Computational Study of Nonheme Iron(IV)-Oxo Complexes
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Iron is an essential element in nonheme enzymes that plays a crucial role in many vital oxidative transformations and metabolic reactions in the human body. Many of those reactions are regio- and stereospecific and it is believed that the selectivity is guided by second-coordination sphere effects in the protein. Here, results are shown of a few engineered biomimetic ligand frameworks based on the N4Py (N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine) scaffold and the second-coordination sphere effects are studied. For the first time, selective substitutions in the ligand framework have been shown to tune the catalytic properties of the iron(IV)-oxo complexes by regulating the steric and electronic factors. In particular, a better positioning of the oxidant and substrate in the rate-determining transition state lowers the reaction barriers. Therefore, an optimum balance between steric and electronic factors mediates the ideal positioning of oxidant and substrate in the rate-determining transition state that affects the reactivity of high-valent reaction intermediates.
- Mukherjee, Gourab,Alili, Aligulu,Barman, Prasenjit,Kumar, Devesh,Sastri, Chivukula V.,de Visser, Sam P.
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p. 5086 - 5098
(2019/03/17)
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- FUSED PYRIMIDINE DERIVATIVES HAVING INHIBITORY ACTIVITY ON FMS KINASES
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Disclosed are a fused pyrimidine derivative of formula (I), and a pharmaceutically acceptable salt, stereoisomer, hydrate and solvate thereof, which have an excellent inhibitory activity on FMS kinases, and a pharmaceutical composition comprising the same is effective in preventing or treating diseases caused by abnormal activation of FMS kinases such as immunologic diseases, metabolic diseases, inflammatory diseases, cancers and tumors.
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Page/Page column 24
(2014/01/17)
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- Facial triad modelling using ferrous pyridinyl prolinate complexes: Synthesis and catalytic applications
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A series of new chiral pyridinyl prolinate (RPyProR) ligands and their corresponding Fe(ii) triflate and chloride complexes are reported. The ligands possess an NN′O coordination motif, as found in the active site of non-heme iron enzymes with the so-called 2-His-1-carboxylate facial triad. The coordination behaviour of these ligands towards iron turned out to be dependent on the counter ion (chloride or triflate), the crystallization conditions (coordinating or non-coordinating solvents) and the presence of substituents on the ligand. In combination with Fe(ii)(OTf)2, coordinatively saturated complexes of the type [Fe(L)2](OTf)2 are formed, in which the ligands adopt a meridional coordination mode. The use of FeCl 2 in a non-coordinating solvent leads to 5-coordinated complexes [Fe(L)(Cl)2] with a meridional N,N′,O ligand. Crystallization of these complexes from a coordinating solvent leads to 6-coordinated [Fe(L)(solv)(Cl)2] complexes (solv = methanol or acetonitrile), in which the N,N′,O ligand is coordinated in a facial manner. For RPyProR ligands bearing a 6-Me substituent on the pyridine ring, solvent coordination and, accordingly, ligand rearrangement are prevented by steric constraints. The complexes were tested as oxidation catalysts in the epoxidation of alkene substrates in acetonitrile with hydrogen peroxide as the oxidant under oxidant limiting conditions. The complexes were shown to be especially active in the epoxidation of styrene type substrates (styrene and trans-beta-methylstyrene). In the best case, complex [Fe(6-Me-PyProNH2)Cl2] (15) allowed for 65% productive consumption of hydrogen peroxide toward epoxide and benzaldehyde products. This journal is the Partner Organisations 2014.
- Moelands, Marcel A. H.,Schamhart, Daniel J.,Folkertsma, Emma,Lutz, Martin,Spek, Anthony L.,Klein Gebbink, Robertus J. M.
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p. 6769 - 6785
(2014/05/06)
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- Characterization and dioxygen reactivity of a new series of coordinatively unsaturated thiolate-ligated manganese(II) complexes
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The synthesis, structural, and spectroscopic characterization of four new coordinatively unsaturated mononuclear thiolate-ligated manganese(II) complexes ([MnII(SMe2N4(6-Me-DPEN))](BF4) (1), [MnII(SMe2N4(6-Me-DPPN))](BPh 4)·MeCN (3), [MnII(SMe2N 4(2-QuinoPN))](PF6)·MeCN·Et2O (4), and [MnII(SMe2N4(6-H-DPEN)(MeOH)](BPh 4) (5)) is described, along with their magnetic, redox, and reactivity properties. These complexes are structurally related to recently reported [MnII(SMe2N4(2-QuinoEN))](PF 6) (2) (Coggins, M. K.; Kovacs, J. A. J. Am. Chem. Soc.2011, 133, 12470). Dioxygen addition to complexes 1-5 is shown to result in the formation of five new rare examples of Mn(III) dimers containing a single, unsupported oxo bridge: [MnIII(SMe2N4(6-Me-DPEN)] 2-(μ-O)(BF4)2·2MeOH (6), [Mn III(SMe2N4(QuinoEN)]2-(μ-O) (PF6)2·Et2O (7), [Mn III(SMe2N4(6-Me-DPPN)]2-(μ-O) (BPh4)2 (8), [MnIII(SMe2N 4(QuinoPN)]2-(μ-O)(BPh4)2 (9), and [MnIII(SMe2N4(6-H-DPEN)] 2-(μ-O)(PF6)2·2MeCN (10). Labeling studies show that the oxo atom is derived from 18O2. Ligand modifications, involving either the insertion of a methylene into the backbone or the placement of an ortho substituent on the N-heterocyclic amine, are shown to noticeably modulate the magnetic and reactivity properties. Fits to solid-state magnetic susceptibility data show that the Mn(III) ions of μ-oxo dimers 6-10 are moderately antiferromagnetically coupled, with coupling constants (2J) that fall within the expected range. Metastable intermediates, which ultimately convert to μ-oxo bridged 6 and 7, are observed in low-temperature reactions between 1 and 2 and dioxygen. Complexes 3-5, on the other hand, do not form observable intermediates, thus illustrating the effect that relatively minor ligand modifications have upon the stability of metastable dioxygen-derived species.
- Coggins, Michael K.,Toledo, Santiago,Shaffer, Erika,Kaminsky, Werner,Shearer, Jason,Kovacs, Julie A.
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experimental part
p. 6633 - 6644
(2012/08/08)
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- SUBSTITUTED N-(1H-INDAZOL-4-YL)IMIDAZO[1,2-a]PYRIDINE-3-CARBOXAMIDE COMPOUNDS AS TYPE III RECEPTOR TYROSINE KINASE INHIBITORS
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Compounds of Formula I: and pharmaceutically acceptable salts thereof in which R1, R2, R3, R4, R5 and R6 have the meanings given in the specification, are inhibitors of cFMS and are useful in the treatment of fibrosis, bone-related diseases, cancer, autoimmune disorders, inflammatory diseases, cardiovascular diseases, pain and burns in a mammal
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Page/Page column 87
(2012/06/30)
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- 5-lipoxygenase-activating protein (FLAP) inhibitors. Part 4: Development of 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin- 2-ylmethoxy)-1 H -indol-2-yl]-2,2-dimethylpropionic acid (AM803), a potent, oral, once daily FLAP inhibitor
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The potent 5-lipoxygenase-activating protein (FLAP) inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2- ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid 11cc is described (AM803, now GSK2190915). Building upon AM103 (1) (Hutchinson et al. J. Med Chem.2009, 52, 5803-5815; Stock et al. Bioorg. Med. Chem. Lett. 2010, 20, 213-217; Stock et al. Bioorg. Med. Chem. Lett.2010, 20, 4598-4601), SAR studies centering around the pyridine moiety led to the discovery of compounds that exhibit significantly increased potency in a human whole blood assay measuring LTB4 inhibition with longer drug preincubation times (15 min vs 5 h). Further studies identified 11cc with a potency of 2.9 nM in FLAP binding, an IC50 of 76 nM for inhibition of LTB4 in human blood (5 h incubation) and excellent preclinical toxicology and pharmacokinetics in rat and dog. 11cc also demonstrated an extended pharmacodynamic effect in a rodent bronchoalveolar lavage (BAL) model. This compound has successfully completed phase 1 clinical studies in healthy volunteers and is currently undergoing phase 2 trials in asthmatic patients.
- Stock, Nicholas S.,Bain, Gretchen,Zunic, Jasmine,Li, Yiwei,Ziff, Jeannie,Roppe, Jeffrey,Santini, Angelina,Darlington, Janice,Prodanovich, Pat,King, Christopher D.,Baccei, Christopher,Lee, Catherine,Rong, Haojing,Chapman, Charles,Broadhead, Alex,Lorrain, Dan,Correa, Lucia,Hutchinson, John H.,Evans, Jilly F.,Prasit, Peppi
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experimental part
p. 8013 - 8029
(2012/03/08)
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- Imidazole derivatives
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The present invention relates to imidazole derivatives of formula I wherein R1, R2, R3, R4, X, Y and R are described hereinabove, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition comprising the imidazole derivatives of formula I, a process for preparing a compound of formula I, and a method of treating or preventing acute and/or chronic neurological disorder comprising administering to a patient in need of such treatment and/or prevention a therapeutically effective amount of said pharmaceutical composition. These disorders include Alzheimer's disease. These disorders also include mild cognitive impairment.
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Page/Page column 10
(2008/06/13)
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