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The synthesis of ruthenium(II) and osmium(II) arene complexes with the closely related indolo[3,2-c]quinolines N-(11H-indolo[3,2-c]quinolin-6-yl)-ethane-1,2-diamine (L ( 1 )) and N'-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (L ( 2 )) and indolo[3,2-d]benzazepines N-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-ethane-1,2-diamine (L ( 3 )) and N'-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-N,N-dimethylethane-1,2-diamine (L ( 4 )) of the general formulas [(eta(6)-p-cymene)M(II)(L ( 1 ))Cl]Cl, where M is Ru (4) and Os (6), [(eta(6)-p-cymene)M(II)(L ( 2 ))Cl]Cl, where M is Ru (5) and Os (7), [(eta(6)-p-cymene)M(II)(L ( 3 ))Cl]Cl, where M is Ru (8) and Os (10), and [(eta(6)-p-cymene)M(II)(L ( 4 ))Cl]Cl, where M is Ru (9) and Os (11), is reported. The compounds have been comprehensively characterized by elemental analysis, electrospray ionization mass spectrometry, spectroscopy (IR, UV-vis, and NMR), and X-ray crystallography (L ( 1 ).HCl, 4.H(2)O, 5, and 9.2.5H(2)O). Structure-activity relationships with regard to cytotoxicity and cell cycle effects in human cancer cells as well as cyclin-dependent kinase (cdk) inhibition and DNA intercalation in cell-free settings have been established. The metal-free indolo[3,2-c]quinolines inhibit cancer cell growth in vitro, with IC(50) values in the high nanomolar range, whereas those of the related indolo[3,2-d]benzazepines are in the low micromolar range. In cell-free experiments, these classes of compounds inhibit the activity of cdk2/cyclin E, but the much higher cytotoxicity and stronger cell cycle effects of indoloquinolines L ( 1 ) and 7 are not paralleled by a substantially higher kinase inhibition compared with indolobenzazepines L ( 4 ) and 11, arguing for additional targets and molecular effects, such as intercalation into DNA.
The class of tetrahydro-1H-3-benzazepines was systematically modified in 1-, 3- and 7-position. In particular, a F-atom was introduced in β- or γ-position of the 4-phenylbutyl side chain in 3-position. Ligands with the F-atom in γ-position possess higher GluN2B affinity than analogs bearing the F-atom in β-position. This effect was attributed to the reduced basicity of β-fluoro amines. 3-Benzazepines with a benzylic OH moiety show moderate GluN2B affinity, but considerable selectivity over the σ2 receptor. However, removal of the benzylic OH moiety led to increased GluN2B affinity, but reduced GluN2B/σ2 selectivity. With respect to GluN2B affinity the phenol 17b with a γ-fluorophenylbutyl moiety in 3-position represents the most interesting fluorinated ligand (Ki(GluN2B) = 16 nM). Most of the synthesized ligands reveal either similar GluN2B and σ1 affinity or higher σ1 affinity than GluN2B affinity. The methyl ether 16b shows high σ1 affinity (Ki(σ1) = 6.6 nM) and high selectivity over a broad panel of receptors and transporters. The high antiallodynic activity in the mouse capsaicin assay proved the σ1 antagonistic activity of 16b.
Following our strategy of coupling cyclin-dependent kinase (Cdk) inhibitors with organometallic moieties to improve their physicochemical properties and bioavailability, five organoruthenium complexes (1c-5c) of the general formula [RuCl(η(6)-arene)(L)]Cl have been synthesized in which the arene is 4-formylphenoxyacetyl-η(6)-benzylamide and L is a Cdk inhibitor [3-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines (L1-L3) and indolo[3,2-d]benzazepines (L4 and L5)]. All of the compounds were characterized by spectroscopic and analytical methods. Upon prolonged standing (2-3 months) at room temperature, the dimethyl sulfoxide (DMSO) solutions of 1c and 2c(-HCl) afforded residues, which after recrystallization from EtOH and EtOH/H(2)O, respectively, were shown by X-ray diffraction to be cis,cis-[Ru(II)Cl(2)(DMSO)(2)(L1)]·H(2)O and mer-[Ru(II)Cl(DMSO)(3)(L2-H)]·H(2)O. Compound 5c, with a coordinated amidine unit, undergoes E/Z isomerization in solution. The antiproliferative activities and effects on the cell cycle of the new compounds were evaluated. Complexes 1c-5c are moderately cytotoxic to cancer cells (CH1, SW480, A549, A2780, and A2780cisR cell lines). Therefore, in order to improve their antiproliferative effects, as well as their drug targeting and delivery to cancer cells, 1c-5c were conjugated to recombinant human serum albumin, potentially exploiting the so-called "enhanced permeability and retention" effect that results in the accumulation of macromolecules in tumors. Notably, a marked increase in cytotoxicity of the albumin conjugates was observed in all cases.
Indolo[3,2-d][1]benzazepines (paullones), indolo[3,2-d][2]benzazepines, and indolo[2,3-d][2]benzazepines (latonduines) are isomeric scaffolds of current medicinal interest. Herein, we prepared a small library of novel indolo[3,2-d][2]benzazepine-derived ligands HL1-HL4 and copper(II) complexes 1-4. All compounds were characterized by spectroscopic methods (1H and 13C NMR, UV-vis, IR) and electrospray ionization (ESI) mass spectrometry, while complexes 2 and 3, in addition, by X-ray crystallography. Their purity was confirmed by HPLC coupled with high-resolution ESI mass spectrometry and/or elemental analysis. The stability of compounds in aqueous solutions in the presence of DMSO was confirmed by 1H NMR and UV-vis spectroscopy measurements. The compounds revealed high antiproliferative activity in vitro in the breast cancer cell line MDA-MB-231 and hepatocellular carcinoma cell line LM3 in the low micromolar to nanomolar concentration range. Important structure-activity relationships were deduced from the comparison of anticancer activities of HL1-HL4 and 1-4 with those of structurally similar paullone-derived (HL5-HL7 and 5-7) and latonduine-derived scaffolds (HL8-HL11 and 8-11). The high anticancer activity of the lead drug candidate 4 was linked to reactive oxygen species and endoplasmic reticulum stress induction, which were confirmed by fluorescent microscopy and Western blot analysis.
N-methyl-D-aspartate receptors (NMDARs), especially GluN2B-containing NMDARs, are associated with neurodegenerative diseases like Parkinson, Alzheimer and Huntington based on their high Ca2+ conductivity. Overactivation leads to high intracellular Ca2+ concentrations and cell death rendering GluN2B-selective inhibitors as promising drug candidates. Ifenprodil represents the first highly potent prototypical, subtype-selective inhibitor of GluN2B-containing NMDARs. However, activity of ifenprodil on serotonergic, adrenergic and sigma receptors limits its therapeutic use. Structural reorganization of the ifenprodil scaffold to obtain 3-benzazepines retained inhibitory GluN2B activity but decreased the affinity at the mentioned non-NMDARs. While scaffold optimization improves the selectivity, the molecular inhibitory mechanism of these compounds is still not known. Here, we show a common inhibitory mechanism of ifenprodil and the related 3-benzazepines by mutational modifications of the receptor binding site, chemical modifications of the 3-benzazepine scaffold and subsequent in silico simulation of the inhibitory mechanism.
Indolo[2,3-d]benzazepines (indololatonduines) are rarely discussed in the literature. In this project, we prepared a series of novel indololatonduine derivatives and their RuII and OsII complexes and investigated their microtubule-targeting properties in comparison with paclitaxel and colchicine. Compounds were fully characterized by spectroscopic techniques (1H NMR and UV-vis), ESI mass-spectrometry, and X-ray crystallography, and their purity was confirmed by elemental analysis. The stabilities of the compounds in DMSO and water were confirmed by 1H and 13C NMR and UV-vis spectroscopy. Novel indololatonduines demonstrated anticancer activity in vitro in a low micromolar concentration range, while their coordination to metal centers resulted in a decrease of cytotoxicity. The preliminary in vivo activity of the RuII complex was investigated. Fluorescence staining and in vitro tubulin polymerization assays revealed the prepared compounds to have excellent microtubule-destabilizing activities, even more potent than the well-known microtubule-destabilizing agent colchicine.
SKF-83959 [6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine] is reported to be a functionally selective dopamine D1 receptor ligand with high bias for D1-mediated phospholipase C (PLC) versus D1-coupled adenylate cyclase signaling. This signaling bias is proposed to explain behavioral activity in both rat and primate Parkinson's disease models, and a D1-D2 heterodimer has been proposed as the underlying mechanism. We have conducted an in-depth pharmacological characterization of this compound in dopamine D1 and D2 receptors in both rat brain and heterologous systems expressing human D1 or D2 receptors. Contrary to common assumptions, SKF-83959 is similar to the classical, well-characterized partial agonist SKF38393 in all systems. It is a partial agonist (not an antagonist) at adenylate cyclase in vitro and ex vivo, and is a partial agonist in D1-mediated β-arrestin recruitment. Contrary to earlier reports, it does not have D1-mediated effects on PLC signaling in heterologous systems. Because drug metabolites can also contribute, its 3-N-demethylated analog also was synthesized and tested. As expected from the known structure-activity relationships of the benzazepines, this compound also had high affinity for the D1 receptor and somewhat higher intrinsic activity than the parent ligand, and also might contribute to in vivo effects of SKF-83959. Together, these data demonstrate that SKF-83959 is not a highly-biased functionally selective D1 ligand, and that its reported behavioral data can be explained solely by its partial D1 agonism in canonical signaling pathway(s). Mechanisms that have been proposed based on the purported signaling novelty of SKF-83959 at PLC should be reconsidered.
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