Selective Nitrile Inhibitors To Modulate the Proteolytic Synergism of Cathepsins S and F

Frizler, Maxim; Schmitz, Janina; Schulz-Fincke, Anna-Christina; Gütschow, Michael

doi:10.1021/jm300734k

Cited by 16 publications

(19 citation statements)

References 29 publications

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“…The synthesis of the four new dyes is based on four known buildingb locks, namely the di-tert-butyl 4,4'-[(4-iodophenyl)azanediyl]dibenzoate( 1), [24] thienyl-diketopyrrrolopyrrole (2), [31] N-(4'-ethynylphenyl)-N'-(octyl)naphthalene-1,8:4,5-tetracarboxydiimide( 5) [32] and the tert-butyl 5-bromothiophene-2-carboxylate (7), [33] which werep repared according to previously reported methods. The synthesis of the DPP dyes TPA-DPP (TPA: tri-phenyla mine-diketopyrrolopyrrole) and TPA-DPP-NDI is shown in Scheme 1a nd the key catalytic reaction is based on the CÀHb onda ctivationo fd iketopyrrolopyrrole substrates.…”

Section: Synthesis Of the Sensitizersmentioning

confidence: 99%

A Blue Diketopyrrolopyrrole Sensitizer with High Efficiency in Nickel‐Oxide‐based Dye‐Sensitized Solar Cells

et al. 2017

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We prepared a series of four new diketopyrrolopyrroles (DPPs)-based sensitizers that exhibit high-molar extinction coefficients, extended absorption into the long wavelengths, and well-suited photoredox properties to act as sensitizers in p-type dye-sensitized solar cells (p-DSSCs). These new DPP dyes, composed of a thienyl DPP core, are substituted on one end either by a thiophene carboxylic (Th) or a 4,4'-[(phenyl)aza]dibenzoic acid as anchoring group and, on the other extremity, either by a proton or a naphthalene diimide (NDI) moiety. These new dyes were completely characterized by absorption and emission spectroscopy along with electrochemistry and they were modeled by time-dependent DFT (TD-DFT) quantum chemical calculations. The photovoltaic study in p-DSSC with iodine-based electrolyte reveals that the Th-DPP-NDI dye is particularly efficient (J =7.38 mA cm ; V =147 mV; FF=0.32; η=0.35 %) and quite active in the low-energy region of the solar spectrum (above 700 nm), where only a few NiO dyes are effective. To illustrate the potential of DPP dyes in photocathodes, we designed a highly efficient tandem DSSC composed of a TiO photoanode sensitized by the dye D35 and a NiO photocathode sensitized by Th-DPP-NDI. This tandem DSSC gives the highest performances ever reported (J =6.73 mA cm ; V =910 mV; η=4.1 %) and, importantly, the tandem cell outcompetes with the sub-cells.

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Section: Synthesis Of the Sensitizersmentioning

confidence: 99%

A Blue Diketopyrrolopyrrole Sensitizer with High Efficiency in Nickel‐Oxide‐based Dye‐Sensitized Solar Cells

et al. 2017

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“…The peptide nitriles have attracted particular attention in the course of inhibitor development for cysteine proteases. 24,30 The S3 pocket in cathepsin S is reduced in size and an unsubstituted or para-fluoro-substituted phenyl residue in P3 turned out to be advantageous. 3,6,12,18,[23][24][25][26] Peptide nitriles represent promising drug candidates.…”

Section: Introductionmentioning

confidence: 99%

Design, characterization and cellular uptake studies of fluorescence-labeled prototypic cathepsin inhibitors

et al. 2015

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Besides their extracellular activity crucial for several pathophysiological conditions, human cysteine cathepsins, in particular cathepsins K and S, represent important intracellular targets for drug development. In the present study, a prototypic dipeptide nitrile inhibitor structure was equipped with a coumarin moiety to function as a fluorescent reporter group. In a second inhibitor, a PEG linker was introduced between the dipeptide nitrile and the fluorophore. These tool compounds 6 and 7 were characterized by kinetic investigations as covalent reversible inhibitors of human cathepsins L, S, K and B. Probe 6 showed a pronounced inhibitory activity against cathepsins K and S, which was corroborated by modeling of inhibition modes. Probe 7 was highly potent (Ki = 93 nM) and selective for cathepsin S. To examine the ability of both probes to enter living cells, human embryonic kidney 293 cells were targeted. At a concentration of 10 μM, cellular uptake of probe 6 was demonstrated by fluorescence measurement after an incubation time of 30 min and 3 h, respectively. The probe's concentration in cell lysates was ascertained on the basis of the emission at 492 nm upon excitation at 450 nm, and the results were expressed as concentrations of probe 6 relative to the protein concentration originating from the lysate. After incubation of 10 μM of probe 6 for 3 h, the cellular uptake was confirmed by fluorescence microscopy. HPLC was used to assess the probes’ lipophilicity, and the obtained

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“…The crude product was purified by column chromatography on silica gel to obtain 4-phenylthiophene-2-carboxylic acid (53%). The product was confirmed by 1 H-NMR [ 51 ].…”

Section: Methodsmentioning

confidence: 99%

Furan- and Thiophene-2-Carbonyl Amino Acid Derivatives Activate Hypoxia-Inducible Factor via Inhibition of Factor Inhibiting Hypoxia-Inducible Factor-1

et al. 2018

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Induction of a series of anti-hypoxic proteins protects cells during exposure to hypoxic conditions. Hypoxia-inducible factor-α (HIF-α) is a major transcription factor that orchestrates this protective effect. To activate HIF exogenously, without exposing cells to hypoxic conditions, many small-molecule inhibitors targeting prolyl hydroxylase domain-containing protein have been developed. In addition, suppression of factor inhibiting HIF-1 (FIH-1) has also been shown to have the potential to activate HIF-α. However, few small-molecule inhibitors of FIH-1 have been developed. In this study, we synthesized a series of furan- and thiophene-2-carbonyl amino acid derivatives having the potential to inhibit FIH-1. The inhibitory activities of these compounds were evaluated in SK-N-BE(2)c cells by measuring HIF response element (HRE) promoter activity. Several furan- and thiophene-2-carbonyl amino acid derivatives inhibited FIH-1 based on correlations among the docking score of the FIH-1 active site, the chemical structure of the compounds, and biological HIF-α/HRE transcriptional activity.

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Selective Nitrile Inhibitors To Modulate the Proteolytic Synergism of Cathepsins S and F

Cited by 16 publications

References 29 publications

A Blue Diketopyrrolopyrrole Sensitizer with High Efficiency in Nickel‐Oxide‐based Dye‐Sensitized Solar Cells

A Blue Diketopyrrolopyrrole Sensitizer with High Efficiency in Nickel‐Oxide‐based Dye‐Sensitized Solar Cells

Design, characterization and cellular uptake studies of fluorescence-labeled prototypic cathepsin inhibitors

Furan- and Thiophene-2-Carbonyl Amino Acid Derivatives Activate Hypoxia-Inducible Factor via Inhibition of Factor Inhibiting Hypoxia-Inducible Factor-1

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