- Synthesis, Biological Evaluation, and Utility of Fluorescent Ligands Targeting the μ-Opioid Receptor
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Fluorescently labeled ligands are useful pharmacological research tools for studying receptor localization, trafficking, and signaling processes via fluorescence imaging. They are also employed in fluorescent binding assays. This study is centered on the design, synthesis, and pharmacological evaluation of fluorescent probes for the opioid receptors, for which relatively few non-peptidic fluorescent probes currently exist. The known μ-opioid receptor (MOR) partial agonist, buprenorphine, was structurally elaborated to include an amidoalkylamine linker moiety that was coupled with a range of fluorophores to afford new fluorescent probes. All compounds proved to be selective MOR antagonists. Confocal fluorescence microscopy studies revealed that the probe incorporating a sulfonated cyanine-5 fluorophore was the most appropriate for imaging studies. This ligand was subsequently employed in an automated fluorescence-based competition binding assay, allowing the pKi values of several well-known opioid ligands to be determined. Thus, this new probe will prove useful in future studies of MOR receptor pharmacology.
- Schembri, Luke S.,Stoddart, Leigh A.,Briddon, Stephen J.,Kellam, Barrie,Canals, Meritxell,Graham, Bim,Scammells, Peter J.
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- Synthesis of azobenzenealkylmaleimide probes to photocontrol the enzyme activity of a bacterial histone deacetylase-like amidohydrolase
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A series of azobenzenealkylmaleimides (AMDs) with different spacer length was synthesized and coupled via Michael-Addition to a specific mutant of a bacterial histone deacetylase-like amidohydrolase (HDAH). Michaelis-Menten parameters (Vmax and Km) were employed to characterize the effect of both, the spacer length and the configuration (cis vs. trans) of the attached azobenzene moiety, on the HDAH enzyme activity. The photoswitch behavior of the AMD/enzyme conjugate activity was clearly influenced by the AMD spacer length. This study highlights the importance of steric rearrangement of the photoswitch with respect to the active site and describes a strategy to optimize the photocontrol of HDAH.
- Horstmann, Benjamin,Korbus, Michael,Friedmann, Tatjana,Wolff, Christiane,Thiele, Christina Marie,Meyer-Almes, Franz-Josef
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- Efficient Synthesis of a Family of Bifunctional Chelators Based on the PCTA[12] Macrocycle Suitable for Bioconjugation
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PCTA[12] is a 12-membered tetraaza-macrocyclic ligand that incorporates a pyridine unit within the macrocyclic ring and three acetate pendant arms. Unlike DOTA and NOTA chelators, PCTA is a recent entry to the field of macrocyclic polyaminocarboxylate ligands available to complex a variety of M2+/M3+ ions for biomedical applications such as diagnostic and radiotherapeutic. Despite the promising properties of its chelates, only a few of bifunctional chelating agents (BFCAs) derived from PCTA have been described so far. Based on our very recent methodology for the preparation of PCTA[12] itself, we report here the efficient synthesis of several BFCAs derived from PCTA bearing a free reactive function group, mainly devoted to conjugation purposes: ester, carboxylic acid, alcohol, aliphatic amine, aromatic amine, maleimide, bromo or azide functions. These functions were introduced either on the 4-position of the pyridine ring or on the methylene carbon atom of the central acetate chelating arm, while keeping the three carboxylate groups available for metal chelation. Moreover, two of these BFCAs-PCTA were used for conjugation with a tetrapeptide (cholecystokinin analogue), a bioactive molecule (biotin), or a solid support (silica gel).
- Leygue, Nadine,Enel, Morgane,Diallo, Abdel,Mestre-Voegtlé, Béatrice,Galaup, Chantal,Picard, Claude
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p. 2899 - 2913
(2019/05/15)
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- AMATOXIN DERIVATIVES AND CONJUGATES THEREOF AS INHIBITORS OF RNA POLYMERASE
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The invention disclosed herein relates to cytotoxic cyclic peptides of Formula (I), methods of inhibiting RNA polymerase with such cyclic peptides, immunoconjugates comprising such cyclic peptides (i.e Antibody Drug Conjugates), pharmaceutical compositions comprising such cyclic peptides immunoconjugates, compositions comprising such cyclic peptides immunoconjugates with a therapeutic co-agent and methods of treatment using such cyclic peptides immunoconjugates: Formula (I).
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- Functionalized phosphonated half-cage molecules as ligands for metal complexes
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Phosphonated molecules, featuring a half-cage structure and a N-lateral chain with additional metal coordinating groups were designed as ligands of metal cations. These compounds were synthesized by a Diels-Alder (DA) strategy, using 1-diethoxyphosphoryl-1,3-butadiene and a series of N-substituted maleimides as dienophiles. Two cycloadducts, bearing a terminal primary alcohol and a terminal iodide, respectively, were used as key intermediates for further functionalizations. Metal coordination properties of the ligands equipped with functionalized N-lateral chains were proven by an ESI-HRMS study. The stoichiometry of one selected EuIII complex with a diphosphonated ligand was determined by photoluminescence spectroscopy in emission mode.
- Villemin, Elise,Herent, Marie-France,Marchand-Brynaert, Jacqueline
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supporting information
p. 6165 - 6178
(2013/01/15)
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