174298-45-4Relevant academic research and scientific papers
Phosphono Bisbenzguanidines as Irreversible Dipeptidomimetic Inhibitors and Activity-Based Probes of Matriptase-2
H?u?ler, Daniela,Mangold, Martin,Furtmann, Norbert,Braune, Annett,Blaut, Michael,Bajorath, Jürgen,Stirnberg, Marit,Gütschow, Michael
, p. 8525 - 8535 (2016/07/07)
Matriptase-2, a type II transmembrane serine protease, plays a key role in human iron homeostasis. Inhibition of matriptase-2 is considered as an attractive strategy for the treatment of iron-overload diseases, such as hemochromatosis and β-thalassemia. In the present study, synthetic routes to nine dipeptidomimetic inactivators were developed. Five active compounds (41–45) were identified and characterized kinetically as irreversible inhibitors of matriptase-2. In addition to a phosphonate warhead, these dipeptides possess two benzguanidine moieties as arginine mimetics to provide affinity for matriptase-2 by binding to the S1 and S3/S4 subpockets, respectively. This binding mode was strongly supported by covalent docking analysis. Compounds 41–45 were obtained as mixtures of two diastereomers and were therefore separated into the single epimers. Compound 45 A, with S configuration at the N-terminal amino acid and R configuration at the phosphonate carbon atom, was the most potent matriptase-2 inactivator with a rate constant of inactivation of 2790 m?1s?1and abolished the activity of membrane-bound matriptase-2 on the surface of intact cells. Based on the chemotyp of phosphono bisbenzguanidines, the design and synthesis of a fluorescent probe (51 A) by insertion of a coumarin label is described. The in-gel fluorescence detection of matriptase-2 was demonstrated by applying 51 A as the first activity-based probe for this enzyme.
Tuning activity-based probe selectivity for serine proteases by on-resin 'click' construction of peptide diphenyl phosphonates
Serim, Sevnur,Mayer, Susanne V.,Verhelst, Steven H. L.
, p. 5714 - 5721 (2013/09/12)
Activity-based probes (ABPs) are powerful tools for functional proteomics studies. Their selectivity can be influenced by modification of a recognition element that interacts with pockets near the active site. For serine proteases there are a limited numb
Convenient syntheses of novel 1-isothiocyano-alkylphosphonate diphenyl ester derivatives with potential biological activity
Psurski, Mateusz,Pigula, Marta,Winiarski, Lukasz,Oleksyszyn, Jozef,Ciekot, Jaroslaw,Wietrzyk, Joanna
, p. 5845 - 5847,3 (2020/08/20)
Herein, we describe a convenient method for the syntheses of novel 1-isothiocyano-alkylphosphonate diaryl ester derivatives and their antiproliferative activity. The syntheses are based on dithiocarbamates obtained in situ with the use of carbon disulfide
