797040-08-5Relevant academic research and scientific papers
N-sulphonylated amino acid derivatives, method for the production and use thereof
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, (2008/06/13)
The present invention relates to N-sulfonylated amino acid derivatives, where an aryl radical is linked via the sulfonyl group N-terminally to the amino acid and a radical which comprises at least one imino group and at least one further basic group which
Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase
Steinmetzer, Torsten,Schweinitz, Andrea,Stürzebecher, Anne,D?nnecke, Daniel,Uhland, Kerstin,Schuster, Oliver,Steinmetzer, Peter,Müller, Friedemann,Friedrich, Rainer,Than, Manuel E.,Bode, Wolfram,Stürzebecher, J?rg
, p. 4116 - 4126 (2007/10/03)
Matriptase is an epithelium-derived type II transmembrane serine protease and has been implicated in the activation of substrates such as pro-HGF/SF and pro-uPA, which are likely involved in tumor progression and metastasis. Through screening, we have identified bis-basic secondary amides of sulfonylated 3-amidinophenylalanine as matriptase inhibitors. X-ray analyses of analogues 8 and 31 in complex with matriptase revealed that these inhibitors occupy, in addition to part of the previously described S4-binding site, the cleft formed by the molecular surface and the unique 60 loop of matriptase. Therefore, optimization of the inhibitors included the incorporation of appropriate sulfonyl substituents that could improve binding of these inhibitors into both characteristic matriptase subsites. The most potent derivatives inhibit matriptase highly selective with Ki values below 5 nM. Molecular modeling revealed that their improved affinity results from interaction with the S4 site of matriptase. Analogues 8 and 59 were studied in an orthotopic xenograft mouse model of prostate cancer. Compared to control, both inhibitors reduced tumor growth, as well as tumor dissemination.
