257628-01-6Relevant academic research and scientific papers
Preparation of L-N(α)-Fmoc-4-[di-(tert- butyl)phosphonomethyl]phenylalanine from L-tyrosine
Yao, Zhu-Jun,Gao, Yang,Burke Jr., Terrence R.
, p. 3727 - 3734 (1999)
The unnatural amino acid analogue, 4-(phosphonomethyl)phenylalanine (Pmp, 2), has proven to be a valuable tool for studying protein-tyrosine kinase dependent signal transduction, where it is most often incorporated into peptides or peptide mimetics as a phosphatase-stable phosphotyrosyl mimetic. Although Pmp has been prepared previously bearing a number of protection strategies, the N(α)-Fmoc 4-[di-(tert-butyl)phosphonomethyl] phenylalanine form [(N(α)-Fmoc-L-Pmp((t)Bu2)-OH, 3] is particularly attractive since it can be cleanly introduced into peptides using standard Fmoc protocols. Synthesis of 3 was first reported as its (D/L)-racemate, and subsequently as its L-3 enantiomer, with the latter synthesis having relied on induction of chirality using a camphor sultam auxillary. Reported herein is an alternate enantioselective synthesis of L-3 in high enantiomeric purity by procedures which derive the stereochemistry of the final product directly from the starting amino acid, without the need for chiral induction. A key feature of the route is the racemization-free nucleophilic substitution of lithium di-tert-butyl phosphite onto protected 4-bromomethylphenylalanine (17).
The substrate-activity-screening methodology applied to receptor tyrosine kinases: A proof-of-concept study
Chapelat, Julien,Berst, Frédéric,Marzinzik, Andreas L.,Moebitz, Henrik,Drueckes, Peter,Trappe, Joerg,Fabbro, Doriano,Seebach, Dieter
supporting information, p. 1 - 9 (2013/01/15)
Protein kinases are widely recognized as important therapeutic targets due to their involvement in signal transduction pathways. These pathways are tightly controlled and regulated, notably by the ability of kinases to selectively phosphorylate a defined set of substrates. A wide variety of disorders can arise as a consequence of abnormal kinase-mediated phosphorylation and numerous kinase inhibitors have earned their place as key components of the modern pharmacopeia. Although "traditional" kinase inhibitors typically act by preventing the interaction between the kinase and ATP, thus stopping substrate phosphorylation, an alternative approach consists in disrupting the protein-protein interaction between the kinase and its downstream partners. In order to facilitate the identification of potential chemical starting points for substrate-site inhibition approaches, we desired to investigate the application of Substrate Activity Screening to kinases. We herein report a proof-of-concept study demonstrating, on a model tyrosine kinase, that the key requirements of this methodology can be met. Namely, using peptides as model substrates, we show that a simple ADP-accumulation assay can be used to monitor substrate efficiency and that efficiency can be optimized in a modular manner. More importantly, we demonstrate that structure-efficiency relationships translate into structure-activity relationships upon conversion of the substrates into inhibitors.
