Browsing by Subject "Solid-phase synthesis"

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    Solid-Phase Synthesis of Arylpiperazine Derivatives and Implementation of the Distributed Drug Discovery (D3) Project in the Search for CNS Agents
    (MDPI, 2011-05) Zajdel, Pawel; Król, Joanna; Grychowska, Katarzyna; Pawłowski, Maciej; Subra, Gilles; Nomezine, Gaël; Martinez, Jean; Satala, Grzegorz; Bojarski, Andrzej J.; Zhou, Ziniu; O'Donnell, Martin J.; Scott, William; Chemistry and Chemical Biology, School of Science
    We have successfully implemented the concept of Distributed Drug Discovery (D3) in the search for CNS agents. Herein, we demonstrate, for the first time, student engagement from different sites around the globe in the development of new biologically active compounds. As an outcome we have synthesized a 24-membered library of arylpiperazine derivatives targeted to 5-HT1A and 5-HT2A receptors. The synthesis was simultaneously performed on BAL-MBHA-PS resin in Poland and the United States, and on BAL-PS-SynPhase Lanterns in France. The D3 project strategy opens the possibility of obtaining potent 5-HT1A/5-HT2A agents in a distributed fashion. While the biological testing is still centralized, this combination of distributed synthesis with screening will enable a D3 network of students world-wide to participate, as part of their education, in the synthesis and testing of this class of biologically active compounds.
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    Solid-Phase Synthesis of N-Carboxyalkyl Unnatural Amino Acids
    (2011-03-09) Fischer, Lindsey Gayle; O'Donnell, Martin J.; Minto, Robert E.; Scott, William L.
    A novel route has been developed for the solid-phase synthesis of N-carboxyalkyl unnatural amino acids as potential metalloprotease inhibitors. The key step involves a nitrogen alkylation of resin-bound amino acids with -bromoesters. Alkylation of the benzophenone imine of glycine on Wang resin was used to introduce unnatural amino acid side chains onto the resin-bound glycine. The benzyl -bromoesters [BrCH(R2)CO2Bn], starting materials for the C-N bond construction, were prepared in solution by diazotization of naturally-occurring amino acids to form the -bromoacids, followed by benzylation of the carboxylic acid to form the benzyl -bromoesters. N-Alkylation of the resin-bound, unnatural amino acids with the benzyl -bromoesters and subsequent cleavage from resin gave the benzyl ester monoacid intermediates. Exploration of reverse-phase cyano-silica gel chromatography and preparative liquid chromatography provided effective purification of the benzyl ester intermediates. Hydrolysis of the analytically pure benzyl ester monoacids afforded clean products as the diacids. The two points of variation introduced through the two on-resin alkylation steps, C-alkylation of the benzophenone imine of glycine and N-alkylation with the benzyl -bromoesters, allow for the combinatorial synthesis of a library of target compounds.