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| - Phosphinic Acid Pseudopeptides Analogous toGlutamyl-γ-glutamate: Synthesis and Coupling to Pteroyl AzidesLeads to Potent Inhibitors of Folylpoly-γ-glutamate Synthetase
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| - Several routes to a complex phosphinate phosphapeptide analogous to the γ-glutamyl peptide Glu-γ-Glu have been investigated. Formation of γ-phosphono glutamate derivatives via addition of aphosphorus-based radical to protected vinylglycine was found to be of limited value because of theelevated temperatures required. Alkylation and conjugate addition reactions of trivalent phosphorus(PIII) species were investigated. In situ generation of bis-trimethylsilyl esters of phosphinous acidsproved to be an effective route to phosphinates of modest structural complexity. However, thischemistry could not be extended to the incorporation of an amino acid moiety at the N-terminalside of the desired phosphinate. A successful synthesis of the target phosphinate phosphapeptidewas effected using PIII chemistry and dehydrohalogenation to yield an α,β-unsaturated phosphinicacid ester, following which conjugate addition of diethylacetamido malonate and acid-mediatedhydrolysis afforded the desired phosphinate phosphapeptide. Coupling of the unprotected phosphinate phosphapeptide with two acyl azides derived from folic acid and methotrexate led to thecorresponding pteroylphosphapeptides of interest as possible mimics of tetrahedral intermediatesin the reaction catalyzed by folylpolyglutamate synthetase.
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