Phosphinic acid pseudopeptides analogous to glutamyl-gamma-glutamate: synthesis and coupling to pteroyl azides leads to potent inhibitors of folylpoly-gamma-glutamate synthetase.
Several routes to a complex phosphinate phosphapeptide analogous to the gamma-glutamyl peptide Glu-gamma-Glu have been investigated. Formation of gamma-phosphono glutamate derivatives via addition of a phosphorus-based radical to protected vinylglycine was found to be of limited value because of the elevated temperatures required. Alkylation and conjugate addition reactions of trivalent phosphorus (P(III)) species were investigated. In situ generation of bis-trimethylsilyl esters of phosphinous acids proved to be an effective route to phosphinates of modest structural complexity. However, this chemistry could not be extended to the incorporation of an amino acid moiety at the N-terminal side of the desired phosphinate. A successful synthesis of the target phosphinate phosphapeptide was effected using P(III) chemistry and dehydrohalogenation to yield an alpha,beta-unsaturated phosphinic acid ester, following which conjugate addition of diethylacetamido malonate and acid-mediated hydrolysis afforded the desired phosphinate phosphapeptide. Coupling of the unprotected phosphinate phosphapeptide with two acyl azides derived from folic acid and methotrexate led to the corresponding pteroylphosphapeptides of interest as possible mimics of tetrahedral intermediates in the reaction catalyzed by folylpolyglutamate synthetase.
Valiaeva
N
N
Departments of Medicinal Chemistry and Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.
Bartley
D
D
Konno
T
T
Coward
J K
JK
D001386:Azides / Q000138:chemical synthesis*; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005971:Glutamates / Q000737:chemistry*; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000737:chemistry*; D010721:Phosphinic Acids / Q000737:chemistry*
D001386:Azides; D004791:Enzyme Inhibitors; D005971:Glutamates; D007202:Indicators and Reagents; D010455:Peptides; D010721:Phosphinic Acids; C433403:glutamyl-gamma-glutamate; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase