Phosphonate and phosphinate analogues of N-acylated gamma-glutamylglutamate. potent inhibitors of glutamate carboxypeptidase II.
Phosphonate and phosphinate analogues of N-acylated gamma-glutamylglutamate were tested for the ability to inhibit glutamate carboxypeptidase II (GCP II). All of the compounds inhibit GCP II with IC(50) values in the low nanomolar range. The comparison of the results to previously reported inhibitory studies of the same compounds toward folylpoly-gamma-glutamyl synthetase (FPGS) and gamma-glutamyl hydrolase (gamma-GH) provides insight into structural and mechanistic features of each enzyme. Potential utility of these compounds as diagnostic agents and probes to understand folate or antifolate poly-gamma-glutamates metabolism is also described.
Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, MD 21224, USA. tsukamotot@guilfordpharm.com
Takashi
T
Tsukamoto
Juliet M
JM
Flanary
Camilo
C
Rojas
Barbara S
BS
Slusher
Nadya
N
Valiaeva
James K
JK
Coward
D001665:Binding Sites; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005971:Glutamates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D005971:Glutamates; D002268:Carboxypeptidases; C026134:glutamate carboxypeptidase