Probing for a hydrophobic a binding register in prostate-specific membrane antigen with phenylalkylphosphonamidates

• Published in: Bioorganic & medicinal chemistry Vol. 12; no. 18; pp. 4969 - 4979
• Main Authors: Maung, Jack, Mallari, Jeremy P., Girtsman, Teri A., Wu, Lisa Y., Rowley, Jennifer A., Santiago, Nicholas M., Brunelle, Alan N., Berkman, Clifford E.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15-09-2004; Elsevier Science
• Subjects: Antigens, Surface - metabolism; Antineoplastic agents; Biological and medical sciences; Cell Line; General aspects; Glutamate carboxypeptidase II; Glutamate Carboxypeptidase II - metabolism; Glutamates - chemistry; Glutamates - metabolism; HPLC; Humans; Hydrophobic and Hydrophilic Interactions; Male; Medical sciences; Pharmacology. Drug treatments; Phosphates - chemistry; Phosphates - metabolism; Phosphonamidate; Protein Binding - physiology; PSMA; γ-Diglutamate; Glutamate carboxypeptidase II; PSMA; Phosphonamidate; γ-Diglutamate; HPLC; Prostate specific antigen; α-Aminoacid; Organic amidophosphonate; Membrane protein; Structure activity relation; Glycoprotein; Enzyme inhibitor; Chemical synthesis; In vitro; Phosphorus Organic compounds
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2004.06.031

A series of phenylalkylphosphonamidate derivatives of glutamic acid were synthesized and evaluated for their inhibitory potencies against PSMA. The greatest inhibitory potency was observed for the inhibitors 1f (n=5) and 1g (n=6) suggesting the presence of a hydrophobic binding register remote from the substrate recognition architecture in the active site of PSMA.
To explore for the existence of an auxiliary hydrophobic binding register remote from the active site of PSMA a series of phenylalkylphosphonamidate derivatives of glutamic acid were synthesized and evaluated for their inhibitory potencies against PSMA. Both the phenyl- and benzylphosphonamidates (1a and 1b) exhibited only modest inhibitory potency against. The phenethyl analog 1c was intermediate in inhibitory potency while inhibitors possessing a longer alkyl tether from the phenyl ring, resulted in markedly improved Ki values. The greatest inhibitory potency was obtained for the inhibitors in which the phenyl ring was extended furthest from the central phosphorus (1f, n=5 and 1g, n=6). The slightly serrated pattern that emerged as the alkyl tether increased from three to six methylene units suggests that inhibitory potency is not simply correlated to increased hydrophobicity imparted by the phenylalkyl chain, but rather that one or more hydrophobic binding registers may exist remote from the substrate recognition architecture in the active site of PSMA.