Phosphoramidate derivatives of hydroxysteroids as inhibitors of prostate-specific membrane antigen.
Prostate-specific membrane antigen (PSMA) is a membrane-bound cell surface peptidase which is over-expressed in prostate cancer cells. The enzymatic activities of PSMA are understood but the role of the enzyme in prostate cancer remains conjectural. We previously confirmed the existence of a hydrophobic binding site remote from the enzyme's catalytic center. To explore the specificity and accommodation of this binding site, we prepared a series of six glutamate-containing phosphoramidate derivatives of various hydroxysteroids (1a-1f). The inhibitory potencies of the individual compounds of the series were comparable to a simple phenylalkyl analog (8), and in all cases IC50 values were sub-micromolar. Molecular docking was used to develop a binding model for these inhibitors and to understand their relative inhibitory potencies against PSMA.
Wu
Lisa Y
LY
Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA.
Do
Jacinda C
JC
Kazak
Marat
M
Page
Helen
H
Toriyabe
Yoko
Y
Anderson
Marc O
MO
Berkman
Clifford E
CE
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000954:Antigens, Surface / Q000737:chemistry; D001665:Binding Sites; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D010756:Phosphoric Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013256:Steroids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000577:Amides; D000954:Antigens, Surface; D010756:Phosphoric Acids; D013256:Steroids; C011067:phosphoramidic acid; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II