title: Phosphoramidate derivatives of hydroxysteroids as inhibitors of prostate-specific membrane antigen.
abstract: 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.
authors.affiliation: Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA.
authors.forename: Lisa Y
authors.initials: LY
authors.lastname: Wu
authors.forename: Jacinda C
authors.initials: JC
authors.lastname: Do
authors.forename: Marat
authors.initials: M
authors.lastname: Kazak
authors.forename: Helen
authors.initials: H
authors.lastname: Page
authors.forename: Yoko
authors.initials: Y
authors.lastname: Toriyabe
authors.forename: Marc O
authors.initials: MO
authors.lastname: Anderson
authors.forename: Clifford E
authors.initials: CE
authors.lastname: Berkman
mesh_terms: 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
chemical_list: D000577:Amides; D000954:Antigens, Surface; D010756:Phosphoric Acids; D013256:Steroids; C011067:phosphoramidic acid; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II