Phosphoramidate derivatives of hydroxysteroids as inhibitors of prostate-specific membrane antigen

Lisa Y Wu; Jacinda C Do; Marat Kazak; Helen Page; Yoko Toriyabe; Marc O Anderson; Clifford E Berkman

doi:10.1016/j.bmcl.2007.10.096

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Phosphoramidate derivatives of hydroxysteroids as inhibitors of prostate-specific membrane antigen

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Phosphoramidate derivatives of hydroxysteroids as inhibitors of prostate-specific membrane antigen

Lisa Y Wu, Jacinda C Do, Marat Kazak, Helen Page, Yoko Toriyabe, Marc O Anderson and Clifford E Berkman

Bioorganic & medicinal chemistry letters, Vol.18(1), pp.281-284

2008

DOI: https://doi.org/10.1016/j.bmcl.2007.10.096

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https://hdl.handle.net/2376/115634

PMCID: PMC2254654

PMID: 18023582

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Abstract

Steroid

Glutamate carboxypeptidase II

PSMA

Phosphoramidate

Molecular docking

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 IC 50 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.

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Title: Phosphoramidate derivatives of hydroxysteroids as inhibitors of prostate-specific membrane antigen
Creators: Lisa Y Wu - Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA
Jacinda C Do - Department of Chemistry & Biochemistry, San Francisco State University, San Francisco, CA 94132-4163, USA
Marat Kazak - Department of Chemistry & Biochemistry, San Francisco State University, San Francisco, CA 94132-4163, USA
Helen Page - Department of Chemistry & Biochemistry, San Francisco State University, San Francisco, CA 94132-4163, USA
Yoko Toriyabe - Department of Chemistry & Biochemistry, San Francisco State University, San Francisco, CA 94132-4163, USA
Marc O Anderson - Department of Chemistry & Biochemistry, San Francisco State University, San Francisco, CA 94132-4163, USA
Clifford E Berkman - Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA
Publication Details: Bioorganic & medicinal chemistry letters, Vol.18(1), pp.281-284
Academic Unit: Chemistry, Department of
Publisher: Elsevier Ltd
Identifiers: 99900547429901842
Language: English
Resource Type: Journal article