Substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine α-hydroxylating monooxygenase (PHM)

DOI

10.1016/j.bmc.2008.10.013

Authors

David J. Merkler, University of South Florida, Tampa
Alexander S. Asser, Duquesne University
Laura E. Baumgart, Duquesne University
Natalie Carballo, University of South Florida, Tampa
Sarah E. Carpenter, University of South Florida, Tampa
Geoffrey H. Chew, University of South Florida, Tampa
Casey C. Cosner, University of South Florida, Tampa
Jodi Dusi, California University of Pennsylvania
Lamar C. Galloway, University of South Florida, Tampa
Andrew B. Lowe, University of Southern Mississippi
Edward W. Lowe, University of South Florida, Tampa
Lawrence King, Duquesne University
Robert D. Kendig, University of South Florida, Tampa
Paul C. Kline, Middle Tennessee State University
Robert Malka, University of South Florida, Tampa
Kathleen A. Merkler, University of South Florida, Tampa
Neil R. McIntyre, University of South Florida, Tampa
Mindy Romero, University of South Florida, Tampa
Benjamin J. Wilcox, Duquesne University

Document Type

Journal Article

Publication Date

12-1-2008

Publication Title

Bioorganic and Medicinal Chemistry

Volume

16

Issue

23

First Page

10061

Last Page

10074

ISSN

9680896

Keywords

Hippurate analog, Peptidylglycine α-hydroxylating monooxygenase, Submicromolar inhibition

Abstract

Peptidyl α-hydroxylating monooxygenase (PHM) functions in vivo towards the biosynthesis of α-amidated peptide hormones in mammals and insects. PHM is a potential target for the development of inhibitors as drugs for the treatment of human disease and as insecticides for the management of insect pests. We show here that relatively simple ground state analogs of the PHM substrate hippuric acid (C6H5-CO-NH-CH2-COOH) inhibit the enzyme with Ki values as low as 0.5 μM. Substitution of sulfur atom(s) into the hippuric acid analog increases the affinity of PHM for the inhibitor. Replacement of the acetylglycine moiety, -CO-NH-CH2-COOH with an S-(thioacetyl)thioglycolic acid moiety, -CS-S-CH2-COOH, yields compounds with the highest PHM affinity. Both S-(2-phenylthioacetyl)thioglycolate and S-(4-ethylthiobenzoyl)thioglycolic acid inhibit the proliferation of cultured human prostate cancer cells at concentrations >100-fold excess of their respective Ki values. Comparison of Ki values between mammalian PHM and insect PHM shows differences in potency suggesting that a PHM-based insecticide with limited human toxicity can be developed. © 2008 Elsevier Ltd. All rights reserved.

Open Access

Green Accepted

Preprint

Link to Author Manuscript

Repository Citation

Merkler, D., Asser, A., Baumgart, L., Carballo, N., Carpenter, S., Chew, G., Cosner, C., Dusi, J., Galloway, L., Lowe, A., Lowe, E., King, L., Kendig, R., Kline, P., Malka, R., Merkler, K., McIntyre, N., Romero, M., & Wilcox, B. (2008). Substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine α-hydroxylating monooxygenase (PHM). Bioorganic and Medicinal Chemistry, 16 (23), 10061-10074. https://doi.org/10.1016/j.bmc.2008.10.013