Title

Substituted Hippurates and Hippurate Analogs As Substrates and Inhibitors of Peptidylglycine Alpha-Hydroxylating Monooxygenase (PHM)

Document Type

Article

Publication Date

12-1-2008

Department

Polymers and High Performance Materials

Abstract

Peptidyl alpha-hydroxylating monooxygenase (PHM) functions in vivo towards the biosynthesis of alpha-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 (C(6)H(5)-CO-NH CH(2)-COOH) inhibit the enzyme with K(i) values as low as 0.5 mu M. 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-CH(2)-COOH with an S-(thioacetyl) thioglycolic acid moiety, -CS-S-CH(2)-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 K(i) 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. (c) 2008 Elsevier Ltd. All rights reserved.

Publication Title

Bioorganic & Medicinal Chemistry

Volume

16

Issue

23

First Page

10061

Last Page

10074