Substituted Hippurates and Hippurate Analogs as Substrates and Inhibitors of Peptidylglycine α-Hydroxylating Monooxygenase (PHM)
Document Type
Article
Publication Date
12-1-2008
Department
Polymers and High Performance Materials
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.
Publication Title
Bioorganic & Medicinal Chemistry
Volume
16
Issue
23
First Page
10061
Last Page
10074
Recommended Citation
Merkler, D. J.,
Asser, A. S.,
Baumgart, L. E.,
Carballo, N.,
Carpenter, S. E.,
Chew, G. H.,
Cosner, C. C.,
Dusi, J.,
Lowe, A. B.,
Lowe, E. W.,
King, L.,
Kendig, R. D.,
Kline, P. C.,
Malka, R.,
Merkler, K. A.,
McIntyre, N. R.,
Romero, M.,
Wilcox, B. J.,
Owen, T. C.
(2008). Substituted Hippurates and Hippurate Analogs as Substrates and Inhibitors of Peptidylglycine α-Hydroxylating Monooxygenase (PHM) . Bioorganic & Medicinal Chemistry, 16(23), 10061-10074.
Available at: https://aquila.usm.edu/fac_pubs/1536