Document Detail


Substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine alpha-hydroxylating monooxygenase (PHM).
MedLine Citation:
PMID:  18952446     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 0.5microM. 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 K(i) values between mammalian PHM and insect PHM shows differences in potency suggesting that a PHM-based insecticide with limited human toxicity can be developed.
Authors:
David J Merkler; Alexander S Asser; Laura E Baumgart; Natalie Carballo; Sarah E Carpenter; Geoffrey H Chew; Casey C Cosner; Jodi Dusi; Lamar C Galloway; Andrew B Lowe; Edward W Lowe; Lawrence King; Robert D Kendig; Paul C Kline; Robert Malka; Kathleen A Merkler; Neil R McIntyre; Mindy Romero; Benjamin J Wilcox; Terence C Owen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-10-11
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  16     ISSN:  1464-3391     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-11-17     Completed Date:  2009-01-09     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  10061-74     Citation Subset:  IM    
Affiliation:
Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., Tampa, FL 33620, USA. merkler@cas.usf.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / chemical synthesis,  chemistry,  pharmacology
Enzyme Inhibitors / chemical synthesis,  chemistry*,  pharmacology
Hippurates / chemical synthesis,  chemistry*,  pharmacology*
Humans
Inhibitory Concentration 50
Insecticides / chemistry*,  metabolism,  pharmacology
Mixed Function Oxygenases / antagonists & inhibitors*,  metabolism
Models, Molecular
Multienzyme Complexes / antagonists & inhibitors*,  metabolism
Rats
Structure-Activity Relationship
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
R15 GM067257-01/GM/NIGMS NIH HHS; R15 GM073659-01/GM/NIGMS NIH HHS; R15-GM067257/GM/NIGMS NIH HHS; R15-GM073659/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Enzyme Inhibitors; 0/Hippurates; 0/Insecticides; 0/Multienzyme Complexes; EC 1.-/Mixed Function Oxygenases; EC 1.14.17.3/peptidylglycine monooxygenase
Comments/Corrections

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