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 0.5microM. 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.
Subject(s)
Enzyme Inhibitors/chemistry , Hippurates/chemistry , Hippurates/pharmacology , Insecticides/chemistry , Mixed Function Oxygenases/antagonists & inhibitors , Multienzyme Complexes/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Hippurates/chemical synthesis , Humans , Inhibitory Concentration 50 , Insecticides/metabolism , Insecticides/pharmacology , Mixed Function Oxygenases/metabolism , Models, Molecular , Multienzyme Complexes/metabolism , Rats , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Test-retest reliability of the Urge-Urinary Distress Inventory (U-UDI) and the Female Sexual Function Index (FSFI) was assessed in women with multiple sclerosis (MS) because it was undetermined whether or not either instrument would yield reliable and valid results in this population. Data from this study suggest that these tools can be reliably used to assess community-dwelling women with mild gait disability and MS-associated symptoms of urinary distress and sexual dysfunction.
