Substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine a-hydroxylating monooxygenase (PHM)
Peptidyl a-hydroxylating monooxygenase (PHM) functions in vivo towards the biosynthesis of a-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 pest...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
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Pergamon
2008
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| Online Access: | http://hdl.handle.net/20.500.11937/5590 |
| _version_ | 1848744839410089984 |
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| author | Merkler, D. Asser, A. Baumgart, L. Carballo, N. Carpenter, S. Chew, G. Cosner, C. Dusi, J. Galloway, L. Lowe, Andrew Lowe, E. King, L. Kendig, R. Kline, P. Malka, R. Merkler, K. McIntyre, N. Romero, M. Wilcox, B. Owen, T. |
| author_facet | Merkler, D. Asser, A. Baumgart, L. Carballo, N. Carpenter, S. Chew, G. Cosner, C. Dusi, J. Galloway, L. Lowe, Andrew Lowe, E. King, L. Kendig, R. Kline, P. Malka, R. Merkler, K. McIntyre, N. Romero, M. Wilcox, B. Owen, T. |
| author_sort | Merkler, D. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Peptidyl a-hydroxylating monooxygenase (PHM) functions in vivo towards the biosynthesis of a-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. |
| first_indexed | 2025-11-14T06:07:50Z |
| format | Journal Article |
| id | curtin-20.500.11937-5590 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T06:07:50Z |
| publishDate | 2008 |
| publisher | Pergamon |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-55902018-03-29T09:05:43Z Substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine a-hydroxylating monooxygenase (PHM) Merkler, D. Asser, A. Baumgart, L. Carballo, N. Carpenter, S. Chew, G. Cosner, C. Dusi, J. Galloway, L. Lowe, Andrew Lowe, E. King, L. Kendig, R. Kline, P. Malka, R. Merkler, K. McIntyre, N. Romero, M. Wilcox, B. Owen, T. Peptidyl a-hydroxylating monooxygenase (PHM) functions in vivo towards the biosynthesis of a-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. 2008 Journal Article http://hdl.handle.net/20.500.11937/5590 10.1016/j.bmc.2008.10.013 Pergamon restricted |
| spellingShingle | Merkler, D. Asser, A. Baumgart, L. Carballo, N. Carpenter, S. Chew, G. Cosner, C. Dusi, J. Galloway, L. Lowe, Andrew Lowe, E. King, L. Kendig, R. Kline, P. Malka, R. Merkler, K. McIntyre, N. Romero, M. Wilcox, B. Owen, T. Substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine a-hydroxylating monooxygenase (PHM) |
| title | Substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine a-hydroxylating monooxygenase (PHM) |
| title_full | Substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine a-hydroxylating monooxygenase (PHM) |
| title_fullStr | Substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine a-hydroxylating monooxygenase (PHM) |
| title_full_unstemmed | Substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine a-hydroxylating monooxygenase (PHM) |
| title_short | Substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine a-hydroxylating monooxygenase (PHM) |
| title_sort | substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine a-hydroxylating monooxygenase (phm) |
| url | http://hdl.handle.net/20.500.11937/5590 |