| Autor: |
Merkler DJ; Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., Tampa, FL 33620, USA. merkler@cas.usf.edu, Asser AS, Baumgart LE, Carballo N, Carpenter SE, Chew GH, Cosner CC, Dusi J, Galloway LC, Lowe AB, Lowe EW Jr, King L 3rd, Kendig RD, Kline PC, Malka R, Merkler KA, McIntyre NR, Romero M, Wilcox BJ, Owen TC |
| Jazyk: |
angličtina |
| Zdroj: |
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2008 Dec 01; Vol. 16 (23), pp. 10061-74. Date of Electronic Publication: 2008 Oct 11. |
| DOI: |
10.1016/j.bmc.2008.10.013 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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