Probing the peptidylglycine alpha-hydroxylating monooxygenase active site with novel 4-phenyl-3-butenoic acid based inhibitors.

Abstract

Specific inhibition of the copper-containing peptidylglycine alpha-hydroxylating monooxygenase (PHM), which catalyzes the post-translational modification of peptides involved in carcinogenesis and tumor progression, constitutes a new approach for combating cancer. We carried out a structure-activity study of new compounds derived from a well-known PHM substrate analogue, the olefinic compound 4-phenyl-3-butenoic acid (PBA). We designed, synthesized, and tested various PBA derivatives both in vitro and in silico. We show that it is possible to increase PBA affinity for PHM by appropriate functionalization of its aromatic nucleus. Compound 2 d, for example, bears a meta-benzyloxy substituent, and exhibits better inhibition features (K(i)=3.9 microM, k(inact)/K(i)=427 M(-1) s(-1)) than the parent PBA (K(i)=19 microM, k(inact)/K(i)=82 M(-1) s(-1)). Docking calculations also suggest two different binding modes for PBA derivatives; these results will aid in the development of further PHM inhibitors with improved features.

• Authors: Emma Langella, Sébastien Pierre, Wadih Ghattas, Michel Giorgi, Marius Réglier, Michele Saviano, Luciana Esposito, Renaud Hardré
• Journal: ChemMedChem (ChemMedChem) Vol. 5 Issue 9 Pg. 1568-76 (Sep 03 2010) ISSN: 1860-7187 [Electronic] Germany
• PMID: 20715282 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(3-benzyloxy-4-methoxy)phenyl-3-butenoic acid
• Enzyme Inhibitors
• Fatty Acids, Monounsaturated
• Multienzyme Complexes
• Phenylbutyrates
• 4-phenyl-3-butenoic acid
• Mixed Function Oxygenases
• peptidylglycine monooxygenase

Topics

• Animals
• Binding Sites
• Catalytic Domain
• Computer Simulation
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Fatty Acids, Monounsaturated (chemical synthesis, chemistry, pharmacology)
• Kinetics
• Mixed Function Oxygenases (antagonists & inhibitors, metabolism)
• Multienzyme Complexes (antagonists & inhibitors, metabolism)
• Phenylbutyrates (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Swine