Mulchande, J.; Guedes, R. C.; Tsang, W.-Y.; Page, M. I.; Moreira, R. and Iley, J.
|DOI (Digital Object Identifier) Link:||http://doi.org/10.1021/jm701257h|
|Google Scholar:||Look up in Google Scholar|
A new class of inhibitors 4-oxo-β-lactams (azetidine-2,4-diones), containing the required structural elements for molecular recognition, inhibit porcine pancreatic elastase (PPE) but show a dramatically lower reactivity toward hydroxide compared with the analogous inhibitors 3-oxo-β-sultams. Inhibition is the result of acylation of the active site serine and electron-withdrawing substituents at the N-(4-aryl) position in 3,3-diethyl-N-aryl derivatives increasing the rate of enzyme acylation and generating a Hammett ρ-value of 0.65. Compared with a ρ-value of 0.96 for the rates of alkaline hydrolysis of the same series, this is indicative of an earlier transition state for the enzyme-catalyzed reaction. Docking studies indicate favorable noncovalent interactions of the inhibitor with the enzyme. Compound 2i, the most potent inhibitor against PPE, emerged as a very potent HLE inhibitor, with a second-order rate for enzyme inactivation of ~5 × 105 M−1 s−1.
|Item Type:||Journal Article|
|Keywords:||elastase; beta-lactams; beta-lactim; imides; PPE; HLE|
|Academic Unit/Department:||Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
|Depositing User:||James Iley|
|Date Deposited:||13 Jun 2008|
|Last Modified:||04 Oct 2016 10:09|
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