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Issue 20, 2005

Parallel synthesis and in vitro activity of novel anthranilic hydroxamate-based inhibitors of the prostaglandin H2 synthase peroxidase activity

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Abstract

Currently available non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin are directed at the cyclooxygenase (COX) site, but not the peroxidase (POX) activity of prostaglandin H2 synthase (PGHS). They are thus unable to inhibit the free-radical induced tissue injury associated with PGHS peroxidase activity, which can occur independently of the COX site. A lead compound, anthranilic hydroxamic acid (AHA) was found to have significant PGHS-POX inhibitory activity (IC50 = 72 µM). To define the critical parameters for PGHS-POX inhibition, we investigated 29 AHA derivatives, synthesised from their acid precursors, using solid phase synthesis. In vitro analysis demonstrated a ten-fold improvement in inhibition with 3,5-diiodoanthranilic hydroxamic acid (IC50 = 7 µM).

Graphical abstract: Parallel synthesis and in vitro activity of novel anthranilic hydroxamate-based inhibitors of the prostaglandin H2 synthase peroxidase activity

Supplementary files

Article information


Submitted
20 Apr 2005
Accepted
02 Aug 2005
First published
08 Sep 2005

Org. Biomol. Chem., 2005,3, 3678-3685
Article type
Paper

Parallel synthesis and in vitro activity of novel anthranilic hydroxamate-based inhibitors of the prostaglandin H2 synthase peroxidase activity

J. Lee, A. J. Chubb, E. Moman, B. M. McLoughlin, C. T. Sharkey, J. G. Kelly, K. B. Nolan, M. Devocelle and D. J. Fitzgerald, Org. Biomol. Chem., 2005, 3, 3678 DOI: 10.1039/B505525C

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