1. COX 2 Inhibitor Interactions
Created by Alyssa Black and Dominic Caputo
Edited by Margaret Hilton
Honors Organic Chemistry
Chem 2321 (Sigman), 2013

2. COX-2 Inhibitors and the COX-2 Active Site
Overview: COX 2 inhibitors were widely used anti-inflammatory drugs until lethal side effects were discovered. These inhibitors interact with the COX 2 enzyme active site, hindering the pathway that leads to several downstream precursor molecules.
Key Interactions in the Active Site
Wiki Page: COX-2 Inhibitors
Other References Selective COX-2 inhibitors by Knaus et al. and COX inhibitory effects by Amini et al.

3. COX-2 Inhibitors and the COX-2 Active Site
Overview: COX 2 inhibitors were widely used anti-inflammatory drugs until lethal side effects were discovered. These inhibitors interact with the COX 2 enzyme active site, hindering the pathway that leads to several downstream precursor molecules.
Examples of COX 2 Inhibitors
Valdecoxib
Vioxx
Celecoxib
Wiki Page: COX-2 Inhibitors
Other References Selective COX-2 inhibitors by Knaus et al. and COX inhibitory effects by Amini et al.

4. Acetylation of COX-2 Active Site by Aspirin
Aspirin can act as a COX-2 inhibitor, yet it is not as selective as most COX-2 inhibitors. Thus, it will also react with COX-1 enzymes, causing undesired side effects. When aspirin interacts with the COX-2 active site, it permanently acetylates a residue in the active site, according to the following mechanism.
Reference: Acetlyation of COX-2 by aspirin by Marnett et al.

5. Problems
Based upon the examples of COX-2 inhibitors, what are some possible analogs that could act in a similar way?
Which of the following amino acids could interact with a COX-2 active site? (Select all that apply.)
a) Lysine b) Glutamic Acid c) Asparagine d) Leucine
Propose a mechanism for this step in the synthesis of a COX-2 inhibitor.
AcOH, TFA
References: Wiki's Amino Acid Page and Synthesis of COX-2 Inhibitors by Reider et al.

6. Contributed by:
Created by Alyssa Black and Dominic Caputo (Undergraduates)
Edited by Margaret Hilton
Honors Organic Chemistry
Chem 2321 (Sigman),
University of Utah
2013