Organic Pedagogical Electronic Network

COX 2 Inhibitor Interactions

Created by Alyssa Black and Dominic CaputoEdited by Margaret Hilton

Honors Organic ChemistryChem 2321 (Sigman), 2013

COX-2 Inhibitors and the COX-2 Active Site

Wiki Page: COX-2 InhibitorsOther References Selective COX-2 inhibitors by Knaus et al. and COX inhibitory effects by Amini et al.

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

HN

NF

SO

O

S

R

NH

H

O

N

N HR'

COX-2 Inhibitors and the COX-2 Active Site

Wiki Page: COX-2 InhibitorsOther References Selective COX-2 inhibitors by Knaus et al. and COX inhibitory effects by Amini et al.

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

Celecoxib

S

NN

CF3

H3C

O

OH2N

Vioxx

SO

OH3C

O

O

Valdecoxib

N

O

CH3

S NH2

O

O

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.

O

CO2

O

OH

RR

O H

R

O

CO2

OO

R

RO

CO2

OO

R

R

R

B

Reference: Acetlyation of COX-2 by aspirin by Marnett et al.

Problems

References: Wiki's Amino Acid Page and Synthesis of COX-2 Inhibitors by Reider et al.

1. Based upon the examples of COX-2 inhibitors, what are some possible analogs that could act in a similar way?

2. 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

3. Propose a mechanism for this step in the synthesis of a COX-2 inhibitor.

AcOH, TFA

R

H2C HC

CH3

CH3

R

H2CCH2

H2CCH2

NH3

R

CH2C

NH2

O

R

CH2H2C

COO

This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.

Contributed by: Created by Alyssa Black and Dominic Caputo (Undergraduates)

Edited by Margaret HiltonHonors Organic ChemistryChem 2321 (Sigman),

University of Utah

2013