Cyclooxygenase-2 (COX-2) plays a key role in the conversion of arachidonic acid (AA) to prostaglandins, which are an important class of bioactive lipids. COX-2 is highly expressed in inflamed tissue, premalignant lesions, and cancers but not in adjacent normal tissue. COX-2 inhibitors, whether isoform-selective or non- selective, exhibit anti-inflammatory, cancer preventive, and adjuvant cancer therapeutic activities as well as cardiovascular side effects in human clinical trials. COX-2 also oxygenates ester and amide derivatives of AA including 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA). 2-AG and AEA are the two best characterized endogenous ligands for the cannabinoid receptors - CB1 and CB2 - and exert a plethora of effects through these receptors. The major focus of endocannabinoid biology has been on the nervous system, but increasing evidence indicates that 2-AG and AEA exert anti-inflammatory and cancer preventive effects. We hypothesize that COX-2-dependent metabolism of 2-AG and AEA lowers endocannabinoid levels, thereby contributing to the development of inflammation and cancer. Our laboratory has studied the structural and functional basis of the interaction of COX-2 with substrates and inhibitors in order to generate detailed insights into the chemical biology of COX-2 and to use this information to synthesize novel agents with which to study or manipulate COX-2 function in vivo. We recently discovered that non-steroidal anti-inflammatory drugs (NSAIDs) that are weak, competitive inhibitors of AA oxygenation by COX-2 are potent, non-competitive inhibitors of 2-AG and AEA oxygenation. This is most dramatic for the (R)-enantiomers of arylpropionic acid NSAIDs (profens), such as (R)-flurbiprofen, (R)-naproxen, and (R)-ibuprofen. While essentially inactive as inhibitors of AA oxygenation, these compounds are moderately potent, substrate-selective inhibitors of COX-2 oxygenation of 2-AG and AEA. These insights provide opportunities to develop chemical probes to investigate the in vivo importance of COX-2 oxygenation of endocannabinoids and may explain the reported anti-inflammatory and cancer preventive activities of (R)-profens. Thus, we propose to (1) use X-ray crystallography, site-directed mutagenesis, and enzyme kinetics studies to determine the structural and functional basis for (R)-profen binding to COX-2 in order to (2) design and synthesize more potent and selective inhibitors of endocannabinoid oxygenation in vitro and in vivo. The optimized molecules will be used to (3) test the hypothesis that COX-2 lowers endocannabinoid levels in models of colonic inflammation and cancer and that endocannabinoid levels can be restored by substrate-selective inhibitors of COX-2. These substrate-selective inhibitors may represent candidate cancer chemopreventive agents that lack the gastrointestinal and cardiovascular side effects of currently marketed NSAIDs.
Compounds called endocannabinoids are naturally occurring regulators of inflammation and cancer. Cyclooxygenase-2 metabolizes endocannabinoids and lowers their levels. The development of selective inhibitors of cyclooxygenase-2-dependent endocannabinoid metabolism may produce novel anti-inflammatory and cancer preventive agents.
|Neumann, Wilma; Crews, Brenda C; Marnett, Lawrence J et al. (2014) Conjugates of cisplatin and cyclooxygenase inhibitors as potent antitumor agents overcoming cisplatin resistance. ChemMedChem 9:1150-3|
|Xu, Shu; Hermanson, Daniel J; Banerjee, Surajit et al. (2014) Oxicams bind in a novel mode to the cyclooxygenase active site via a two-water-mediated H-bonding Network. J Biol Chem 289:6799-808|
|Hermanson, Daniel J; Gamble-George, Joyonna C; Marnett, Lawrence J et al. (2014) Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation. Trends Pharmacol Sci 35:358-67|
|Laube, Markus; Neumann, Wilma; Scholz, Matthias et al. (2013) 2-Carbaborane-3-phenyl-1H-indoles--synthesis via McMurry reaction and cyclooxygenase (COX) inhibition activity. ChemMedChem 8:329-35|
|Uddin, Md Jashim; Crews, Brenda C; Ghebreselasie, Kebreab et al. (2013) Design, synthesis, and structure-activity relationship studies of fluorescent inhibitors of cycloxygenase-2 as targeted optical imaging agents. Bioconjug Chem 24:712-23|
|Windsor, Matthew A; Valk, Pieter L; Xu, Shu et al. (2013) Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib. Bioorg Med Chem Lett 23:5860-4|
|Liedtke, Andy J; Adeniji, Adegoke O; Chen, Mo et al. (2013) Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17*-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer. J Med Chem 56:2429-46|
|Hermanson, Daniel J; Hartley, Nolan D; Gamble-George, Joyonna et al. (2013) Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation. Nat Neurosci 16:1291-8|
|Liedtke, Andy J; Crews, Brenda C; Daniel, Cristina M et al. (2012) Cyclooxygenase-1-selective inhibitors based on the (E)-2'-des-methyl-sulindac sulfide scaffold. J Med Chem 55:2287-300|
|Rouzer, Carol A; Marnett, Lawrence J (2011) Endocannabinoid oxygenation by cyclooxygenases, lipoxygenases, and cytochromes P450: cross-talk between the eicosanoid and endocannabinoid signaling pathways. Chem Rev 111:5899-921|
Showing the most recent 10 out of 59 publications