MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on August 1, 2008; DOI: 10.1124/mol.108.046664

0026-895X/08/7405-1381-1391$20.00
Mol Pharmacol 74:1381-1391, 2008

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow All Versions of this Article:
mol.108.046664v1
74/5/1381    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hagos, G. K.
Right arrow Articles by Thatcher, G. R. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hagos, G. K.
Right arrow Articles by Thatcher, G. R. J.

Anti-Inflammatory, Antiproliferative, and Cytoprotective Activity of NO Chimera Nitrates of Use in Cancer ChemopreventionFormula

Ghenet K. Hagos, Samer O. Abdul-Hay, Johann Sohn, Praneeth D. Edirisinghe, R. Esala P. Chandrasena, Zhiqiang Wang, Qian Li, and Gregory R. J. Thatcher

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois

Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown promise in colorectal cancer (CRC), but they are compromised by gastrotoxicity. NO-NSAIDs are hybrid nitrates conjugated to an NSAID designed to exploit the gastroprotective properties of NO bioactivity. The NO chimera ethyl 2-((2,3-bis(nitrooxy)propyl)disulfanyl)benzoate (GT-094), a novel nitrate containing an NSAID and disulfide pharmacophores, is effective in vivo in rat models of CRC and is a lead compound for design of agents of use in CRC. Preferred chemopreventive agents possess 1) antiproliferative and 2) anti-inflammatory actions and 3) the ability to induce cytoprotective phase 2 enzymes. To determine the contribution of each pharmacophore to the biological activity of GT-094, these three biological activities were studied in vitro in compounds that deconstructed the structural elements of the lead GT-094. The anti-inflammatory and antiproliferative actions of GT-094 in vivo were recapitulated in vitro, and GT-094 was seen to induce phase 2 enzymes via the antioxidant responsive element. In the variety of colon, macrophage-like, and liver cell lines studied, the evidence from structure-activity relationships was that the disulfide structural element of GT-094 is the dominant contributor in vitro to the anti-inflammatory activity, antiproliferation, and enzyme induction. The results provide a direction for lead compound refinement. The evidence for a contribution from the NO mimetic activity of nitrates in vitro was equivocal, and combinations of nitrates with acetylsalicylic acid were inactive.

Received for publication February 23, 2008.

Accepted for publication August 1, 2008.

Address correspondence to: Dr. Gregory R. J. Thatcher, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612. E-mail: thatcher{at}uic.edu






Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2008 by the American Society for Pharmacology and Experimental Therapeutics