Abstract |
In an inflammatory state where HOCl is generated, glycine readily reacts with HOCl to produce glycine chloramine, an anti-inflammatory oxidant. Colonic delivery of celecoxib elicits anticolitic effects in a trinitrobenzene sulfonic acid-induced rat colitis model. Glycine-bearing celecoxib derivatives were prepared and evaluated as a colon-specific mutual prodrug acting on nuclear factor-κB (NFκB), an anticolitic target. Glycylcelecoxib (GC), N-glycylaspart-1-ylcelecoxib (N-GA1C), and C-glycylaspart-1-ylcelecoxib (C-GA1C) were synthesized and their structures identified using infrared and proton nuclear magnetic resonance spectrometer. The celecoxib derivatives were chemically stable in pH 6.8 and 1.2 buffers. GC and C-GA1C were resistant to degradation in the small intestinal contents, while N-GA1C was substantially cleaved to release celecoxib. In contrast, all the celecoxib derivatives were degraded to liberate celecoxib in the cecal content. These results suggest that GC and C-GA1C could be delivered to and liberate celecoxib and glycine in the large intestine. In human colon carcinoma HCT116 and murine macrophage RAW264.7 cells, combined celecoxib- glycine chloramine treatment additively suppressed the production of proinflammatory NFκB target gene products. Collectively, our data suggest that C-GA1C is a potential colon-specific mutual prodrug acting against NFκB.
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Authors | Sunyoung Lee, Yonghyun Lee, Wooseong Kim, Joon Nam, Seongkeun Jeong, Jin-Wook Yoo, Min-Soo Kim, Hyung Ryong Moon, Yunjin Jung |
Journal | Drug design, development and therapy
(Drug Des Devel Ther)
Vol. 9
Pg. 4227-37
( 2015)
ISSN: 1177-8881 [Electronic] New Zealand |
PMID | 26300626
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anti-Inflammatory Agents
- NF-kappa B
- Prodrugs
- Celecoxib
- Glycine
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Topics |
- Animals
- Anti-Inflammatory Agents
(chemical synthesis, chemistry, pharmacology)
- Celecoxib
(chemical synthesis, chemistry, pharmacology)
- Cell Line
- Colitis
(drug therapy)
- Colon
(metabolism)
- Drug Delivery Systems
- Drug Stability
- Glycine
(chemistry)
- HCT116 Cells
- Humans
- Hydrogen-Ion Concentration
- Inflammation
(drug therapy)
- Macrophages
(drug effects, metabolism)
- Male
- Mice
- NF-kappa B
(metabolism)
- Prodrugs
(chemical synthesis, chemistry, pharmacology)
- Rats
- Rats, Sprague-Dawley
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