title: Evaluation of glycine-bearing celecoxib derivatives as a colon-specific mutual prodrug acting on nuclear factor-κB, an anti-inflammatory target.
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.
authors: College of Pharmacy, Pusan National University, Busan, South Korea.
authors: Sunyoung
authors: S
authors: Lee
authors: College of Pharmacy, Pusan National University, Busan, South Korea ; Bio-Nanomedicine Lab, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
authors: Yonghyun
authors: Y
authors: Lee
authors: College of Pharmacy, Pusan National University, Busan, South Korea.
authors: Wooseong
authors: W
authors: Kim
authors: College of Pharmacy, Pusan National University, Busan, South Korea.
authors: Joon
authors: J
authors: Nam
authors: College of Pharmacy, Pusan National University, Busan, South Korea.
authors: Seongkeun
authors: S
authors: Jeong
authors: College of Pharmacy, Pusan National University, Busan, South Korea.
authors: Jin-Wook
authors: JW
authors: Yoo
authors: College of Pharmacy, Pusan National University, Busan, South Korea.
authors: Min-Soo
authors: MS
authors: Kim
authors: College of Pharmacy, Pusan National University, Busan, South Korea.
authors: Hyung Ryong
authors: HR
authors: Moon
authors: College of Pharmacy, Pusan National University, Busan, South Korea.
authors: Yunjin
authors: Y
authors: Jung
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000068579:Celecoxib / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003092:Colitis / Q000188:drug therapy; D003106:Colon / Q000378:metabolism*; D016503:Drug Delivery Systems; D004355:Drug Stability; D005998:Glycine / Q000737:chemistry*; D045325:HCT116 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007249:Inflammation / Q000188:drug therapy; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D011355:Prodrugs; D000068579:Celecoxib; D005998:Glycine
keywords: celecoxib; colon-specific drug delivery; glycine chloramine; mutual prodrug; nuclear factor kappa-B